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Weekley BH, Ahmed NI, Maze I. Elucidating neuroepigenetic mechanisms to inform targeted therapeutics for brain disorders. iScience 2025; 28:112092. [PMID: 40160416 PMCID: PMC11951040 DOI: 10.1016/j.isci.2025.112092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025] Open
Abstract
The evolving field of neuroepigenetics provides important insights into the molecular foundations of brain function. Novel sequencing technologies have identified patient-specific mutations and gene expression profiles involved in shaping the epigenetic landscape during neurodevelopment and in disease. Traditional methods to investigate the consequences of chromatin-related mutations provide valuable phenotypic insights but often lack information on the biochemical mechanisms underlying these processes. Recent studies, however, are beginning to elucidate how structural and/or functional aspects of histone, DNA, and RNA post-translational modifications affect transcriptional landscapes and neurological phenotypes. Here, we review the identification of epigenetic regulators from genomic studies of brain disease, as well as mechanistic findings that reveal the intricacies of neuronal chromatin regulation. We then discuss how these mechanistic studies serve as a guideline for future neuroepigenetics investigations. We end by proposing a roadmap to future therapies that exploit these findings by coupling them to recent advances in targeted therapeutics.
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Affiliation(s)
- Benjamin H. Weekley
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Newaz I. Ahmed
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ian Maze
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Howard Hughes Medical Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Song Y, Dou Z, Liu W, Zhang A, Gao X, Shi H, Zhang Z, Gao J, Jin Y. The chromatin remodeler Brg1 is essential for cochlear sensory epithelium differentiation and patterning. Hum Mol Genet 2025:ddaf019. [PMID: 39927735 DOI: 10.1093/hmg/ddaf019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 01/14/2025] [Accepted: 01/30/2025] [Indexed: 02/11/2025] Open
Abstract
Human genome analyses have revealed that abnormal BAF (BRG1/BRM-associated factor) complex is highly associated with hearing loss. However, the underlying pathogenesis remains largely unknown. Disrupted structure and function of the organ of Corti is the most prevalent cause of sensorineural hearing loss in mammals. Here, we investigated the role of Brg1-based BAF complex during the differentiation and development of the auditory sensory epithelium, a crucial period for the formation of the organ of Corti. Our findings indicate that deletion of Brg1 leads to premature hair cell (HC) differentiation by inactivating Sonic hedgehog (Shh) signaling. Despite the formation of HCs, subsequent differentiation of inner hair cells (IHCs) and outer hair cells (OHCs) was impaired. Additionally, we observed that the mosaic-like arrangement of HCs and supporting cells (SCs) was disrupted resulting in abnormal sensory epithelium patterning. Furthermore, we found the planar cell polarity of the Brg1-deficient cochlea was abnormal. Our study demonstrates the pivotal role of Brg1 in the differentiation and patterning of the organ of Corti.
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Affiliation(s)
- Yuning Song
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, 27 Shanda Nanlu, Jinan 250100, China
| | - Zhilin Dou
- Key Laboratory for Experimental Teratology of the Ministry of Education, Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xilu, Jinan 250012, China
| | - Wenwen Liu
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, 4 Duanxing Xilu, Jinan 250022, China
| | - Aizhen Zhang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, 4 Duanxing Xilu, Jinan 250022, China
| | - Xiaotong Gao
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, 27 Shanda Nanlu, Jinan 250100, China
| | - Hongbiao Shi
- Key Laboratory for Experimental Teratology of the Ministry of Education, Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xilu, Jinan 250012, China
| | - Zhixiong Zhang
- Key Laboratory for Experimental Teratology of the Ministry of Education, Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xilu, Jinan 250012, China
| | - Jiangang Gao
- Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, 27 Shanda Nanlu, Jinan 250100, China
| | - Yecheng Jin
- Key Laboratory for Experimental Teratology of the Ministry of Education, Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xilu, Jinan 250012, China
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Wang Y, Zhang L, Zhu J, Yang L, Wang C, Zou N. SMARCA4-related Coffin-Siris syndrome in newborn: a case report and literature review. Front Pediatr 2025; 12:1493380. [PMID: 39906730 PMCID: PMC11790585 DOI: 10.3389/fped.2024.1493380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 12/31/2024] [Indexed: 02/06/2025] Open
Abstract
Objective Our objective was to examine the clinical and genetic features of Coffin-Siris syndrome resulting from a pathogenic variant in the SMARCA4 gene. Methods The clinical data and molecular genetic test results of a newbron with Coffin-Siris syndrome involving a pathogenic variant in the SMARCA4 gene were retrospectively analyzed, and the related literatures were reviewed. Results A newborn exhibited inspiratory dyspnea following birth and developmental anomalies (coarse appearance, thick hair, long eyelashes, broad nasal tip, flat nasal bridge, thin upper lip, thick lower lip, digital anomalies, cleft palate, supraglottic laryngeal chondromalacia, stenosis of the left upper bronchus and hypotonia). Whole exome sequencing revealed a heterozygous missense variant in SMARCA4 gene (NM_003072.5 c.3127C > T, p.Arg1043Trp). Parents did not find the above pathogenic variant, which was a new pathogenic variant. In addition to our case, we also retrieved 22 cases of Coffin-Siris Syndrome in SMARCA4 gene variation, which is a congenital multi-system dysfunction syndrome characterized by abnormal appearance and developmental retardation. The common otolaryngologic features of 23 patients with CSS in SMARCA4 gene variant included palate abnormalities, feeding difficulties, ear abnormalities and hearing loss. Conclusion Coffin-Siris syndrome is a rare genetic disease inherited in an autosomal-dominated manner. It is often associated with malformations in the otorhinolaryngologic system. This case has many common features with previously reported CSS cases with pathogenic variant in the SMARCA4 gene, which further characterizes the performance of the pathogenic variant, suggesting that palatal abnormalities may be a significant feature of the genotype. For patients with developmental abnormalities, whole-genome sequencing or whole-exome sequencing is particularly important to assist diagnosis. Currently, there is no known treatment for CSS, and individuals with CSS experience various complications affecting multiple systems.
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Affiliation(s)
| | | | | | | | | | - Ning Zou
- Department of Pediatrics, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China
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Guo Z, Bai J, Liu Y, Zhang X, Yang W, Wang J, Zhang Y, Xiao H, Hao B, Liao S. A novel mutation in SMARCB1 associated with adult Coffin-Siris syndrome and meningioma. Acta Biochim Biophys Sin (Shanghai) 2024. [PMID: 39563460 DOI: 10.3724/abbs.2024204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2024] Open
Abstract
SMARCB1 encodes a core subunit of the SWI/SNF chromatin remodeling complex, which plays a crucial role in the regulation of gene expression. Germline mutations in the SMARCB1 gene have been linked to early childhood Coffin-Siris syndrome type 3 (CSS3), a rare congenital malformation syndrome characterized by severe developmental delay and intellectual disability. In this study, we report a family of two adult CSS3 patients with a novel missense SMARCB1 mutation (c.1091A>C, p.Lys364Thr) identified through whole-exome sequencing (WES). Both patients exhibit selective difficulties in verbal learning and experience language delays. Additionally, the development of meningioma is confirmed in one of the patients. Mechanistic studies suggest that this missense mutation may abnormally activate the MAPK signaling pathway, which is implicated in the pathogenesis of tumor progression and neurodevelopmental disorders. This is the first reported case of a germline mutation in the SMARCB1 gene associated with both CSS3 and meningioma, thereby expanding the phenotypic spectrum of SMARCB1-related disorders.
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Affiliation(s)
- Zhenglong Guo
- Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450000, China
- School of Medicine, People's Hospital of Henan University, Henan University, Zhengzhou 450000, China
| | - Jie Bai
- Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450000, China
- School of Medicine, People's Hospital of Henan University, Henan University, Zhengzhou 450000, China
| | - Yang Liu
- Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450000, China
- School of Medicine, People's Hospital of Henan University, Henan University, Zhengzhou 450000, China
| | - Xianwei Zhang
- Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450000, China
- School of Medicine, People's Hospital of Henan University, Henan University, Zhengzhou 450000, China
| | - Wenke Yang
- Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450000, China
- School of Medicine, People's Hospital of Henan University, Henan University, Zhengzhou 450000, China
| | - Jinming Wang
- Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450000, China
- School of Medicine, People's Hospital of Henan University, Henan University, Zhengzhou 450000, China
| | - Yuwei Zhang
- Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450000, China
- School of Medicine, People's Hospital of Henan University, Henan University, Zhengzhou 450000, China
| | - Hai Xiao
- Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450000, China
- School of Medicine, People's Hospital of Henan University, Henan University, Zhengzhou 450000, China
| | - Bingtao Hao
- Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450000, China
- Department of Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
- Henan Eye Institute, Henan Academy of Innovations in Medical Science, Zhengzhou 450000, China
| | - Shixiu Liao
- Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450000, China
- School of Medicine, People's Hospital of Henan University, Henan University, Zhengzhou 450000, China
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Bai G, Yuan R, Yuan J, Liu Y, Zhao S, Zhang X. A rare Coffin-Siris syndrome induced by SOX11: a de novo nonsense variant of short stature. BMC Med Genomics 2024; 17:262. [PMID: 39501269 PMCID: PMC11539493 DOI: 10.1186/s12920-024-02036-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 10/23/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND Coffin-Siris syndrome is a clinically elusive and rare genetic disease characterized by a wide range of clinical manifestations. This study deeply analyzed and identified the clinical phenotype and genetic variant location in a pediatric patient with Coffin-Siris syndrome, aiming to enhance the understanding of this syndrome and assist in its screening and diagnosis. METHODS A combination of advanced diagnostic tools, including high-throughput whole-exome sequencing (WES) and first-generation sequencing technologies, was employed to ascertain the etiology of the disease in the child. RESULTS The clinical phenotype was characterized by stunted growth, reduced stature, spina bifida, enuresis, and a ventricular septal defect. WES revealed a de novo variant in the SOX11 gene locus (c.700G > T), identified as pathogenic. It is noteworthy that this variant has not been previously reported. CONCLUSIONS The combination of clinical presentation and genetic testing results supports that the patient suffers from Coffin-Siris syndrome due to a genetic variant in the SOX11 gene. This de novo variant expands our understanding of human gene variation, which is conducive to genetic counseling and screening for early diagnosis of Coffin-Siris syndrome.
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Affiliation(s)
- Guibin Bai
- Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, China
| | - Rougang Yuan
- Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, China
| | - Jian Yuan
- Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, China
| | - Yanqin Liu
- Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, China
| | - Shaozhi Zhao
- Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, China
| | - Xinwen Zhang
- Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, China.
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Prada E, Meossi C, Marafon DP, Grilli F, Scuvera G, Marchisio PG, Agostoni CV, Natacci F, Milani D. The overlapping of phenotypes in Wiedemann-Steiner, Kleefstra and Coffin-Siris syndromes: a study of eleven patients. Ital J Pediatr 2024; 50:187. [PMID: 39294711 PMCID: PMC11411858 DOI: 10.1186/s13052-024-01763-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 09/08/2024] [Indexed: 09/21/2024] Open
Abstract
BACKGROUND Some chromatinopathies may present with common clinical findings (intellectual disability, brain and limb malformation, facial dysmorphism). Furthermore, one of their cardinal shared features is growth dysregulation.We aimed to assess and deepen this resemblance in three specific conditions, namely Wiedemann-Steiner (WDSTS), Kleefstra (KLEFS1) and Coffin-Siris syndrome (CSS1), with a particular focus on possible metabolic roots. METHODS Eleven patients were enrolled, three with WDSTS, five with KLEFS1 and three with CSS1, referring to Fondazione IRCCS Ca' Granda Ospedale Maggiore, Milan, Italy. We performed both a physical examination with detailed anthropometric measurements and an evaluation of the patients' REE (rest energy expenditure) by indirect calorimetry, comparing the results with age- and sex-matched healthy controls. RESULTS We observed new clinical features and overlap between these conditions suggesting that different disturbances of epigenetic machinery genes can converge on a common effect, leading to overlapping clinical phenotypes.
The REE was not distinguishable between the three conditions and healthy controls. CONCLUSIONS Epigenetic machinery plays an essential role both in growth regulation and in neurodevelopment; we recommend evaluating skeletal [craniovertebral junction abnormalities (CVJ) polydactyly], otolaryngological [obstructive sleep apnea syndrome (OSAs), recurrent otitis media], dental [tooth agenesis, talon cusps], and central nervous system (CNS) [olfactory bulbs and cerebellum anomalies] features. These features could be included in monitoring guidelines. Further studies are needed to deepen the knowledge about energy metabolism.
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Affiliation(s)
- Elisabetta Prada
- Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
- Ospedale Sant'Anna, ASST Lariana, Como, Italy
| | - Camilla Meossi
- Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
- Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, Italy.
| | | | - Federico Grilli
- Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Giulietta Scuvera
- Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Paola Giovanna Marchisio
- Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
- Università degli Studi di Milano, Milano, Italy
| | - Carlo Virginio Agostoni
- Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
- Università degli Studi di Milano, Milano, Italy
| | - Federica Natacci
- Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Donatella Milani
- Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
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Bosch E, Güse E, Kirchner P, Winterpacht A, Walther M, Alders M, Kerkhof J, Ekici AB, Sticht H, Sadikovic B, Reis A, Vasileiou G. The missing link: ARID1B non-truncating variants causing Coffin-Siris syndrome due to protein aggregation. Hum Genet 2024; 143:965-978. [PMID: 39028335 PMCID: PMC11303441 DOI: 10.1007/s00439-024-02688-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 07/07/2024] [Indexed: 07/20/2024]
Abstract
ARID1B is the most frequently mutated gene in Coffin-Siris syndrome (CSS). To date, the vast majority of causative variants reported in ARID1B are truncating, leading to nonsense-mediated mRNA decay. In the absence of experimental data, only few ARID1B amino acid substitutions have been classified as pathogenic, mainly based on clinical data and their de novo occurrence, while most others are currently interpreted as variants of unknown significance. The present study substantiates the pathogenesis of ARID1B non-truncating/NMD-escaping variants located in the SMARCA4-interacting EHD2 and DNA-binding ARID domains. Overexpression assays in cell lines revealed that the majority of EHD2 variants lead to protein misfolding and formation of cytoplasmic aggresomes surrounded by vimentin cage-like structures and co-localizing with the microtubule organisation center. ARID domain variants exhibited not only aggresomes, but also nuclear aggregates, demonstrating robust pathological effects. Protein levels were not compromised, as shown by quantitative western blot analysis. In silico structural analysis predicted the exposure of amylogenic segments in both domains due to the nearby variants, likely causing this aggregation. Genome-wide transcriptome and methylation analysis in affected individuals revealed expression and methylome patterns consistent with those of the pathogenic haploinsufficiency ARID1B alterations in CSS cases. These results further support pathogenicity and indicate two approaches for disambiguation of such variants in everyday practice. The few affected individuals harbouring EHD2 non-truncating variants described to date exhibit mild CSS clinical traits. In summary, this study paves the way for the re-evaluation of previously unclear ARID1B non-truncating variants and opens a new era in CSS genetic diagnosis.
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Affiliation(s)
- Elisabeth Bosch
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - Esther Güse
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - Philipp Kirchner
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - Andreas Winterpacht
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - Mona Walther
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - Marielle Alders
- Amsterdam University Medical Center, University of Amsterdam, Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
| | - Jennifer Kerkhof
- Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada
| | - Arif B Ekici
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - Heinrich Sticht
- Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - Bekim Sadikovic
- Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
| | - André Reis
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
- Centre for Rare Diseases Erlangen (ZSEER), Universitätsklinikum Erlangen, Erlangen, Germany
| | - Georgia Vasileiou
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
- Centre for Rare Diseases Erlangen (ZSEER), Universitätsklinikum Erlangen, Erlangen, Germany.
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Zhou M, Wang F, Dai Q, Dou J, Wu Y, Zhu Y. Identification of a novel de novo mutation in SOX4 for syndromic tooth agenesis. Clin Oral Investig 2024; 28:287. [PMID: 38684576 DOI: 10.1007/s00784-024-05659-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 04/12/2024] [Indexed: 05/02/2024]
Abstract
OBJECTIVES Coffin-Siris Syndrome (CSS) is a congenital disorder characterized by delayed growth, dysmorphic facial features, hypoplastic nails and phalanges of the fifth digit, and dental abnormalities. Tooth agenesis has been reported in CSS patients, but the mechanisms regulating this syndromic tooth agenesis remain largely unknown. This study aims to identify the pathogenic mutation of CSS presenting tooth genesis and explore potential regulatory mechanisms. MATERIALS AND METHODS We utilized whole-exome sequencing to identify variants in a CSS patient, followed by Sanger validation. In silico analysis including conservation analysis, pathogenicity predictions, and 3D structural assessments were carried out. Additionally, single-cell RNA sequencing and fluorescence in situ hybridization (FISH) were applied to explore the spatio-temporal expression of Sox4 expression during murine tooth development. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to examine the functional role of SOX4. RESULTS A novel de novo SOX4 missense mutation (c.1255C > G, p.Leu419Val) was identified in a Chinese CSS patient exhibiting tooth agenesis. Single-cell RNA sequencing and FISH further verified high expression of Sox4 during murine tooth development, and WGCNA confirmed its central role in tooth development pathways. Enriched functions included cell-substrate junctions, focal adhesion, and RNA splicing. CONCLUSIONS Our findings link a novel SOX4 mutation to syndromic tooth agenesis in CSS. This is the first report of SOX4 missense mutation causing syndromic tooth agenesis. CLINICAL RELEVANCE This study not only enhances our understanding of the pathogenic mutation for syndromic tooth agenesis but also provides genetic diagnosis and potential therapeutic insights for syndromic tooth agenesis.
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Grants
- YBKB202101 Project of Biobank of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine
- YBKB202101 Project of Biobank of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine
- YBKB202101 Project of Biobank of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine
- 21ZR1436900, 21ZR1437700 Natural Science Foundation of Shanghai
- 21ZR1436900, 21ZR1437700 Natural Science Foundation of Shanghai
- KQYJXK2020 Research Discipline fund from Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, and College of Stomatology, Shanghai Jiao Tong University
- KQYJXK2020 Research Discipline fund from Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, and College of Stomatology, Shanghai Jiao Tong University
- 82271004 National Natural Science Foundation of China
- 82271004 National Natural Science Foundation of China
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Affiliation(s)
- Mengqi Zhou
- Department of General Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, Shanghai, China
- National Clinical Research Center for Oral Diseases, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Department of Second Dental Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feng Wang
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, Shanghai, China
- National Clinical Research Center for Oral Diseases, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Department of Second Dental Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qinggang Dai
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, Shanghai, China
- National Clinical Research Center for Oral Diseases, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Department of Second Dental Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiaqi Dou
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, Shanghai, China
- National Clinical Research Center for Oral Diseases, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Department of Second Dental Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiqun Wu
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China.
- National Center for Stomatology, Shanghai, China.
- National Clinical Research Center for Oral Diseases, Shanghai, China.
- Shanghai Key Laboratory of Stomatology, Shanghai, China.
- Department of Second Dental Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Yaqin Zhu
- Department of General Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China.
- National Center for Stomatology, Shanghai, China.
- National Clinical Research Center for Oral Diseases, Shanghai, China.
- Shanghai Key Laboratory of Stomatology, Shanghai, China.
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Lomeli C. S, Kristin B. A. Epigenetic regulation of craniofacial development and disease. Birth Defects Res 2024; 116:e2271. [PMID: 37964651 PMCID: PMC10872612 DOI: 10.1002/bdr2.2271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 10/13/2023] [Accepted: 10/24/2023] [Indexed: 11/16/2023]
Abstract
BACKGROUND The formation of the craniofacial complex relies on proper neural crest development. The gene regulatory networks (GRNs) and signaling pathways orchestrating this process have been extensively studied. These GRNs and signaling cascades are tightly regulated as alterations to any stage of neural crest development can lead to common congenital birth defects, including multiple syndromes affecting facial morphology as well as nonsyndromic facial defects, such as cleft lip with or without cleft palate. Epigenetic factors add a hierarchy to the regulation of transcriptional networks and influence the spatiotemporal activation or repression of specific gene regulatory cascades; however less is known about their exact mechanisms in controlling precise gene regulation. AIMS In this review, we discuss the role of epigenetic factors during neural crest development, specifically during craniofacial development and how compromised activities of these regulators contribute to congenital defects that affect the craniofacial complex.
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Affiliation(s)
- Shull Lomeli C.
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Artinger Kristin B.
- Department of Diagnostic and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, MN, USA
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10
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Abstract
Higher cognition in humans, compared to other primates, is often attributed to an increased brain size, especially forebrain cortical surface area. Brain size is determined through highly orchestrated developmental processes, including neural stem cell proliferation, differentiation, migration, lamination, arborization, and apoptosis. Disruption in these processes often results in either a small (microcephaly) or large (megalencephaly) brain. One of the key mechanisms controlling these developmental processes is the spatial and temporal transcriptional regulation of critical genes. In humans, microcephaly is defined as a condition with a significantly smaller head circumference compared to the average head size of a given age and sex group. A growing number of genes are identified as associated with microcephaly, and among them are those involved in transcriptional regulation. In this review, a subset of genes encoding transcription factors (e.g., homeobox-, basic helix-loop-helix-, forkhead box-, high mobility group box-, and zinc finger domain-containing transcription factors), whose functions are important for cortical development and implicated in microcephaly, are discussed.
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Affiliation(s)
- Youngshin Lim
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Department of Biomedical Science Education, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
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11
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Bosch E, Popp B, Güse E, Skinner C, van der Sluijs PJ, Maystadt I, Pinto AM, Renieri A, Bruno LP, Granata S, Marcelis C, Baysal Ö, Hartwich D, Holthöfer L, Isidor B, Cogne B, Wieczorek D, Capra V, Scala M, De Marco P, Ognibene M, Jamra RA, Platzer K, Carter LB, Kuismin O, van Haeringen A, Maroofian R, Valenzuela I, Cuscó I, Martinez-Agosto JA, Rabani AM, Mefford HC, Pereira EM, Close C, Anyane-Yeboa K, Wagner M, Hannibal MC, Zacher P, Thiffault I, Beunders G, Umair M, Bhola PT, McGinnis E, Millichap J, van de Kamp JM, Prijoles EJ, Dobson A, Shillington A, Graham BH, Garcia EJ, Galindo MK, Ropers FG, Nibbeling EAR, Hubbard G, Karimov C, Goj G, Bend R, Rath J, Morrow MM, Millan F, Salpietro V, Torella A, Nigro V, Kurki M, Stevenson RE, Santen GWE, Zweier M, Campeau PM, Severino M, Reis A, Accogli A, Vasileiou G. Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals. Genet Med 2023; 25:100950. [PMID: 37551667 DOI: 10.1016/j.gim.2023.100950] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 08/01/2023] [Accepted: 08/01/2023] [Indexed: 08/09/2023] Open
Abstract
PURPOSE Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort. METHODS Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays. RESULTS Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD. CONCLUSION This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.
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Affiliation(s)
- Elisabeth Bosch
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Bernt Popp
- Berlin Institute of Health at Charitè, Universitätsklinikum Berlin, Centre of Functional Genomics, Berlin, Germany; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
| | - Esther Güse
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | | | | | - Isabelle Maystadt
- Center for Human Genetics, Institute of Pathology and Genetics, Gosselies, Belgium
| | - Anna Maria Pinto
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Alessandra Renieri
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Medical Genetics Unit, University of Siena, Siena, Italy
| | - Lucia Pia Bruno
- Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
| | - Stefania Granata
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Medical Genetics Unit, University of Siena, Siena, Italy
| | - Carlo Marcelis
- Human Genetics department, Radboud university medical center, Nijmegen, The Netherlands
| | - Özlem Baysal
- Human Genetics department, Radboud university medical center, Nijmegen, The Netherlands
| | - Dewi Hartwich
- Institute of Human Genetics - University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - Laura Holthöfer
- Institute of Human Genetics - University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - Bertrand Isidor
- Nantes Université, CHU de Nantes, Service de Génétique médicale, Nantes, France; Nantes Université, CHU de Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France
| | - Benjamin Cogne
- Nantes Université, CHU de Nantes, Service de Génétique médicale, Nantes, France; Nantes Université, CHU de Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France
| | - Dagmar Wieczorek
- Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
| | - Valeria Capra
- Genomics and Clinical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Marcello Scala
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy; Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Patrizia De Marco
- Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Marzia Ognibene
- Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Rami Abou Jamra
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
| | - Konrad Platzer
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
| | - Lauren B Carter
- Department of Pediatrics, Division of Medical Genetics, Levine Children's Hospital, Atrium Health, Charlotte, NC
| | - Outi Kuismin
- Department of Clinical Genetics, Research Unit of Clinical Medicine, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Arie van Haeringen
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Reza Maroofian
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
| | - Irene Valenzuela
- Department of Clinical and Molecular Genetics, University Hospital Vall d'Hebron, Barcelona, Spain; Medicine Genetics Group, Valle Hebron Research Institute, Barcelona, Spain
| | - Ivon Cuscó
- Department of Clinical and Molecular Genetics, University Hospital Vall d'Hebron, Barcelona, Spain; Medicine Genetics Group, Valle Hebron Research Institute, Barcelona, Spain
| | - Julian A Martinez-Agosto
- Departments of Human Genetics, Pediatrics, and Psychiatry, UCLA David Geffen School of Medicine, Los Angeles, CA
| | - Ahna M Rabani
- Department of Pediatrics & Institute for Precision Health, UCLA David Geffen School of Medicine, Los Angeles, CA
| | - Heather C Mefford
- Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN
| | - Elaine M Pereira
- Division of Clinical Genetics, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY
| | - Charlotte Close
- Division of Clinical Genetics, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY
| | - Kwame Anyane-Yeboa
- Division of Clinical Genetics, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY
| | - Mallory Wagner
- Division of Pediatric Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics, University of Michigan Health System, University of Michigan, Ann Arbor, MI
| | - Mark C Hannibal
- Division of Pediatric Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics, University of Michigan Health System, University of Michigan, Ann Arbor, MI
| | - Pia Zacher
- Epilepsy Center Kleinwachau, Radeberg, Germany
| | - Isabelle Thiffault
- Department of Pediatrics and Pathology, Genomic Medicine Center, Children's Mercy Kansas City and Children's Mercy Research Institute, Kansas City, MO
| | - Gea Beunders
- Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - Muhammad Umair
- Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, MNGHA, Riyadh, Saudi Arabia; Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan
| | - Priya T Bhola
- Department of Genetics, Children's Hospital of Eastern Ontario (CHEO), Ottawa, Canada
| | - Erin McGinnis
- Division of Neurology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
| | - John Millichap
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Jiddeke M van de Kamp
- Department of Human Genetics, Amsterdam UMC, location VU Medical Center, Amsterdam, The Netherlands
| | | | | | - Amelle Shillington
- Department of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Brett H Graham
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN
| | - Evan-Jacob Garcia
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN
| | | | - Fabienne G Ropers
- Willem-Alexander Children's Hospital, Department of Pediatrics, Leiden University Medical Center, The Netherlands
| | - Esther A R Nibbeling
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Gail Hubbard
- Department of Medical Genetics, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA
| | - Catherine Karimov
- Department of Medical Genetics, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA
| | - Guido Goj
- Vestische Kinder- und Jugendklinik, Datteln, Germany
| | - Renee Bend
- PreventionGenetics, Part of Exact Sciences, Marshfield, WI
| | - Julie Rath
- PreventionGenetics, Part of Exact Sciences, Marshfield, WI
| | | | | | - Vincenzo Salpietro
- Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, United Kingdom; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Annalaura Torella
- Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Department of Precision Medicine, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Vincenzo Nigro
- Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Department of Precision Medicine, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Mitja Kurki
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA
| | | | - Gijs W E Santen
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Markus Zweier
- Institute of Medical Genetics, University of Zürich, Schlieren-Zurich, Switzerland
| | - Philippe M Campeau
- Department of Pediatrics, CHU Sainte-Justine and University of Montreal, Montreal, QC, Canada
| | | | - André Reis
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Centre for Rare Diseases Erlangen (ZSEER), Erlangen, Germany
| | - Andrea Accogli
- Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Centre; Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, QC, Canada
| | - Georgia Vasileiou
- Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Centre for Rare Diseases Erlangen (ZSEER), Erlangen, Germany.
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Kubota N, Takeda R, Kobayashi J, Hidaka E, Nishi E, Takano K, Wakui K. Reanalysis of Chromosomal Microarray Data Using a Smaller Copy Number Variant Call Threshold Identifies Four Cases with Heterozygous Multiexon Deletions of ARID1B, EHMT1, and FOXP1 Genes. Mol Syndromol 2023; 14:394-404. [PMID: 37901861 PMCID: PMC10601822 DOI: 10.1159/000530252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 03/16/2023] [Indexed: 10/31/2023] Open
Abstract
Introduction Chromosomal microarray (CMA) is a highly accurate and established method for detecting copy number variations (CNVs) in clinical genetic testing. CNVs are important etiological factors for disorders such as intellectual disability, developmental delay, and multiple congenital anomalies. Recently developed analytical methods have facilitated the identification of smaller CNVs. Therefore, reanalyzing CMA data using a smaller CNV calling threshold may yield useful information. However, this method was left to the discretion of each institution. Methods We reanalyzed the CMA data of 131 patients using a smaller CNV call threshold: 50 kb 50 probes for gain and 25 kb 25 probes for loss. We interpreted the reanalyzed CNVs based on the most recently available information. In the reanalysis, we filtered the data using the Clinical Genome Resource dosage sensitivity gene list as an index to quickly and efficiently check morbid genes. Results The number of copy number loss was approximately 20 times greater, and copy number gain was approximately three times greater compared to those in the previous analysis. We detected new likely pathogenic CNVs in four participants: a 236.5 kb loss within ARID1B, a 50.6 kb loss including EHMT1, a 46.5 kb loss including EHMT1, and an 89.1 kb loss within the FOXP1 gene. Conclusion The method employed in this study is simple and effective for CMA data reanalysis using a smaller CNV call threshold. Thus, this method is efficient for both ongoing and repeated analyses. This study may stimulate further discussion of reanalysis methodology in clinical laboratories.
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Affiliation(s)
- Noriko Kubota
- Life Science Research Center, Nagano Children’s Hospital, Azumino, Japan
| | - Ryojun Takeda
- Life Science Research Center, Nagano Children’s Hospital, Azumino, Japan
- Division of Medical Genetics, Nagano Children’s Hospital, Azumino, Japan
| | - Jun Kobayashi
- Life Science Research Center, Nagano Children’s Hospital, Azumino, Japan
| | - Eiko Hidaka
- Life Science Research Center, Nagano Children’s Hospital, Azumino, Japan
| | - Eriko Nishi
- Division of Medical Genetics, Nagano Children’s Hospital, Azumino, Japan
| | - Kyoko Takano
- Division of Medical Genetics, Nagano Children’s Hospital, Azumino, Japan
- Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan
- Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan
| | - Keiko Wakui
- Life Science Research Center, Nagano Children’s Hospital, Azumino, Japan
- Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan
- Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan
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13
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Liu PP, Lu SP, Li X, Tang GB, Liu X, Dai SK, Jiao LF, Lin XW, Li XG, Hu B, Jiao J, Teng ZQ, Han CS, Liu CM. Abnormal chromatin remodeling caused by ARID1A deletion leads to malformation of the dentate gyrus. Cell Death Differ 2023; 30:2187-2199. [PMID: 37543710 PMCID: PMC10483045 DOI: 10.1038/s41418-023-01199-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 07/15/2023] [Accepted: 07/27/2023] [Indexed: 08/07/2023] Open
Abstract
ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be a tumor suppressor. Recently, loss-of-function of ARID1A gene has been shown to cause intellectual disability. Here we generate Arid1a conditional knockout mice and investigate Arid1a function in the hippocampus. Disruption of Arid1a in mouse forebrain significantly decreases neural stem/progenitor cells (NSPCs) proliferation and differentiation to neurons within the dentate gyrus (DG), increasing perinatal and postnatal apoptosis, leading to reduced hippocampus size. Moreover, we perform single-cell RNA sequencing (scRNA-seq) to investigate cellular heterogeneity and reveal that Arid1a is necessary for the maintenance of the DG progenitor pool and survival of post-mitotic neurons. Transcriptome and ChIP-seq analysis data demonstrate that ARID1A specifically regulates Prox1 by altering the levels of histone modifications. Overexpression of downstream target Prox1 can rescue proliferation and differentiation defects of NSPCs caused by Arid1a deletion. Overall, our results demonstrate a critical role for Arid1a in the development of the hippocampus and may also provide insight into the genetic basis of intellectual disabilities such as Coffin-Siris syndrome, which is caused by germ-line mutations or microduplication of Arid1a.
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Affiliation(s)
- Pei-Pei Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Shi-Ping Lu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Xiao Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Gang-Bin Tang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Xiao Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Shang-Kun Dai
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Lin-Fei Jiao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xi-Wen Lin
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Xing-Guo Li
- Graduate Institute of Biomedical Sciences, China Medical University, No.91, Hsueh-Shih Road, Taichung, 40402, Taiwan
| | - Baoyang Hu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jianwei Jiao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhao-Qian Teng
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Chun-Sheng Han
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Chang-Mei Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China.
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14
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Milutinovic L, Grujicic R, Mandic Maravic V, Joksic I, Ljubomirovic N, Pejovic Milovancevic M. Autism spectrum disorder and Coffin-Siris syndrome-Case report. Front Psychiatry 2023; 14:1199710. [PMID: 37692302 PMCID: PMC10483805 DOI: 10.3389/fpsyt.2023.1199710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 07/28/2023] [Indexed: 09/12/2023] Open
Abstract
Introduction Autism spectrum disorders (ASDs) are a group of developmental disorders characterized by deficits in social communicative skills and the occurrence of repetitive and/or stereotyped behaviors. Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degrees, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. In this study, we present a detailed description of autistic traits in a boy diagnosed with CSS and further discuss their genetic backgrounds. Case description An 8-year-old boy with ASD, congenital anomalies, and neurological problems had been diagnosed with Coffin-Siris syndrome after genetic testing. Genetic testing revealed a heterozygous de novo pathogenic variant (class 5) c.1638_1647del in the ARID1B gene that is causative of Coffin-Siris syndrome but also other intellectual disability (ID)-related disorders, including autism. Tests that preceded the diagnoses, as well as congenital anomalies and developmental issues, were further described in an attempt to better present his phenotype. Conclusion Both autism and ARID1B-related disorders are on a spectrum. This report points out the importance and necessity of further research regarding the genetic backgrounds of these disorders to understand their complex etiology.
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Affiliation(s)
- Luka Milutinovic
- Clinical Department for Children and Adolescents, Institute of Mental Health, Belgrade, Serbia
| | - Roberto Grujicic
- Clinical Department for Children and Adolescents, Institute of Mental Health, Belgrade, Serbia
| | - Vanja Mandic Maravic
- Day Hospital for Psychotic Disorders, Institute of Mental Health, Belgrade, Serbia
| | - Ivana Joksic
- Clinic for Gynecology and Obstetrics “Narodni Front”, Belgrade, Serbia
| | - Natasa Ljubomirovic
- Clinical Department for Children and Adolescents, Institute of Mental Health, Belgrade, Serbia
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15
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Aryal S, Anand D, Huang H, Reddy AP, Wilmarth PA, David LL, Lachke SA. Proteomic profiling of retina and retinal pigment epithelium combined embryonic tissue to facilitate ocular disease gene discovery. Hum Genet 2023; 142:927-947. [PMID: 37191732 PMCID: PMC10680127 DOI: 10.1007/s00439-023-02570-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 05/04/2023] [Indexed: 05/17/2023]
Abstract
To expedite gene discovery in eye development and its associated defects, we previously developed a bioinformatics resource-tool iSyTE (integrated Systems Tool for Eye gene discovery). However, iSyTE is presently limited to lens tissue and is predominantly based on transcriptomics datasets. Therefore, to extend iSyTE to other eye tissues on the proteome level, we performed high-throughput tandem mass spectrometry (MS/MS) on mouse embryonic day (E)14.5 retina and retinal pigment epithelium combined tissue and identified an average of 3300 proteins per sample (n = 5). High-throughput expression profiling-based gene discovery approaches-involving either transcriptomics or proteomics-pose a key challenge of prioritizing candidates from thousands of RNA/proteins expressed. To address this, we used MS/MS proteome data from mouse whole embryonic body (WB) as a reference dataset and performed comparative analysis-termed "in silico WB-subtraction"-with the retina proteome dataset. In silico WB-subtraction identified 90 high-priority proteins with retina-enriched expression at stringency criteria of ≥ 2.5 average spectral counts, ≥ 2.0 fold-enrichment, false discovery rate < 0.01. These top candidates represent a pool of retina-enriched proteins, several of which are associated with retinal biology and/or defects (e.g., Aldh1a1, Ank2, Ank3, Dcn, Dync2h1, Egfr, Ephb2, Fbln5, Fbn2, Hras, Igf2bp1, Msi1, Rbp1, Rlbp1, Tenm3, Yap1, etc.), indicating the effectiveness of this approach. Importantly, in silico WB-subtraction also identified several new high-priority candidates with potential regulatory function in retina development. Finally, proteins exhibiting expression or enriched-expression in the retina are made accessible in a user-friendly manner at iSyTE ( https://research.bioinformatics.udel.edu/iSyTE/ ), to allow effective visualization of this information and facilitate eye gene discovery.
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Affiliation(s)
- Sandeep Aryal
- Department of Biological Sciences, University of Delaware, Newark, DE, 19716, USA
| | - Deepti Anand
- Department of Biological Sciences, University of Delaware, Newark, DE, 19716, USA
| | - Hongzhan Huang
- Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE, 19713, USA
| | - Ashok P Reddy
- Proteomics Shared Resource, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Phillip A Wilmarth
- Proteomics Shared Resource, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Larry L David
- Proteomics Shared Resource, Oregon Health and Science University, Portland, OR, 97239, USA
- Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Salil A Lachke
- Department of Biological Sciences, University of Delaware, Newark, DE, 19716, USA.
- Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE, 19713, USA.
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16
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Ke NY, Zhao TY, Wang WR, Qian YT, Liu C. Role of brahma-related gene 1/brahma-associated factor subunits in neural stem/progenitor cells and related neural developmental disorders. World J Stem Cells 2023; 15:235-247. [PMID: 37181007 PMCID: PMC10173807 DOI: 10.4252/wjsc.v15.i4.235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/12/2023] [Accepted: 03/20/2023] [Indexed: 04/26/2023] Open
Abstract
Different fates of neural stem/progenitor cells (NSPCs) and their progeny are determined by the gene regulatory network, where a chromatin-remodeling complex affects synergy with other regulators. Here, we review recent research progress indicating that the BRG1/BRM-associated factor (BAF) complex plays an important role in NSPCs during neural development and neural developmental disorders. Several studies based on animal models have shown that mutations in the BAF complex may cause abnormal neural differentiation, which can also lead to various diseases in humans. We discussed BAF complex subunits and their main characteristics in NSPCs. With advances in studies of human pluripotent stem cells and the feasibility of driving their differentiation into NSPCs, we can now investigate the role of the BAF complex in regulating the balance between self-renewal and differentiation of NSPCs. Considering recent progress in these research areas, we suggest that three approaches should be used in investigations in the near future. Sequencing of whole human exome and genome-wide association studies suggest that mutations in the subunits of the BAF complex are related to neurodevelopmental disorders. More insight into the mechanism of BAF complex regulation in NSPCs during neural cell fate decisions and neurodevelopment may help in exploiting new methods for clinical applications.
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Affiliation(s)
- Nai-Yu Ke
- The First Clinical Medical College, Anhui Medical University, Hefei 230032, Anhui Province, China
- Institute of Stem cells and Tissue Engineering, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Tian-Yi Zhao
- Institute of Stem cells and Tissue Engineering, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Wan-Rong Wang
- The First Clinical Medical College, Anhui Medical University, Hefei 230032, Anhui Province, China
- Institute of Stem cells and Tissue Engineering, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Yu-Tong Qian
- The First Clinical Medical College, Anhui Medical University, Hefei 230032, Anhui Province, China
- Institute of Stem cells and Tissue Engineering, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Chao Liu
- Institute of Stem cells and Tissue Engineering, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
- Department of Histology and Embryology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China.
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17
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Cell context-dependent CFI-1/ARID3 functions control neuronal terminal differentiation. Cell Rep 2023; 42:112220. [PMID: 36897776 PMCID: PMC10124151 DOI: 10.1016/j.celrep.2023.112220] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 12/21/2022] [Accepted: 02/20/2023] [Indexed: 03/11/2023] Open
Abstract
AT-rich interaction domain 3 (ARID3) transcription factors are expressed in the nervous system, but their mechanisms of action are largely unknown. Here, we provide, in vivo, a genome-wide binding map for CFI-1, the sole C. elegans ARID3 ortholog. We identify 6,396 protein-coding genes as putative direct targets of CFI-1, most of which encode neuronal terminal differentiation markers. In head sensory neurons, CFI-1 directly activates multiple terminal differentiation genes, thereby acting as a terminal selector. In motor neurons, however, CFI-1 acts as a direct repressor, continuously antagonizing three transcriptional activators. By focusing on the glr-4/GRIK4 glutamate receptor locus, we identify proximal CFI-1 binding sites and histone methyltransferase activity as necessary for glr-4 repression. Rescue assays reveal functional redundancy between core and extended DNA-binding ARID domains and a strict requirement for REKLES, the ARID3 oligomerization domain. Altogether, this study uncovers cell-context-dependent mechanisms through which a single ARID3 protein controls the terminal differentiation of distinct neuron types.
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18
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Nguyen VT, Tessema M, Weissman BE. The SWI/SNF Complex: A Frequently Mutated Chromatin Remodeling Complex in Cancer. Cancer Treat Res 2023; 190:211-244. [PMID: 38113003 DOI: 10.1007/978-3-031-45654-1_7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2023]
Abstract
The switch/sucrose non-fermenting (SWI/SNF) chromatin remodeling complex is a global regulator of gene expression known to maintain nucleosome-depleted regions at active enhancers and promoters. The mammalian SWI/SNF protein subunits are encoded by 29 genes and 11-15 subunits including an ATPase domain of either SMARCA4 (BRG1) or SMARCA2 (BRM) are assembled into a complex. Based on the distinct subunits, SWI/SNF are grouped into 3 major types (subfamilies): the canonical BRG1/BRM-associated factor (BAF/cBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (GBAF/ncBAF). Pan-cancer genome sequencing studies have shown that nearly 25% of all cancers bear mutations in subunits of the SWI/SNF complex, many of which are loss of function (LOF) mutations, suggesting a tumor suppressor role. Inactivation of SWI/SNF complex subunits causes widespread epigenetic dysfunction, including increased dependence on antagonistic components such as polycomb repressor complexes (PRC1/2) and altered enhancer regulation, likely promoting an oncogenic state leading to cancer. Despite the prevalence of mutations, most SWI/SNF-mutant cancers lack targeted therapeutic strategies. Defining the dependencies created by LOF mutations in SWI/SNF subunits will identify better targets for these cancers.
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Affiliation(s)
- Vinh The Nguyen
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
- Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
| | - Mathewos Tessema
- Lung Cancer Program, Lovelace Biomedical Research Institute, Albuquerque, NM, USA
| | - Bernard Ellis Weissman
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
- Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
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19
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Asegaonkar P, Kotecha U, Dongre M, Mistri M, Sharda S. Expanding the spectrum of ADNP-related disorder-Antenatally diagnosed congenital diaphragmatic hernia and a novel de novo mutation in ADNP gene. Am J Med Genet A 2023; 191:275-279. [PMID: 36321748 DOI: 10.1002/ajmg.a.63017] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 09/07/2022] [Accepted: 09/24/2022] [Indexed: 12/13/2022]
Abstract
De novo heterozygous ADNP variants have been associated with a complex neurological phenotype characterized primarily by neurodevelopmental delay. Cardiac and renal anomalies have additionally been observed in a few patients. All reported cases to date have been ascertained postnatally. Congenital diaphragmatic hernia (CDH) has been previously observed in one child diagnosed with a de novo ADNP-related neurodevelopmental disorder. We report a fetus who presented with syndromic CDH associated with a de novo heterozygous ADNP variant.
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Affiliation(s)
| | | | | | - Mehul Mistri
- Neuberg Centre for Genomic Medicine, Ahmedabad, India
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20
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Hollander N, ten Tusscher GW. Coffin-Siris syndrome: Clinical description of two cases. Clin Case Rep 2022; 10:e6598. [PMID: 36540875 PMCID: PMC9755812 DOI: 10.1002/ccr3.6598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 10/12/2022] [Accepted: 10/19/2022] [Indexed: 12/23/2022] Open
Abstract
Coffin-Siris syndrome is a rare disorder, which can be difficult to recognize. A broad spectrum of nonspecific clinical features is associated with Coffin-Siris syndrome, and the expression of these features is diverse. We describe two cases with Coffin-Siris syndrome with mutations in the ARID1A gene, with dissimilar presentation and clinical course.
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Affiliation(s)
- Nina Hollander
- Department of Pediatrics and NeonatologyDijklander HospitalHoornThe Netherlands
| | - Gavin William ten Tusscher
- Department of Pediatrics and NeonatologyDijklander HospitalHoornThe Netherlands
- Department of General Practice, Public Health and MethodologyAmsterdam University Medical CenterAmsterdamThe Netherlands
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21
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Ding Y, Chen J, Tang Y, Chen LN, Yao RE, Yu T, Yin Y, Wang X, Wang J, Li N. Identification and functional analysis of novel SOX11 variants in Chinese patients with Coffin-Siris syndrome 9. Front Genet 2022; 13:940776. [PMID: 35938035 PMCID: PMC9354949 DOI: 10.3389/fgene.2022.940776] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
SOX11 is a transcription factor belonging to the sex determining region Y-related high-mobility group box family that plays a vital role in early embryogenesis and neurogenesis. De novo variants in SOX11 have been initially reported to cause a rare neurodevelopmental disorder, mainly referred to Coffin-siris syndrome 9 (CSS9, OMIM# 615866) which is characterized with growth deficiency, intellectual disability (ID), microcephaly, coarse facies, and hypoplastic nails of the fifth fingers and/or toes. A recent large-scale cohort study suggests that SOX11 variation would result in a clinically and molecularly distinct disease from CSS. Here, we describe three unrelated Chinese cases with variable phenotype, mainly involving developmental delay, ID, short statute, microcephaly, facial deformities (i.e., prominent forehead, arched eye brow, flat nasal bridge, broad nose and short philtrum), and cryptorchidism. Whole-exome sequencing (WES) revealed three novel heterozygous variants in the SOX11 gene, including two missense variants of c.337T>C (p.Y113H) and c.425C>G (p.A142G), and one nonsense variant of c.820A>T (p. K142*). Luciferase reporting assay shows that the two missense variants impair the transcriptional activity of the SOX11 target gene GDF5. Additionally, WES uncovered a 4,300 kb deletion involving the region of 1q24.2-q25.1 (hg19,chr1:169,433,149-173,827,682) in patient 1, which also contributes to the condition of the patient. In summary, this is the first report of Chinese cases with de novo variants of SOX11. Our study partially supports the previous observation that the phenotype caused by SOX11 variants somewhat differs from classical CSS.
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Affiliation(s)
- Yu Ding
- Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiande Chen
- Department of Respiratory Medicine, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yijun Tang
- Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li-Na Chen
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ru-En Yao
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Shanghai, China
- Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai, China
| | - Tingting Yu
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Shanghai, China
- Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai, China
| | - Yong Yin
- Department of Respiratory Medicine, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiumin Wang
- Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian Wang
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Shanghai, China
- Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai, China
- *Correspondence: Niu Li, ; Jian Wang,
| | - Niu Li
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Shanghai, China
- Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai, China
- *Correspondence: Niu Li, ; Jian Wang,
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22
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Zhang X, Chen H, Song Y, Chen Z, Liu X, Rong P, Ma R. Ten-year follow-up of Nicolaides-Baraitser syndrome with a de novo mutation and analysis of 58 gene loci of SMARCA2-associated NCBRS. Mol Genet Genomic Med 2022; 10:e2009. [PMID: 35811451 PMCID: PMC9482403 DOI: 10.1002/mgg3.2009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 05/10/2022] [Accepted: 06/08/2022] [Indexed: 01/11/2023] Open
Abstract
As a clinical subtype of SWI/SNF‐related intellectual disability syndromes, Nicolaides–Baraitser syndrome (NCBRS, OMIM601358) has a unique genotype–phenotype. Due to the scarcity of the number of cases reported and the limitations of diagnosis methods, so far only more than 80 cases have been reported worldwide. In this article, a new patient with a de novo mutation was followed up for 10 years; it includes the epilepsy treatment process, the characteristics of NBCRS with seizures, typical faces, sparse hair, prominent interphalangeal joints, and intellectual disability, and we also summarized the genotype–phenotype of the 80 reported cases for comparison. Due to insufficient studies and lack of attention paid to the syndrome, it is believed that the actual number of cases should be far more than the reported number. The syndrome is phased and progressive. The genotype–phenotype correlation of the disease is related to the location of the gene locus, especially closely related to the SNF2 ATPase domain.
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Affiliation(s)
- Xilian Zhang
- Department of Pediatrics, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Hanjiang Chen
- Department of Pediatrics, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Ying Song
- Graduate College of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhaoyuan Chen
- Graduate College of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xuan Liu
- Department of Pediatrics, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Ping Rong
- Department of Pediatrics, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Rong Ma
- Department of Pediatrics, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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23
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Simmers R, Goodwin A, Al Saif H, Couser N. Ophthalmologic and facial abnormalities of Nicolaides-Baraitser syndrome. Ophthalmic Genet 2022; 43:699-702. [PMID: 35762114 DOI: 10.1080/13816810.2022.2089358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
BACKGROUND Nicolaides-Baraitser syndrome (NCBRS), first described in 1993, is a rare autosomal dominant disease caused by pathogenic variants in the SMARCA2 gene on chromosome 9p24.3. NCBRS typically presents with dysmorphic facial features, seizures, intellectual disability, and developmental delays. Abnormal findings of the eye and ocular adnexa associated with NCBRS have not been systematically evaluated and summarized in literature. This report presents the case of a 4-year-old male with NCBRS along with a systematic review of literature of the abnormal ophthalmologic and facial features of NCBRS cases. METHODS A systematic review of literature of published cases of molecularly confirmed NCBRS was performed and the frequencies of eye, ocular adnexa, and facial abnormalities were calculated. RESULTS Our patient's abnormal eye features include myopia, down slanting palpebral fissures, sagging inferior periorbital skin, hypertelorism, and long eyelashes. From the systemic review of literature, the most common abnormal eye and ocular adnexa features include prominent/long eyelashes, thick eyebrows, sagging periorbital skin, down slanting palpebral fissures, and ptosis. The most common facial dysmorphic features include thick/everted lower lip, coarse facial features, wide/large mouth, and thin upper lip. Dental abnormalities are also commonly reported. CONCLUSIONS NCBRS frequently presents with well-defined ophthalmic and facial abnormalities. Prompt ophthalmologic evaluation following NCBRS diagnosis may be recommended to screen for several eye disorders. Surgical correction of ptosis may be indicated for NCBRS patients. This report may help further delineate the phenotype of this condition, which may allow for more rapid identification of those affected and provide incentive for additional studies.
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Affiliation(s)
- Russell Simmers
- Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Allison Goodwin
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Department of Pediatrics, Virginia Commonwealth University School of Medicine, Children's Hospital of Richmond at VCU, Richmond, Virginia, USA
| | - Hind Al Saif
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Department of Pediatrics, Virginia Commonwealth University School of Medicine, Children's Hospital of Richmond at VCU, Richmond, Virginia, USA
| | - Natario Couser
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Department of Ophthalmology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Department of Pediatrics, Virginia Commonwealth University School of Medicine, Children's Hospital of Richmond at VCU, Richmond, Virginia, USA
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24
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MacDonald SK, Marshall AE, Lemire G, Hartley T, Kernohan KD, Boycott KM. A novel intragenic DPF2 deletion identified by genome sequencing in an adult with clinical features of Coffin-Siris syndrome. Am J Med Genet A 2022; 188:2493-2496. [PMID: 35607970 DOI: 10.1002/ajmg.a.62849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/18/2022] [Accepted: 03/22/2022] [Indexed: 11/09/2022]
Affiliation(s)
- Stella K MacDonald
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Aren E Marshall
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Gabrielle Lemire
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Taila Hartley
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | | | - Kristin D Kernohan
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.,Newborn Screening Ontario, Ottawa, Ontario, Canada
| | - Kym M Boycott
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.,Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
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25
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Munabi NCO, Mikhail S, Toubat O, Webb M, Auslander A, Sanchez-Lara PA, Manojlovic Z, Schmidt RJ, Craig D, Magee WP, Kumar SR. High prevalence of deleterious mutations in concomitant nonsyndromic cleft and outflow tract heart defects. Am J Med Genet A 2022; 188:2082-2095. [PMID: 35385219 PMCID: PMC9197864 DOI: 10.1002/ajmg.a.62748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 02/26/2022] [Accepted: 03/18/2022] [Indexed: 11/18/2022]
Abstract
Our previous work demonstrating enrichment of outflow tract (OFT) congenital heart disease (CHD) in children with cleft lip and/or palate (CL/P) suggests derangements in common underlying developmental pathways. The current pilot study examines the underlying genetics of concomitant nonsyndromic CL/P and OFT CHD phenotype. Of 575 patients who underwent CL/P surgery at Children's Hospital Los Angeles, seven with OFT CHD, negative chromosomal microarray analysis, and no recognizable syndromic association were recruited with their parents (as available). Whole genome sequencing of blood samples paired with whole‐blood‐based RNA sequencing for probands was performed. A pathogenic or potentially pathogenic variant was identified in 6/7 (85.7%) probands. A total of seven candidate genes were mutated (CHD7, SMARCA4, MED12, APOB, RNF213, SETX, and JAG1). Gene ontology analysis of variants predicted involvement in binding (100%), regulation of transcription (42.9%), and helicase activity (42.9%). Four patients (57.1%) expressed gene variants (CHD7, SMARCA4, MED12, and RNF213) previously involved in the Wnt signaling pathway. Our pilot analysis of a small cohort of patients with combined CL/P and OFT CHD phenotype suggests a potentially significant prevalence of deleterious mutations. In our cohort, an overrepresentation of mutations in molecules associated with Wnt‐signaling was found. These variants may represent an expanded phenotypic heterogeneity within known monogenic disease genes or provide novel evidence of shared developmental pathways. The mechanistic implications of these mutations and subsequent developmental derangements resulting in the CL/P and OFT CHD phenotype require further analysis in a larger cohort of patients.
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Affiliation(s)
- Naikhoba C O Munabi
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA
| | | | - Omar Toubat
- Division of Cardiac Surgery, Department of Surgery, Keck School of Medicine of USC, Los Angeles, California, USA
| | - Michelle Webb
- Department of Translational Genomics, Keck School of Medicine of USC, Los Angeles, California, USA
| | | | - Pedro A Sanchez-Lara
- Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Zarko Manojlovic
- Department of Translational Genomics, Keck School of Medicine of USC, Los Angeles, California, USA
| | - Ryan J Schmidt
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California, USA.,Department of Pathology, Keck School of Medicine of USC, Los Angeles, California, USA
| | - David Craig
- Department of Translational Genomics, Keck School of Medicine of USC, Los Angeles, California, USA
| | - William P Magee
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA.,Division of Plastic and Maxillofacial Surgery, Children's Hospital Los Angeles, Los Angeles, California, USA.,Department of Plastic Surgery, Shriners Hospital for Children, Los Angeles, California, USA
| | - Subramanyan Ram Kumar
- Division of Cardiac Surgery, Department of Surgery, Keck School of Medicine of USC, Los Angeles, California, USA.,Heart Institute, Children's Hospital Los Angeles, Los Angeles, California, USA
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26
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Liu M, Wan L, Wang C, Yuan H, Peng Y, Wan N, Tang Z, Yuan X, Chen D, Long Z, Shi Y, Qiu R, Tang B, Jiang H, Chen Z. Coffin-Siris syndrome in two chinese patients with novel pathogenic variants of ARID1A and SMARCA4. Genes Genomics 2022; 44:1061-1070. [PMID: 35353340 DOI: 10.1007/s13258-022-01231-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 02/05/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Coffin-Siris syndrome (CSS) is a rare congenital syndrome characterized by developmental delay, intellectual disability, microcephaly, coarse face and hypoplastic nail of the fifth digits. Heterozygous variants of different BAF complex-related genes were reported to cause CSS, including ARID1A and SMARCA4. So far, no CSS patients with ARID1A and SMARCA4 variants have been reported in China. OBJECTIVE The aim of the current study was to identify the causes of two Chinese patients with congenital growth deficiency and intellectual disability. METHODS Genomic DNA was extracted from the peripheral venous blood of patients and their family members. Genetic analysis included whole-exome and Sanger sequencing. Pathogenicity assessments of variants were performed according to the guideline of the American College of Medical Genetics and Genomics. The phenotypic characteristics of all CSS subtypes were summarized through literature review. RESULTS We identified two Chinese CSS patients carrying novel variants of ARID1A and SMARCA4 respectively. The cases presented most core symptoms of CSS except for the digits involvement. Additionally, we performed a review of the phenotypic characteristics in CSS, highlighting phenotypic varieties and related potential causes. CONCLUSIONS We reported the first Chinese CSS2 and CSS4 patients with novel variants of ARID1A and SMARCA4. Our study expanded the genetic and phenotypic spectrum of CSS, providing a comprehensive overview of genotype-phenotype correlations of CSS.
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Affiliation(s)
- Mingjie Liu
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Linlin Wan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chunrong Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hongyu Yuan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yun Peng
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Na Wan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhichao Tang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xinrong Yuan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Daji Chen
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhe Long
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuting Shi
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, China
| | - Rong Qiu
- School of Computer Science and Engineering, Central South University, Changsha, Hunan, China
| | - Beisha Tang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Diseases, Central South University, Changsha, Hunan, China
- Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China
- Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, China
| | - Hong Jiang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- School of Basic Medical Science, Central South University, Changsha, Hunan, China
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Diseases, Central South University, Changsha, Hunan, China
- Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China
- Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, China
- National International Collaborative Research Center for Medical Metabolomics, Central South University, Changsha, Hunan, China
| | - Zhao Chen
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, China.
- National Clinical Research Center for Geriatric Diseases, Central South University, Changsha, Hunan, China.
- Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, China.
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27
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Abstract
Though melanocytic nevi are ubiquitous in the general population, they can also be key cutaneous manifestations of genetic syndromes. We describe genodermatoses associated with melanocytic nevi and discuss their clinical characteristics, cutaneous manifestations, underlying genetics, and, if applicable, guidelines for when genetic testing should be performed. We categorized these genodermatoses based on their association with congenital nevi, acquired nevi, or nevi whose first appearance is unknown. In many cases, the distinctive morphology or distribution of melanocytic nevi can be an important clue that an underlying genetic syndrome is present, allowing both the patient as well as family members to be screened for the more serious complications of their genetic disorder and receive education on potential preventative measures. As we continue to advance our understanding of how various genotypes give rise to the wide spectrum of phenotypes observed in these genodermatoses, we shall be able to better stratify risk and tailor our screening methods to clinically manage the heterogeneous manifestations of genodermatoses among these patients.
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Affiliation(s)
- Julie Y Ramseier
- Department of Dermatology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520
| | - Sara H Perkins
- Department of Dermatology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520.
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28
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Slavotinek A, Lefebvre M, Brehin AC, Thauvin C, Patrier S, Sparks TN, Norton M, Yu J, Huang E. Prenatal presentation of multiple anomalies associated with haploinsufficiency for ARID1A. Eur J Med Genet 2022; 65:104407. [PMID: 34942405 PMCID: PMC9162882 DOI: 10.1016/j.ejmg.2021.104407] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 11/04/2021] [Accepted: 12/14/2021] [Indexed: 02/03/2023]
Abstract
The ARID1A gene is an infrequent cause of Coffin-Siris syndrome (CSS) and has been associated with severe to profound developmental delays and hypotonia in addition to characteristic craniofacial and digital findings. We present three fetuses and a male neonate with ventriculomegaly/hydrocephalus, absence of the corpus callosum (ACC), cerebellar hypoplasia, retinal dysplasia, lung lobulation defects, renal dysplasia, imperforate or anteriorly placed anus, thymus hypoplasia and a single umbilical artery. Facial anomalies included downslanting palpebral fissures, wide-spaced eyes, low-set and posteriorly rotated ears, a small jaw, widely spaced nipples and hypoplastic nails. All fetuses had heterozygous variants predicting premature protein truncation in ARID1A (c.4886dup:p.Val1630Cysfs*18; c.4860dup:p.Pro1621Thrfs*27; and c.175G>T:p.Glu59*) and the baby's microarray demonstrated mosaicism for a deletion at chromosome 1p36.11 (arr[GRCh37] 1p36.11(26,797,508_27,052,080)×1∼2), that contained the first exon of ARID1A. Although malformations, in particular ACC, have been described with CSS caused by pathogenic variants in ARID1A, prenatal presentations associated with this gene are rare. Retinal dysplasia, lung lobulation defects and absent thymus were novel findings in association with ARID1A variants. Studies in cancer have demonstrated that pathogenic ARID1A variants hamper nuclear import of the protein and/or affect interaction with the subunits of SWI/SNF complex, resulting in dysregulation of the PI3K/AKT pathway and perturbed PTEN and PIKC3A signaling. As haploinsufficiency for PTEN and PIKC3A can be associated with ventriculomegaly/hydrocephalus, aberrant expression of these genes is a putative mechanism for the brain malformations demonstrated in patients with ARID1A variants.
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Affiliation(s)
- Anne Slavotinek
- Dept. Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA.
| | - Mathilde Lefebvre
- UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231, Génétique des Anomalies du Développement, Dijon, France
| | | | - Christel Thauvin
- UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231, Génétique des Anomalies du Développement, Dijon, France
| | - Sophie Patrier
- Department of Pathology, CHU Rouen, F-76000, Rouen, France
| | - Teresa N Sparks
- Department of Obstetrics, Gynecology, & Reproductive Sciences, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Mary Norton
- Department of Obstetrics, Gynecology, & Reproductive Sciences, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Jingwei Yu
- Dept. Cytogenetics, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Eric Huang
- Dept. Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
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29
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Chen CA, Lattier J, Zhu W, Rosenfeld J, Wang L, Scott TM, Du H, Patel V, Dang A, Magoulas P, Streff H, Sebastian J, Svihovec S, Curry K, Delgado MR, Hanchard N, Lalani S, Marom R, Madan-Khetarpal S, Saenz M, Dai H, Meng L, Xia F, Bi W, Liu P, Posey JE, Scott DA, Lupski JR, Eng CM, Xiao R, Yuan B. Retrospective analysis of a clinical exome sequencing cohort reveals the mutational spectrum and identifies candidate disease-associated loci for BAFopathies. Genet Med 2022; 24:364-373. [PMID: 34906496 PMCID: PMC8957292 DOI: 10.1016/j.gim.2021.09.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 06/19/2021] [Accepted: 06/19/2021] [Indexed: 02/03/2023] Open
Abstract
PURPOSE BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex that plays a critical role in gene regulation. Defects in the genes encoding BAF subunits lead to BAFopathies, a group of neurodevelopmental disorders with extensive locus and phenotypic heterogeneity. METHODS We retrospectively analyzed data from 16,243 patients referred for clinical exome sequencing (ES) with a focus on the BAF complex. We applied a genotype-first approach, combining predicted genic constraints to propose candidate BAFopathy genes. RESULTS We identified 127 patients carrying pathogenic variants, likely pathogenic variants, or de novo variants of unknown clinical significance in 11 known BAFopathy genes. Those include 34 patients molecularly diagnosed using ES reanalysis with new gene-disease evidence (n = 21) or variant reclassifications in known BAFopathy genes (n = 13). We also identified de novo or predicted loss-of-function variants in 4 candidate BAFopathy genes, including ACTL6A, BICRA (implicated in Coffin-Siris syndrome during this study), PBRM1, and SMARCC1. CONCLUSION We report the mutational spectrum of BAFopathies in an ES cohort. A genotype-driven and pathway-based reanalysis of ES data identified new evidence for candidate genes involved in BAFopathies. Further mechanistic and phenotypic characterization of additional patients are warranted to confirm their roles in human disease and to delineate their associated phenotypic spectrums.
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Affiliation(s)
- Chun-An Chen
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
| | | | | | - Jill Rosenfeld
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
| | - Lei Wang
- Baylor Genetics Laboratory, Houston, TX
| | - Tiana M. Scott
- Texas Children’s Hospital, Houston, TX, Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT
| | - Haowei Du
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
| | | | - Anh Dang
- Baylor Genetics Laboratory, Houston, TX
| | - Pilar Magoulas
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, Texas Children’s Hospital, Houston, TX
| | - Haley Streff
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, Texas Children’s Hospital, Houston, TX
| | | | - Shayna Svihovec
- University of Colorado Anschutz Medical Campus; Children’s Hospital Colorado, Aurora, CO
| | - Kathryn Curry
- Genetics and Metabolic Department, St. Luke’s Health System
| | - Mauricio R. Delgado
- Texas Scottish Rite Hospital for Children, Dallas, TX, USA, Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Neil Hanchard
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, Texas Children’s Hospital, Houston, TX
| | - Seema Lalani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, Texas Children’s Hospital, Houston, TX
| | - Ronit Marom
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, Texas Children’s Hospital, Houston, TX
| | | | - Margarita Saenz
- University of Colorado Anschutz Medical Campus; Children’s Hospital Colorado, Aurora, CO
| | - Hongzheng Dai
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, Baylor Genetics Laboratory, Houston, TX
| | - Linyan Meng
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, Baylor Genetics Laboratory, Houston, TX
| | - Fan Xia
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, Baylor Genetics Laboratory, Houston, TX
| | - Weimin Bi
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, Baylor Genetics Laboratory, Houston, TX
| | - Pengfei Liu
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, Baylor Genetics Laboratory, Houston, TX
| | - Jennifer E. Posey
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
| | - Daryl A. Scott
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, Texas Children’s Hospital, Houston, TX, Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX
| | - James R. Lupski
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, Texas Children’s Hospital, Houston, TX, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, Department of Pediatrics, Baylor College of Medicine, Houston, TX
| | - Christine M. Eng
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, Baylor Genetics Laboratory, Houston, TX
| | - Rui Xiao
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, Baylor Genetics Laboratory, Houston, TX
| | - Bo Yuan
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, Baylor Genetics Laboratory, Houston, TX, Current address: Department of Laboratories, Seattle Children’s Hospital, Seattle, WA
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30
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Turan S, Boerstler T, Kavyanifar A, Loskarn S, Reis A, Winner B, Lie DC. A novel human stem cell model for Coffin-Siris syndrome-like syndrome reveals the importance of SOX11 dosage for neuronal differentiation and survival. Hum Mol Genet 2021; 28:2589-2599. [PMID: 31035284 DOI: 10.1093/hmg/ddz089] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 04/03/2019] [Accepted: 04/17/2019] [Indexed: 11/14/2022] Open
Abstract
The SOXC transcription factors Sox4, Sox11 and Sox12, are critical neurodevelopmental regulators that are thought to function in a highly redundant fashion. Surprisingly, heterozygous missense mutations or deletions of SOX11 were recently detected in patients with Coffin-Siris syndrome-like syndrome (CSSLS), a neurodevelopmental disorder associated with intellectual disability, demonstrating that in humans SOX11 haploinsufficiency cannot be compensated and raising the question of the function of SOX11 in human neurodevelopment. Here, we describe the generation of SOX11+/- heterozygous human embryonic stem cell (hESC) lines by CRISPR/Cas9 genome engineering. SOX11 haploinsufficiency impaired the generation of neurons and resulted in a proliferation/differentiation imbalance of neural precursor cells and enhanced neuronal cell death. Using the SOX11+/- hESC model we provide for the first time experimental evidence that SOX11 haploinsufficiency is sufficient to impair key processes of human neurodevelopment, giving a first insight into the pathophysiology of CSSLS and SOX11 function in human neurodevelopment.
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Affiliation(s)
- Soeren Turan
- Institute of Biochemistry.,Department of Stem Cell Biology
| | | | | | | | - André Reis
- Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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31
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Ciptasari U, van Bokhoven H. The phenomenal epigenome in neurodevelopmental disorders. Hum Mol Genet 2021; 29:R42-R50. [PMID: 32766754 PMCID: PMC7530535 DOI: 10.1093/hmg/ddaa175] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 07/16/2020] [Accepted: 07/30/2020] [Indexed: 12/12/2022] Open
Abstract
Disruption of chromatin structure due to epimutations is a leading genetic etiology of neurodevelopmental disorders, collectively known as chromatinopathies. We show that there is an increasing level of convergence from the high diversity of genes that are affected by mutations to the molecular networks and pathways involving the respective proteins, the disrupted cellular and subcellular processes, and their consequence for higher order cellular network function. This convergence is ultimately reflected by specific phenotypic features shared across the various chromatinopathies. Based on these observations, we propose that the commonly disrupted molecular and cellular anomalies might provide a rational target for the development of symptomatic interventions for defined groups of genetically distinct neurodevelopmental disorders.
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Affiliation(s)
- Ummi Ciptasari
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud university medical center, 6500 HB Nijmegen, The Netherlands
| | - Hans van Bokhoven
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud university medical center, 6500 HB Nijmegen, The Netherlands.,Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud university medical center, 6500 HB Nijmegen, The Netherlands
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32
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Santos-Terra J, Deckmann I, Fontes-Dutra M, Schwingel GB, Bambini-Junior V, Gottfried C. Transcription factors in neurodevelopmental and associated psychiatric disorders: A potential convergence for genetic and environmental risk factors. Int J Dev Neurosci 2021; 81:545-578. [PMID: 34240460 DOI: 10.1002/jdn.10141] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/23/2021] [Accepted: 07/02/2021] [Indexed: 12/16/2022] Open
Abstract
Neurodevelopmental disorders (NDDs) are a heterogeneous and highly prevalent group of psychiatric conditions marked by impairments in the nervous system. Their onset occurs during gestation, and the alterations are observed throughout the postnatal life. Although many genetic and environmental risk factors have been described in this context, the interactions between them challenge the understanding of the pathways associated with NDDs. Transcription factors (TFs)-a group of over 1,600 proteins that can interact with DNA, regulating gene expression through modulation of RNA synthesis-represent a point of convergence for different risk factors. In addition, TFs organize critical processes like angiogenesis, blood-brain barrier formation, myelination, neuronal migration, immune activation, and many others in a time and location-dependent way. In this review, we summarize important TF alterations in NDD and associated disorders, along with specific impairments observed in animal models, and, finally, establish hypotheses to explain how these proteins may be critical mediators in the context of genome-environment interactions.
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Affiliation(s)
- Júlio Santos-Terra
- Translational Research Group in Autism Spectrum Disorders (GETTEA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.,School of Pharmacology and Biomedical Sciences, University of Central Lancashire, Autism Wellbeing And Research Development (AWARD) Institute, BR-UK-CA, Preston, UK
| | - Iohanna Deckmann
- Translational Research Group in Autism Spectrum Disorders (GETTEA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.,School of Pharmacology and Biomedical Sciences, University of Central Lancashire, Autism Wellbeing And Research Development (AWARD) Institute, BR-UK-CA, Preston, UK
| | - Mellanie Fontes-Dutra
- Translational Research Group in Autism Spectrum Disorders (GETTEA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.,School of Pharmacology and Biomedical Sciences, University of Central Lancashire, Autism Wellbeing And Research Development (AWARD) Institute, BR-UK-CA, Preston, UK
| | - Gustavo Brum Schwingel
- Translational Research Group in Autism Spectrum Disorders (GETTEA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.,School of Pharmacology and Biomedical Sciences, University of Central Lancashire, Autism Wellbeing And Research Development (AWARD) Institute, BR-UK-CA, Preston, UK
| | - Victorio Bambini-Junior
- Translational Research Group in Autism Spectrum Disorders (GETTEA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.,School of Pharmacology and Biomedical Sciences, University of Central Lancashire, Autism Wellbeing And Research Development (AWARD) Institute, BR-UK-CA, Preston, UK.,School of Pharmacology and Biomedical Sciences, University of Central Lancashire, Preston, UK
| | - Carmem Gottfried
- Translational Research Group in Autism Spectrum Disorders (GETTEA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.,School of Pharmacology and Biomedical Sciences, University of Central Lancashire, Autism Wellbeing And Research Development (AWARD) Institute, BR-UK-CA, Preston, UK
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Min Z, Qian C, Ying D. Novel ARID1B variant inherited from somatogonadal mosaic mother in siblings with Coffin-Siris syndrome 1. Exp Ther Med 2021; 21:614. [PMID: 33936271 PMCID: PMC8082577 DOI: 10.3892/etm.2021.10046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 04/21/2020] [Indexed: 12/20/2022] Open
Abstract
Coffin-Siris syndrome1 (CSS1; Online Mendelian Inheritance in Man no. 135900) is a multiple malformation syndrome characterized by intellectual and/or developmental delay, and hypoplastic or absent fifth fingernails and/or toenails. AT-rich interaction domain-containing protein 1B (ARID1B) is the most frequently mutated gene in CSS1 and the majority of reported cases have been sporadic. Using whole-exome sequencing, the present study identified two siblings with CSS1 with a novel heterozygous co-segregating pathogenic variant in the ARID1B gene (c.3468_3471del). Additionally, the current study confirmed a 4% somatic ARID1B mosaicism in the patient's mother. The results expanded the spectrum of known ARID1B pathogenic variants. To the best of our knowledge, the present study is the first to provide experimental evidence that an ARID1B pathogenic variant can be inherited from a clinically healthy somatogonadal mosaic mother.
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Affiliation(s)
- Zhong Min
- Department of Neurology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China.,Pediatric Research Institute, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Engineering Research Center of Stem Cell Therapy, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, P.R. China.,National Clinical Research Center for Child Health and Disorders, Chongqing 400014, P.R. China.,Department of Pediatric, Qianjiang Central Hospital of Chongqing, Chongqing 409000, P.R. China
| | - Cheng Qian
- Pediatric Research Institute, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Engineering Research Center of Stem Cell Therapy, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, P.R. China.,National Clinical Research Center for Child Health and Disorders, Chongqing 400014, P.R. China.,Department of Primary Child Health Care, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
| | - Dai Ying
- Pediatric Research Institute, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Engineering Research Center of Stem Cell Therapy, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, P.R. China.,National Clinical Research Center for Child Health and Disorders, Chongqing 400014, P.R. China.,Department of Primary Child Health Care, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
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34
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Maternal transmission of a mild Coffin-Siris syndrome phenotype caused by a SOX11 missense variant. Eur J Hum Genet 2021; 30:126-132. [PMID: 33785884 PMCID: PMC8738766 DOI: 10.1038/s41431-021-00865-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 02/19/2021] [Accepted: 03/10/2021] [Indexed: 11/08/2022] Open
Abstract
Here we report for the first time on the maternal transmission of mild Coffin-Siris syndrome (CSS) caused by a SOX11 missense variant. We present two sisters with intellectual disability and muscular hypotonia born to non-consanguineous parents. Cogan ocular motor apraxia was present in both sisters. Body measurements were in a normal range. The mother and both daughters showed hypoplastic nails of the fifth toes. A missense variant in SOX11 [c.139 G > A; p.(Gly47Ser)] in both sisters and their mother was identified. Since 2014, variants in SOX11 are known to cause mild CSS. Most described patients showed intellectual disability, especially concerning acquired language. All of them had hypoplastic nails of the fifth toes. It is of note, that some of these patients show Cogan ocular motor apraxia. The facial dysmorphic features seem not to be specific. We suggest that the combination of Cogan ocular motor apraxia, hypoplastic nails of fifth toes, and developmental delay give the important diagnostic clue for a variant in the SOX11 gene (OMIM 615866, MR 27).
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35
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Fujita T, Ihara Y, Hayashi H, Ishii A, Ideguchi H, Inoue T, Imaizumi T, Yamamoto T, Hirose S. Coffin-Siris syndrome with bilateral macular dysplasia caused by a novel exonic deletion in ARID1B. Congenit Anom (Kyoto) 2020; 60:189-193. [PMID: 32618029 DOI: 10.1111/cga.12383] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 06/06/2020] [Accepted: 06/27/2020] [Indexed: 12/19/2022]
Abstract
Coffin-Siris syndrome (CSS) is a congenital anomaly syndrome characterized by developmental delay, coarse facial features, and hypoplasia of the fifth digit's nail or phalanges. Herein, we report a case of the 8-year-old female patient who showed developmental delay associated with dysplasia in the macular and large toe area. Comprehensive genomic analysis showed no possible candidate variants, but the subsequent genomic copy number analysis revealed a novel exonic deletion in the coding region of AT-rich interactive domain-containing protein 1B (ARID1B), a gene responsible for CSS. Genomic copy number analysis can aid in diagnosing CSS by confirming undiagnosed exonic deletions in ARID1B. Furthermore, this is the first report of CSS associated with bilateral macular dysplasia.
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Affiliation(s)
- Takako Fujita
- Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan
| | - Yukiko Ihara
- Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan
| | - Hitomi Hayashi
- Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan
| | - Atsushi Ishii
- Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan
| | - Hiroshi Ideguchi
- Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan
| | - Takahito Inoue
- Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan
| | - Taichi Imaizumi
- Department of Pediatrics, School of Medicine, St. Marianna Medical University, Tokyo, Japan
| | - Toshiyuki Yamamoto
- Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan
| | - Shinichi Hirose
- Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan
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36
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Abstract
The Trithorax group (TrxG) of proteins is a large family of epigenetic regulators that form multiprotein complexes to counteract repressive developmental gene expression programmes established by the Polycomb group of proteins and to promote and maintain an active state of gene expression. Recent studies are providing new insights into how two crucial families of the TrxG - the COMPASS family of histone H3 lysine 4 methyltransferases and the SWI/SNF family of chromatin remodelling complexes - regulate gene expression and developmental programmes, and how misregulation of their activities through genetic abnormalities leads to pathologies such as developmental disorders and malignancies.
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37
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Mitrakos A, Lazaros L, Pantou A, Mavrou A, Kanavakis E, Tzetis M. Coffin-Siris Syndrome 4-Related Spectrum in a Young Woman Caused by a Heterozygous SMARCA4 Deletion Detected by High-Resolution aCGH. Mol Syndromol 2020; 11:141-145. [PMID: 32903985 DOI: 10.1159/000508563] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 04/26/2020] [Indexed: 11/19/2022] Open
Abstract
Coffin-Siris Syndrome 4 is an autosomal dominant congenital malformation syndrome caused by heterozygous mutations in the SMARCA4 gene with its main features being intellectual disability, developmental delay, behavioral abnormalities, and hypoplastic or absent fifth fingernails and fifth distal phalanges. Here, we report a young woman with developmental delay, moderate intellectual disability, and bilateral sensorineural hearing loss, referred for genetic testing. High-resolution chromosomal microarray analysis identified a 428-kb deletion in chromosome 19 which included the SMARCA4 gene. We conclude that haploinsufficiency of SMARCA4 may be a valid pathophysiological mechanism leading to milder Coffin-Siris syndrome phenotypes.
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Affiliation(s)
- Anastasios Mitrakos
- Genesis Genoma Lab, Genetic Diagnosis, Clinical Genetics & Research, Athens, Greece.,Department of Medical Genetics, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Leandros Lazaros
- Genesis Genoma Lab, Genetic Diagnosis, Clinical Genetics & Research, Athens, Greece
| | - Amelia Pantou
- Genesis Genoma Lab, Genetic Diagnosis, Clinical Genetics & Research, Athens, Greece
| | - Ariadni Mavrou
- Genesis Genoma Lab, Genetic Diagnosis, Clinical Genetics & Research, Athens, Greece
| | - Emmanuel Kanavakis
- Genesis Genoma Lab, Genetic Diagnosis, Clinical Genetics & Research, Athens, Greece
| | - Maria Tzetis
- Department of Medical Genetics, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Sato A, Suzuki T, Ikeno M, Takeda J, Yamamoto Y, Shinohara M, Makino S, Takeda S, Shimizu T, Itakura A. Pure 9p duplication syndrome with aplasia of the middle phalanges of the fifth fingers. Eur J Med Genet 2020; 63:104005. [PMID: 32693209 DOI: 10.1016/j.ejmg.2020.104005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 06/12/2020] [Accepted: 07/07/2020] [Indexed: 11/29/2022]
Abstract
9p duplication syndrome is a common congenital anomaly syndrome with specific facial features, mental and developmental retardations, and characteristic fingers. Pure 9p duplication without other chromosomal structural variations is very rare. It has recently been reported that cases with partial 9p duplication including SMARCA2 have phenotypes overlapping with Coffin-Siris syndrome (CSS). Herein, we present a family with pure 9p duplication syndrome in which phenotypes partially characteristic of CSS were identified. In one of two siblings, X-ray examination revealed hypoplasia of the distal phalanges of the fifth fingers, aplasia of the middle phalanges of the fifth fingers, and aplasia of the distal phalanges of the second to fifth toes. In pure 9p duplication together with our one affected case, 9 out of 14 cases (64.3%), excluding cases whose clinical data were unavailable, presented the absence or hypoplasia of the middle phalanges of fingers or toes. Interestingly, there are no reports on CSS with aplasia or hypoplasia of the middle phalanx. Therefore, this family might suggest that the aplasia or hypoplasia of the middle phalanges of the fifth fingers or toes is a distinct finding that can distinguish between pure 9p duplication and CSS.
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Affiliation(s)
- Anna Sato
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Toshifumi Suzuki
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan; Department of Obstetrics and Gynecology, Keiai Hospital, Saitama, Japan.
| | - Mitsuru Ikeno
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Jun Takeda
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yuka Yamamoto
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Mitsuko Shinohara
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Shintaro Makino
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Satoru Takeda
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan; Aiiku Research Institute for Maternal, Child Health and Welfare, Tokyo, Japan
| | - Toshiaki Shimizu
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Atsuo Itakura
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
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Bellad A, Bandari AK, Pandey A, Girimaji SC, Muthusamy B. A Novel Missense Variant in PHF6 Gene Causing Börjeson-Forssman-Lehman Syndrome. J Mol Neurosci 2020; 70:1403-1409. [PMID: 32399860 DOI: 10.1007/s12031-020-01560-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 04/22/2020] [Indexed: 12/27/2022]
Abstract
Börjeson-Forssman-Lehman Syndrome (BFLS) is a rare X-linked recessive syndrome characterized by intellectual disability, developmental delay, obesity, epilepsy, swelling of the subcutaneous tissues of the face, large but not deformed ears, hypogonadism, and gynecomastia. Pathogenic mutations in PHD finger protein 6 (PHF6) have been reported to cause BFLS. In this study, we describe two male siblings with mild intellectual disability, global developmental delay, short stature, microcephaly, and nyctalopia. Whole exome sequencing of the affected siblings and the parents identified a missense variant (c.413C > G) in the PHF6 gene, which leads to alteration of a serine residue at position 138 to cysteine. This mutation is located in a highly conserved region. Sanger sequencing confirmed the segregation of this mutation in the family in an X-linked recessive fashion. Multiple mass spectrometry-based proteomic studies have reported phosphorylation at serine 138 that describes the possible role of serine 138 in signaling. This novel variant in PHF6 gene helped in establishing a diagnosis of BFLS.
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Affiliation(s)
- Anikha Bellad
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India
- Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India
- Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Aravind K Bandari
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India
- Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India
- Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Akhilesh Pandey
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Satish Chandra Girimaji
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
- Department of Child and Adolescent Psychiatry, NIMHANS, Hosur Road, Bangalore, 560029, India.
| | - Babylakshmi Muthusamy
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India.
- Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India.
- Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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van der Vaart A, Godfrey M, Portegijs V, van den Heuvel S. Dose-dependent functions of SWI/SNF BAF in permitting and inhibiting cell proliferation in vivo. SCIENCE ADVANCES 2020; 6:eaay3823. [PMID: 32494730 PMCID: PMC7250657 DOI: 10.1126/sciadv.aay3823] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 03/09/2020] [Indexed: 05/14/2023]
Abstract
SWI/SNF (switch/sucrose nonfermenting) complexes regulate transcription through chromatin remodeling and opposing gene silencing by Polycomb group (PcG) proteins. Genes encoding SWI/SNF components are critical for normal development and frequently mutated in human cancer. We characterized the in vivo contributions of SWI/SNF and PcG complexes to proliferation-differentiation decisions, making use of the reproducible development of the nematode Caenorhabditis elegans. RNA interference, lineage-specific gene knockout, and targeted degradation of SWI/SNF BAF components induced either overproliferation or acute proliferation arrest of precursor cells, depending on residual protein levels. Our data show that a high SWI/SNF BAF dosage is needed to arrest cell division during differentiation and to oppose PcG-mediated repression. In contrast, a low SWI/SNF protein level is necessary to sustain cell proliferation and hyperplasia, even when PcG repression is blocked. These observations show that incomplete inactivation of SWI/SNF components can eliminate a tumor-suppressor activity while maintaining an essential transcription regulatory function.
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Affiliation(s)
| | | | - Vincent Portegijs
- Developmental Biology, Department of Biology, Faculty of Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, Netherlands
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Lin B, Kesserwan C, Quinn EA, Einhaus SL, Wright KD, Azzato EM, Orr BA, Upadhyaya SA. Anaplastic Astrocytoma in a Child With Coffin-Siris Syndrome and a Germline SMARCE1 Mutation: A Case Report. J Pediatr Hematol Oncol 2020; 42:e177-e180. [PMID: 30499906 DOI: 10.1097/mph.0000000000001361] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Coffin-Siris syndrome (CSS) is a rare congenital disorder with variable clinical phenotype consisting of developmental delay and characteristic facial features. It is caused by mutations in the chromatin remodeling switch/sucrose nonfermenting complex. Although SWI/SNF genes are widely implicated in tumorigenesis, only 8 cases of neoplasm have been reported in patients with CSS. We report a case of anaplastic astrocytoma (WHO grade III) in an 18-month-old child with CSS due to a de novo germline missense SMARCE1 mutation. Additional molecular features of the tumor are described as well. The role of missense SMARCE1 mutations in tumor predisposition in children with CSS should be further investigated to better inform genetic counselling.
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Affiliation(s)
- Beryl Lin
- Faculty of Medicine, University of New South Wales, Australia
| | | | - Emily A Quinn
- Department of Human Genetics and Genetic Counseling, Keck Graduate Institute, Claremont, CA
| | | | - Karen D Wright
- Department of Hematology/Oncology, Dana-Farber Cancer and Blood Disorders Center, Boston, MA
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Milone R, Gnazzo M, Stefanutti E, Serafin D, Novelli A. A new missense mutation in DPF2 gene related to Coffin Siris syndrome 7: Description of a mild phenotype expanding DPF2-related clinical spectrum and differential diagnosis among similar syndromes epigenetically determined. Brain Dev 2020; 42:192-198. [PMID: 31706665 DOI: 10.1016/j.braindev.2019.10.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 10/15/2019] [Accepted: 10/21/2019] [Indexed: 10/25/2022]
Abstract
BACKGROUND Coffin-Siris syndrome (CSS) is a neurodevelopmental disorder characterized by somatic dysmorphic features, developmental and speech delay. It is due to mutations in many different genes, belonging to BAF chromatin-remodelling complex. The last gene involved in this complex, recently individuated and related to CSS, was DPF2, although only nine patients have been reported until now. METHOD Here we report on a boy with a history of developmental delay, especially regarding speech and language, and dysmorphic features resembling a syndromic condition. Array-Comparative Genomic Hybridization (CGH) and a custom Next Generation Sequencing (NGS) panel including developmental delay related genes were executed. RESULTS Array-CGH was negative while NGS panel revealed a novel mutation in DPF2 gene. CONCLUSIONS We add the clinical description of another patient with a novel mutation in DPF2, with a mild phenotype, thus trying to contribute to enlarge CSS phenotypic variability. Moreover, we briefly discuss about cohesinopathies and major differential diagnosis among syndromes with phenotypes overlapping to CSS.
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Affiliation(s)
- Roberta Milone
- U.O. Neuropsichiatria Infantile, AULSS 7 Pedemontana Regione Veneto, Distretto 2 Alto Vicentino, Thiene, VI, Italy.
| | - Maria Gnazzo
- Medical Genetics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Elena Stefanutti
- U.O. Neuropsichiatria Infantile, AULSS 7 Pedemontana Regione Veneto, Distretto 2 Alto Vicentino, Thiene, VI, Italy
| | - Dorella Serafin
- U.O. Neuropsichiatria Infantile, AULSS 7 Pedemontana Regione Veneto, Distretto 2 Alto Vicentino, Thiene, VI, Italy
| | - Antonio Novelli
- Medical Genetics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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Reed L, Grady A, Wilson C, Stocks R. SMARCE1-related Coffin-Siris Syndrome: Case report and otolaryngologic manifestations of the syndrome. Int J Pediatr Otorhinolaryngol 2020; 128:109735. [PMID: 31675646 DOI: 10.1016/j.ijporl.2019.109735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 10/14/2019] [Accepted: 10/16/2019] [Indexed: 10/25/2022]
Abstract
Coffin-Siris Syndrome (CSS) is a genetic syndrome associated with multiple congenital anomalies due to mutations in the BAF-complex or SOX gene. Although well characterized overall, the subunits of the BAF-complex or SOX gene affected demonstrate phenotypic differences which are continuing to be defined. Among the variants is the SMARCE1 mutation, the least common identified genotype. This case report presents a pediatric patient with SMARCE1-related CSS, the seventh case reported in the literature. The congenital anomalies are discussed and compared to the reported cases of SMARCE1-related CSS and CSS overall with an emphasis on otolaryngologic manifestations.
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Affiliation(s)
- Leighton Reed
- University of Tennessee Health Science Center, Department of Otolaryngology, Head & Neck Surgery, 910 Madison Avenue, Suite 420, Memphis, TN, 38163, United States.
| | - Anthony Grady
- University of Tennessee Health Science Center, Department of Otolaryngology, Head & Neck Surgery, 910 Madison Avenue, Suite 420, Memphis, TN, 38163, United States
| | - Caleb Wilson
- University of Tennessee Health Science Center, Department of Otolaryngology, Head & Neck Surgery, 910 Madison Avenue, Suite 420, Memphis, TN, 38163, United States
| | - Rosemary Stocks
- University of Tennessee Health Science Center, Department of Otolaryngology, Head & Neck Surgery, 910 Madison Avenue, Suite 420, Memphis, TN, 38163, United States
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Valencia AM, Collings CK, Dao HT, St Pierre R, Cheng YC, Huang J, Sun ZY, Seo HS, Mashtalir N, Comstock DE, Bolonduro O, Vangos NE, Yeoh ZC, Dornon MK, Hermawan C, Barrett L, Dhe-Paganon S, Woolf CJ, Muir TW, Kadoch C. Recurrent SMARCB1 Mutations Reveal a Nucleosome Acidic Patch Interaction Site That Potentiates mSWI/SNF Complex Chromatin Remodeling. Cell 2019; 179:1342-1356.e23. [PMID: 31759698 PMCID: PMC7175411 DOI: 10.1016/j.cell.2019.10.044] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 09/02/2019] [Accepted: 10/30/2019] [Indexed: 12/21/2022]
Abstract
Mammalian switch/sucrose non-fermentable (mSWI/SNF) complexes are multi-component machines that remodel chromatin architecture. Dissection of the subunit- and domain-specific contributions to complex activities is needed to advance mechanistic understanding. Here, we examine the molecular, structural, and genome-wide regulatory consequences of recurrent, single-residue mutations in the putative coiled-coil C-terminal domain (CTD) of the SMARCB1 (BAF47) subunit, which cause the intellectual disability disorder Coffin-Siris syndrome (CSS), and are recurrently found in cancers. We find that the SMARCB1 CTD contains a basic α helix that binds directly to the nucleosome acidic patch and that all CSS-associated mutations disrupt this binding. Furthermore, these mutations abrogate mSWI/SNF-mediated nucleosome remodeling activity and enhancer DNA accessibility without changes in genome-wide complex localization. Finally, heterozygous CSS-associated SMARCB1 mutations result in dominant gene regulatory and morphologic changes during iPSC-neuronal differentiation. These studies unmask an evolutionarily conserved structural role for the SMARCB1 CTD that is perturbed in human disease.
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Affiliation(s)
- Alfredo M Valencia
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Chemical Biology Program, Harvard University, Cambridge, MA 02138, USA
| | - Clayton K Collings
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Hai T Dao
- Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
| | - Roodolph St Pierre
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Chemical Biology Program, Harvard University, Cambridge, MA 02138, USA
| | - Yung-Chih Cheng
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Junwei Huang
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Zhen-Yu Sun
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Hyuk-Soo Seo
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Nazar Mashtalir
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Dawn E Comstock
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Olubusayo Bolonduro
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Nicholas E Vangos
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Zoe C Yeoh
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Mary Kate Dornon
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Crystal Hermawan
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Lee Barrett
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Sirano Dhe-Paganon
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Clifford J Woolf
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Tom W Muir
- Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
| | - Cigall Kadoch
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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Jancewicz I, Siedlecki JA, Sarnowski TJ, Sarnowska E. BRM: the core ATPase subunit of SWI/SNF chromatin-remodelling complex-a tumour suppressor or tumour-promoting factor? Epigenetics Chromatin 2019; 12:68. [PMID: 31722744 PMCID: PMC6852734 DOI: 10.1186/s13072-019-0315-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 10/31/2019] [Indexed: 02/07/2023] Open
Abstract
BRM (BRAHMA) is a core, SWI2/SNF2-type ATPase subunit of SWI/SNF chromatin-remodelling complex (CRC) involved in various important regulatory processes including development. Mutations in SMARCA2, a BRM-encoding gene as well as overexpression or epigenetic silencing were found in various human diseases including cancer. Missense mutations in SMARCA2 gene were recently connected with occurrence of Nicolaides-Baraitser genetics syndrome. By contrast, SMARCA2 duplication rather than mutations is characteristic for Coffin-Siris syndrome. It is believed that BRM usually acts as a tumour suppressor or a tumour susceptibility gene. However, other studies provided evidence that BRM function may differ depending on the cancer type and the disease stage, where BRM may play a role in the disease progression. The existence of alternative splicing forms of SMARCA2 gene, leading to appearance of truncated functional, loss of function or gain-of-function forms of BRM protein suggest a far more complicated mode of BRM-containing SWI/SNF CRCs actions. Therefore, the summary of recent knowledge regarding BRM alteration in various types of cancer and highlighting of differences and commonalities between BRM and BRG1, another SWI2/SNF2 type ATPase, will lead to better understanding of SWI/SNF CRCs function in cancer development/progression. BRM has been recently proposed as an attractive target for various anticancer therapies including the use of small molecule inhibitors, synthetic lethality induction or proteolysis-targeting chimera (PROTAC). However, such attempts have some limitations and may lead to severe side effects given the homology of BRM ATPase domain to other ATPases, as well as due to the tissue-specific appearance of BRM- and BRG1-containing SWI/SNF CRC classes. Thus, a better insight into BRM-containing SWI/SNF CRCs function in human tissues and cancers is clearly required to provide a solid basis for establishment of new safe anticancer therapies.
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Affiliation(s)
- Iga Jancewicz
- Department of Molecular and Translational Oncology, The Maria Sklodowska-Curie Institute-Oncology Center in Warsaw, Wawelska 15B, 02-034, Warsaw, Poland
| | - Janusz A Siedlecki
- Department of Molecular and Translational Oncology, The Maria Sklodowska-Curie Institute-Oncology Center in Warsaw, Wawelska 15B, 02-034, Warsaw, Poland
| | - Tomasz J Sarnowski
- Institute of Biochemistry and Biophysics Polish Academy of Sciences, Pawinskiego 5A, 02-106, Warsaw, Poland.
| | - Elzbieta Sarnowska
- Department of Molecular and Translational Oncology, The Maria Sklodowska-Curie Institute-Oncology Center in Warsaw, Wawelska 15B, 02-034, Warsaw, Poland.
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Chabanon RM, Morel D, Postel-Vinay S. Exploiting epigenetic vulnerabilities in solid tumors: Novel therapeutic opportunities in the treatment of SWI/SNF-defective cancers. Semin Cancer Biol 2019; 61:180-198. [PMID: 31568814 DOI: 10.1016/j.semcancer.2019.09.018] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 09/23/2019] [Accepted: 09/24/2019] [Indexed: 12/12/2022]
Abstract
Mammalian switch/sucrose non-fermentable (mSWI/SNF) family complexes are pivotal elements of the chromatin remodeling machinery, which contribute to the regulation of several major cellular functions. Large-scale exome-wide sequencing studies have identified mutations in genes encoding mSWI/SNF subunits in 20% of all human cancers, establishing mSWI/SNF deficiency as a recurrent oncogenic alteration. Accumulating evidence now supports that several mSWI/SNF defects represent targetable vulnerabilities in cancer; notably, recent research advances have unveiled unexpected synthetic lethal opportunities that foster the development of novel biomarker-driven and mechanism-based therapeutic approaches for the treatment of mSWI/SNF-deficient tumors. Here, we review the latest breakthroughs and discoveries that inform our understanding of the mSWI/SNF complexes biology in carcinogenesis, and discuss the most promising therapeutic strategies to target mSWI/SNF defects in human solid malignancies.
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Affiliation(s)
- Roman M Chabanon
- Université Paris Saclay, Université Paris-Sud, Faculté de médicine, Le Kremlin Bicêtre, France; ATIP-Avenir Group, Inserm Unit U981, Gustave Roussy, Villejuif, France; The Breast Cancer Now Toby Robins Breast Cancer Research Centre, France; CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom
| | - Daphné Morel
- Université Paris Saclay, Université Paris-Sud, Faculté de médicine, Le Kremlin Bicêtre, France; ATIP-Avenir Group, Inserm Unit U981, Gustave Roussy, Villejuif, France
| | - Sophie Postel-Vinay
- Université Paris Saclay, Université Paris-Sud, Faculté de médicine, Le Kremlin Bicêtre, France; ATIP-Avenir Group, Inserm Unit U981, Gustave Roussy, Villejuif, France; DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), Gustave Roussy, Villejuif, France.
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Knapp KM, Poke G, Jenkins D, Truter W, Bicknell LS. Expanding the phenotypic spectrum associated with DPF2: A new case report. Am J Med Genet A 2019; 179:1637-1641. [PMID: 31207137 DOI: 10.1002/ajmg.a.61262] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 03/26/2019] [Accepted: 06/01/2019] [Indexed: 11/07/2022]
Abstract
Coffin-Siris syndrome (CSS) is a clinically and genetically heterogeneous developmental disorder, linked to disruption of the BAF chromatin-remodeling complex. Recently, de novo missense and truncating variants have been reported in DPF2 in patients sharing some of the common features of CSS. Here we report a further individual harboring a novel de novo missense DPF2 variant, c.1066T>G, p.Cys356Gly. Structural modeling indicated that the predicted amino acid substitution affects a core residue required for zinc ion coordination and would likely alter the PHD2 domain structure of DPF2. The clinical presentation of Pierre Robin sequence and diaphragmatic hernia did not immediately suggest CSS, with the more common CSS features of hypoplastic toenails and characteristic facial features very subtle. This individual further broadens the phenotypic features of DPF2-related CSS, as well as CSS more generally.
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Affiliation(s)
- Karen M Knapp
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Gemma Poke
- Genetic Health Service New Zealand, Wellington, New Zealand
| | - Danielle Jenkins
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Werner Truter
- Department of Child Health, MidCentral District Health Board, Palmerston North, New Zealand
| | - Louise S Bicknell
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
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48
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Altun D, Demir G, Ayhan A, Türköz A. Successful anesthetic and airway management in Coffin-Siris syndrome with congenital heart disease: Case report. EGYPTIAN JOURNAL OF ANAESTHESIA 2019. [DOI: 10.1016/j.egja.2016.08.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Affiliation(s)
- Dilek Altun
- Baskent University, Istanbul Training and Research Center, Anesthesiology and Reanimation (Cardiovascular Intensive Care Unit), Turkey
| | - Güray Demir
- Bakirkoy Dr. Sadi Konuk Training & Research Hospital, Anesthesiology and Reanimation, Turkey
| | - Asude Ayhan
- Baskent University, Ankara Training and Reasearch Center, Anesthesiology and Reanimation, Turkey
| | - Ayda Türköz
- Baskent University, Istanbul Training and Reasearch Center, Anesthesiology and Reanimation, Turkey
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Bell S, Rousseau J, Peng H, Aouabed Z, Priam P, Theroux JF, Jefri M, Tanti A, Wu H, Kolobova I, Silviera H, Manzano-Vargas K, Ehresmann S, Hamdan FF, Hettige N, Zhang X, Antonyan L, Nassif C, Ghaloul-Gonzalez L, Sebastian J, Vockley J, Begtrup AG, Wentzensen IM, Crunk A, Nicholls RD, Herman KC, Deignan JL, Al-Hertani W, Efthymiou S, Salpietro V, Miyake N, Makita Y, Matsumoto N, Østern R, Houge G, Hafström M, Fassi E, Houlden H, Klein Wassink-Ruiter JS, Nelson D, Goldstein A, Dabir T, van Gils J, Bourgeron T, Delorme R, Cooper GM, Martinez JE, Finnila CR, Carmant L, Lortie A, Oegema R, van Gassen K, Mehta SG, Huhle D, Abou Jamra R, Martin S, Brunner HG, Lindhout D, Au M, Graham JM, Coubes C, Turecki G, Gravel S, Mechawar N, Rossignol E, Michaud JL, Lessard J, Ernst C, Campeau PM. Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons. Am J Hum Genet 2019; 104:815-834. [PMID: 31031012 PMCID: PMC6507050 DOI: 10.1016/j.ajhg.2019.03.022] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 03/01/2019] [Indexed: 02/04/2023] Open
Abstract
We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.
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Affiliation(s)
- Scott Bell
- Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada
| | - Justine Rousseau
- CHU-Sainte Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada
| | - Huashan Peng
- Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada
| | - Zahia Aouabed
- Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada
| | - Pierre Priam
- Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Jean-Francois Theroux
- Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada
| | - Malvin Jefri
- Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada
| | - Arnaud Tanti
- Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada
| | - Hanrong Wu
- Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada
| | - Ilaria Kolobova
- Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada
| | - Heika Silviera
- Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada
| | - Karla Manzano-Vargas
- Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada
| | - Sophie Ehresmann
- CHU-Sainte Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada
| | - Fadi F Hamdan
- CHU-Sainte Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada
| | - Nuwan Hettige
- Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada
| | - Xin Zhang
- Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada
| | - Lilit Antonyan
- Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada
| | - Christina Nassif
- CHU-Sainte Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada
| | - Lina Ghaloul-Gonzalez
- Department of Pediatrics, Division of Medical Genetics, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
| | - Jessica Sebastian
- Department of Pediatrics, Division of Medical Genetics, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
| | - Jerry Vockley
- Department of Pediatrics, Division of Medical Genetics, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
| | | | | | | | - Robert D Nicholls
- Department of Pediatrics, Division of Medical Genetics, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
| | - Kristin C Herman
- University of California at Davis Medical Center, Section of Medical Genomics, Sacramento, CA 95817, USA
| | - Joshua L Deignan
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Walla Al-Hertani
- Departments of Medical Genetics and Paediatrics, Cumming School of Medicine, Alberta Children's Hospital and University of Calgary, Calgary, AB T3B 6A8, Canada
| | - Stephanie Efthymiou
- Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, WC1N 3BG London, UK
| | - Vincenzo Salpietro
- Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, WC1N 3BG London, UK
| | - Noriko Miyake
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Yoshio Makita
- Education Center, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Naomichi Matsumoto
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Rune Østern
- Department of Pediatrics, St. Olav's Hospital, Trondheim University Hospital, Postbox 3250, Sluppen 7006 Trondheim, Norway
| | - Gunnar Houge
- Department of Medical Genetics, Haukeland University Hospital, 5021 Bergen, Norway
| | - Maria Hafström
- Department of Pediatrics, St. Olav's Hospital, Trondheim University Hospital, Postbox 3250, Sluppen 7006 Trondheim, Norway
| | - Emily Fassi
- Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Henry Houlden
- Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, WC1N 3BG London, UK
| | - Jolien S Klein Wassink-Ruiter
- Department of Genetics, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, the Netherlands
| | - Dominic Nelson
- McGill University, Department of Human Genetics, Montreal, QC H3G 0B1, Canada
| | - Amy Goldstein
- Division of Child Neurology, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Tabib Dabir
- Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, UK
| | - Julien van Gils
- Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, University Paris Diderot, Paris 75015, France
| | - Thomas Bourgeron
- Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, University Paris Diderot, Paris 75015, France
| | - Richard Delorme
- Assistance Publique Hôpitaux de Paris (APHP), Robert Debré Hospital, Child and Adolescent Psychiatry Department, Paris, France
| | - Gregory M Cooper
- HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA
| | | | | | - Lionel Carmant
- Children's Rehabilitation Service, Mobile, AL 36604, USA
| | - Anne Lortie
- Department of Neurology, University of Montreal, Montreal, QC, Canada
| | - Renske Oegema
- Department of Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the Netherlands
| | - Koen van Gassen
- Department of Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the Netherlands
| | - Sarju G Mehta
- Department of Clinical Genetics, Addenbrookes Hospital, Cambridge CB2 0QQ, UK
| | - Dagmar Huhle
- Department of Clinical Genetics, Addenbrookes Hospital, Cambridge CB2 0QQ, UK
| | - Rami Abou Jamra
- Institute of Human Genetics, University Medical Center Leipzig, 04103 Leipzig, Germany
| | - Sonja Martin
- Institute of Human Genetics, University Medical Center Leipzig, 04103 Leipzig, Germany
| | - Han G Brunner
- Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen 6500 GA, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands
| | - Dick Lindhout
- Department of Genetics, University Medical Center Utrecht, Utrecht & Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands
| | - Margaret Au
- Medical Genetics, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - John M Graham
- Medical Genetics, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Christine Coubes
- Service de génétique clinique, Département de génétique médicale, Maladies rares et médecine personnalisée, Centre de Référence Anomalies du développement et Syndromes malformatifs du Sud-Ouest Occitanie Réunion, CHU de Montpellier, 34295 Montpellier Cedex 5, France
| | - Gustavo Turecki
- Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada
| | - Simon Gravel
- Department of Genetics, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, the Netherlands
| | - Naguib Mechawar
- Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada
| | - Elsa Rossignol
- CHU-Sainte Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada
| | - Jacques L Michaud
- CHU-Sainte Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada
| | - Julie Lessard
- Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Carl Ernst
- Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada.
| | - Philippe M Campeau
- CHU-Sainte Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada.
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Cappuccio G, Brunetti-Pierri R, Torella A, Pinelli M, Castello R, Casari G, Nigro V, Banfi S, Simonelli F, Brunetti-Pierri N. Retinal dystrophy in an individual carrying a de novo missense variant of SMARCA4. Mol Genet Genomic Med 2019; 7:e682. [PMID: 30973214 PMCID: PMC6565552 DOI: 10.1002/mgg3.682] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 03/14/2019] [Accepted: 03/18/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Coffin-Siris syndrome (CSS) is characterized by intellectual disability, dysmorphic facial features, growth deficiency, microcephaly, and abnormalities of the fifth fingers/toes. CSS is caused by mutations in several genes of the BRG1-associated factor pathway including SMARCA4. METHODS Whole-exome sequencing was performed on a 14-year-old female individual who presented with mild intellectual disability and dysmorphic features, tooth abnormalities, and short stature. She had brachydactyly but no aplasia or hypoplasia of the distal phalanx or nail of the fifth digit. She was also found to have retinal dystrophy that has not been previously reported in CSS. RESULTS The individual presented herein was found to harbor a previously unreported de novo variant in SMARCA4. CONCLUSION This case expands the phenotypic spectrum of CSS manifestations.
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Affiliation(s)
- Gerarda Cappuccio
- Department of Translational Medicine, Federico II University, Naples, Italy.,Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
| | - Raffaella Brunetti-Pierri
- Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Annalaura Torella
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.,Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Michele Pinelli
- Department of Translational Medicine, Federico II University, Naples, Italy.,Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
| | | | - Giorgio Casari
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
| | - Vincenzo Nigro
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.,Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Sandro Banfi
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.,Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Francesca Simonelli
- Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | | | - Nicola Brunetti-Pierri
- Department of Translational Medicine, Federico II University, Naples, Italy.,Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
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