|
1
|
Ukita N, Ogawa T, Yamada M, Takeuchi C, Kosaki K, Moriyama K. Functional Analyses of SATB2 Variants Reveal Pathogenicity Mechanisms Linked With SATB2-Associated Syndrome. Am J Med Genet A 2025; 197:e64005. [PMID: 39887889 DOI: 10.1002/ajmg.a.64005] [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: 10/24/2024] [Revised: 12/16/2024] [Accepted: 01/16/2025] [Indexed: 02/01/2025]
Abstract
SATB2-associated syndrome (SAS) is characterized by intellectual disability, neurodevelopmental disorders, cleft palate, and dental abnormalities. SAS is caused by variants in the special AT-rich sequence-binding protein 2 (SATB2), which encodes a transcription factor containing two CUT domains and a homeobox (HOX) domain. Here, we report the case of a 16-year-old male diagnosed with SAS using exome sequencing and investigate the functional consequences of previously reported SATB2 variants, including those in this case. The patient carried a heterozygous missense variant (c.1147G>C, p.A383P) in SATB2, which was predicted to be pathogenic in silico but was absent from public databases. Immunofluorescence assays demonstrated that SATB2 proteins with variants in the CUT2 domain predominantly localized to the cytoplasm. Functional analysis further revealed that wild-type SATB2 increased the activity of the Msx1 promoter, which is involved in palatogenesis and tooth development, whereas variants in the CUT1 domain disrupted this transcriptional activation. These findings suggest that the nuclear localization signal of SATB2 resides in the CUT2 domain and that Msx1 promoter impairment owing to SATB2 variants may contribute to the pathogenesis of cleft palate and tooth agenesis in SAS. This research highlights a novel pathogenic variant and the functional implications for understanding SAS.
Collapse
Affiliation(s)
- Nao Ukita
- Department of Maxillofacial Orthognathics, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Takuya Ogawa
- Department of Maxillofacial Orthognathics, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Mamiko Yamada
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Chisen Takeuchi
- Department of Clinical Genetics, Jikei University Hospital, Tokyo, Japan
| | - Kenjiro Kosaki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Keiji Moriyama
- Department of Maxillofacial Orthognathics, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| |
Collapse
|
|
2
|
Green CE, Albaba S, Sobey GJ, Bowen JM, Donnelly DE, Colombi M, Ritelli M, Melville A, Ghali N, van Dijk FS, Hobson E, Radley JA, Kinning E, Dixit A, McCullough S, Baker D, Johnson DS. Vascular Ehlers Danlos Syndrome and Chromosome 2q32 Microdeletion Syndrome. Eur J Hum Genet 2025:10.1038/s41431-025-01849-2. [PMID: 40247137 DOI: 10.1038/s41431-025-01849-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 12/19/2024] [Accepted: 03/28/2025] [Indexed: 04/19/2025] Open
Abstract
Interstitial deletions of 2q32 are typically identified after investigation for developmental delay. Two genes associated with Ehlers Danlos Syndrome (EDS); COL3A1 and COL5A2 associated with vascular EDS and classical EDS respectively, may be incorporated in the region. Although many reports of 2q32 microdeletion patients exist, there is little mention of these genes with only a few reports highlighting features potentially linked with EDS. This paper reviews the literature and presents eleven new patients with 2q32 deletions that encompass COL3A1 and COL5A2. We describe their clinical manifestations with a particular focus on the EDS phenotype. Most patients showed some minor features of vascular EDS and one patient had vessel rupture at a young age. Analysis of skin biopsy findings from two patients showed features consistent with vascular EDS but no features of classical EDS. The findings from this cohort provide additional evidence that haploinsufficiency is an important disease mechanism in COL3A1 but not COL5A2. We highlight the importance of pre-test counselling for incidental findings from broad genetic testing and appropriate post-test counselling to ensure follow up is provided to manage the implications of a vascular EDS diagnosis.
Collapse
Affiliation(s)
- Claire E Green
- Ehlers-Danlos Syndrome National Diagnostic Service, Sheffield Children's Hospital, OPD2, Northern General Hospital, Sheffield, UK.
| | - Shadi Albaba
- Sheffield Diagnostic Genetics Service, Sheffield, UK
| | - Glenda J Sobey
- Ehlers-Danlos Syndrome National Diagnostic Service, Sheffield Children's Hospital, OPD2, Northern General Hospital, Sheffield, UK
| | - Jessica M Bowen
- Ehlers-Danlos Syndrome National Diagnostic Service, Sheffield Children's Hospital, OPD2, Northern General Hospital, Sheffield, UK
| | | | - Marina Colombi
- Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Marco Ritelli
- Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Athalie Melville
- Wessex Clinical Genetics Service Level G, Princess Anne Hospital, Southampton, UK
| | - Neeti Ghali
- Ehlers-Danlos Syndrome National Diagnostic Service, North West London Hospitals NHS Trust, Harrow, Middlesex, UK
| | - Fleur S van Dijk
- Ehlers-Danlos Syndrome National Diagnostic Service, North West London Hospitals NHS Trust, Harrow, Middlesex, UK
| | - Emma Hobson
- Department of Clinical Genetics, Chapel Allerton Hospital, Yorkshire Regional Genetics Service, Leeds, UK
| | - Jessica A Radley
- North West Thames Regional Genetics Service, Harrow, Middlesex, UK
| | - Esther Kinning
- West Midlands Clinical Genetics Service, Clinical Genetics Unit, Birmingham Women's Hospital, Edgbaston, Birmingham, UK
| | - Abhijit Dixit
- Nottingham Clinical Genetics Department, The Gables, Nottingham City Hospital, Nottingham, UK
| | - Simon McCullough
- Northern Ireland Regional Genetics Centre, Belfast, Northern Ireland
| | - Duncan Baker
- Sheffield Diagnostic Genetics Service, Sheffield, UK
| | - Diana S Johnson
- Ehlers-Danlos Syndrome National Diagnostic Service, Sheffield Children's Hospital, OPD2, Northern General Hospital, Sheffield, UK.
| |
Collapse
|
|
3
|
Shimojima Yamamoto K, Shimomura R, Shoji H, Yamamoto T. Glass syndrome derived from chromosomal breakage downstream region of SATB2. Brain Dev 2024; 46:281-285. [PMID: 38972777 DOI: 10.1016/j.braindev.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/16/2024] [Accepted: 06/20/2024] [Indexed: 07/09/2024]
Abstract
BACKGROUND Glass syndrome, derived from chromosomal 2q33.1 microdeletions, manifests with intellectual disability, microcephaly, epilepsy, and distinctive features, including micrognathia, down-slanting palpebral fissures, cleft palate, and crowded teeth. Recently, SATB2 located within the deletion region, was identified as the causative gene responsible for Glass syndrome. Numerous disease-causing variants within the SATB2 coding region have been reported. OBJECTIVE Given the presentation of intellectual disability and multiple congenital anomalies in a patient with a de novo reciprocal translocation between chromosomes 1 and 2, disruption of the causative gene(s) was suspected. This study sought to identify the causative gene in the patient. METHODS Long-read whole-genome sequencing was performed, and the expression level of the candidate gene was analyzed. RESULTS The detection of breakpoints was successful. While the breakpoint on chromosome 1 disrupted RNF220, it was not deemed to be a genetic cause. Conversely, SATB2 is located in the approximately 100-kb telomeric region of the breakpoint on chromosome 2. The patient's clinical features resembled those of previously reported cases of Glass syndrome, despite the lack of confirmed reduced SATB2 expression. CONCLUSION The patient was diagnosed with Glass syndrome due to the similarity in clinical features. This led us to hypothesize that disruption in the downstream region of SATB2 could result in Glass syndrome. The microhomologies identified in the breakpoint junctions indicate a potential molecular mechanism involving microhomology-mediated break-induced repair mechanism or template switching.
Collapse
Affiliation(s)
- Keiko Shimojima Yamamoto
- Department of Transfusion Medicine and Cell Processing, Tokyo Women's Medical University, Tokyo, Japan; Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan; Division of Gene Medicine, Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Rina Shimomura
- Division of Gene Medicine, Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan; Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan
| | - Hiromichi Shoji
- Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Toshiyuki Yamamoto
- Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan; Division of Gene Medicine, Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
| |
Collapse
|
|
4
|
Kurosaka H, Yamamoto S, Hirasawa K, Yanagishita T, Fujioka K, Yagasaki H, Nagata M, Ishihara Y, Yonei A, Asano Y, Nagata N, Tsujimoto T, Inubushi T, Yamamoto T, Sakai N, Yamashiro T. Craniofacial and dental characteristics of three Japanese individuals with genetically diagnosed SATB2-associated syndrome. Am J Med Genet A 2023. [PMID: 37141439 DOI: 10.1002/ajmg.a.63225] [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: 10/17/2022] [Revised: 04/12/2023] [Accepted: 04/20/2023] [Indexed: 05/06/2023]
Abstract
Craniofacial defects are one of the most frequent phenotypes in syndromic diseases. More than 30% of syndromic diseases are associated with craniofacial defects, which are important for the precise diagnosis of systemic diseases. Special AT-rich sequence-binding protein 2 (SATB2)-associated syndrome (SAS) is a rare syndromic disease associated with a wide variety of phenotypes, including intellectual disability and craniofacial defects. Among them, dental anomalies are the most frequently observed phenotype and thus becomes an important diagnostic criterion for SAS. In this report, we demonstrate three Japanese cases of genetically diagnosed SAS with detailed craniofacial phenotypes. The cases showed multiple dental problems, which have been previously reported to be linked to SAS, including abnormal crown morphologies and pulp stones. One case showed a characteristic enamel pearl at the root furcation. These phenotypes add new insights for differentiating SAS from other disorders.
Collapse
Affiliation(s)
- Hiroshi Kurosaka
- Department of Orthodontics and Dentofacial Orthopedics, Osaka University Graduate School of Dentistry, Suita, Japan
| | - Sayuri Yamamoto
- Department of Orthodontics and Dentofacial Orthopedics, Osaka University Graduate School of Dentistry, Suita, Japan
| | - Kyoko Hirasawa
- Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan
| | - Tomoe Yanagishita
- Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan
| | - Kaoru Fujioka
- Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Hideaki Yagasaki
- Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Miho Nagata
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yasuki Ishihara
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Ayumi Yonei
- Department of Genetic Counseling Osaka University Hospital, Osaka, Japan
| | - Yoshihiro Asano
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Namiki Nagata
- Department of Orthodontics and Dentofacial Orthopedics, Osaka University Graduate School of Dentistry, Suita, Japan
| | - Takayuki Tsujimoto
- Department of Orthodontics and Dentofacial Orthopedics, Osaka University Graduate School of Dentistry, Suita, Japan
| | - Toshihiro Inubushi
- Department of Orthodontics and Dentofacial Orthopedics, Osaka University Graduate School of Dentistry, Suita, Japan
| | - Toshiyuki Yamamoto
- Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan
| | - Norio Sakai
- Department of Genetic Counseling Osaka University Hospital, Osaka, Japan
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
- Department of Health Science, Child Healthcare and Genetic Science, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takashi Yamashiro
- Department of Orthodontics and Dentofacial Orthopedics, Osaka University Graduate School of Dentistry, Suita, Japan
| |
Collapse
|
|
5
|
Copelli MDM, Pairet E, Atique-Tacla M, Vieira TP, Appenzeller S, Helaers R, Vikkula M, Gil-da-Silva-Lopes VL. SATB2-Associated Syndrome Due to a c.715C>T:p(Arg239*) Variant in Adulthood: Natural History and Literature Review. Genes (Basel) 2023; 14:genes14040882. [PMID: 37107640 PMCID: PMC10137462 DOI: 10.3390/genes14040882] [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: 03/24/2023] [Revised: 04/03/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
SATB2-associated syndrome (SAS) is a rare condition, and it is characterized by severe developmental delay/intellectual disability, especially severe speech delay/or absence, craniofacial abnormalities, and behavioral problems. Most of the published reports are limited to children, with little information about the natural history of the disease and the possible novel signs and symptoms or behavioral changes in adulthood. We describe the management and follow-up of a 25-year-old male with SAS due to a de novo heterozygous nonsense variant SATB2:c.715C>T:p.(Arg239*) identified by whole-exome sequencing and review the literature. The case herein described contributes to a better characterization of the natural history of this genetic condition and in addition to the genotype-phenotype correlation of the SATB2:c.715C>T:p.(Arg239*) variant in SAS, highlights some particularities of its management.
Collapse
Affiliation(s)
- Matheus de Mello Copelli
- Department of Translational Medicine, Area of Medical Genetics and Genomic Medicine, University of Campinas (UNICAMP), Campinas CEP 13083-887, SP, Brazil
| | - Eleonore Pairet
- Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium
| | - Milena Atique-Tacla
- Department of Translational Medicine, Area of Medical Genetics and Genomic Medicine, University of Campinas (UNICAMP), Campinas CEP 13083-887, SP, Brazil
| | - Társis Paiva Vieira
- Department of Translational Medicine, Area of Medical Genetics and Genomic Medicine, University of Campinas (UNICAMP), Campinas CEP 13083-887, SP, Brazil
| | - Simone Appenzeller
- Department of Orthopedics, Rheumatology and Traumatology, School of Medical Science, University of Campinas (UNICAMP), Campinas CEP 13083-887, SP, Brazil
| | - Raphaël Helaers
- Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium
| | - Miikka Vikkula
- Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium
| | - Vera Lúcia Gil-da-Silva-Lopes
- Department of Translational Medicine, Area of Medical Genetics and Genomic Medicine, University of Campinas (UNICAMP), Campinas CEP 13083-887, SP, Brazil
| |
Collapse
|
|
6
|
Li X, Ye X, Su J. The dental phenotype of primary dentition in SATB2-associated syndrome: a report of three cases and literature review. BMC Oral Health 2022; 22:522. [PMID: 36457071 PMCID: PMC9717407 DOI: 10.1186/s12903-022-02594-4] [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: 05/30/2022] [Accepted: 11/13/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND SATB2-associated syndrome (SAS; OMIM: 612,313) is an autosomal dominant inherited multisystemic disorder caused by several variants of the SATB2 gene. SAS is characterized by intellectual disability, developmental delay, severe speech anomalies, craniofacial anomalies, and dental abnormalities. Here, we report the dental phenotype of primary dentition of three Chinese children with SAS. CASE PRESENTATION All three cases with SAS showed intellectual disability, speech and language anomalies, and palate anomalies. For the dental phenotype, all three cases showed macrodontia, crowded dentition, extensive caries, periapical abscesses and fistulas. Radiographs showed the wide-open root apex of deciduous teeth, loss of mandibular second bicuspids, delayed root formation of permanent teeth, rotated teeth, and taurodontism. Sanger sequencing of case 1 showed that there was a heterozygous code shift variation, c1985delT (p.F662Sfs*9) in the SATB2 gene, which has not been reported in literature. Root canal therapy, carious restoration, and teeth extraction were managed promptly, while preventive dental care was given regularly. CONCLUSIONS The dental phenotype of primary dentition in SAS may show macrodontia, crowded dentition, severe caries, wide-open root apex of deciduous teeth, loss of mandibular second bicuspids, delayed root formation of permanent teeth, rotated teeth, and taurodontism. Regular oral hygiene instructions and preventive dental care are both required.
Collapse
Affiliation(s)
- Xiaojing Li
- grid.13402.340000 0004 1759 700XDepartment of Stomatology, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052 Zhejiang China
| | - Xiaowei Ye
- grid.13402.340000 0004 1759 700XDepartment of Stomatology, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052 Zhejiang China
| | - Jimei Su
- grid.13402.340000 0004 1759 700XDepartment of Stomatology, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052 Zhejiang China
| |
Collapse
|
|
7
|
Lin GW, Liang YC, Wu P, Chen CK, Lai YC, Jiang TX, Haung YH, Chuong CM. Regional specific differentiation of integumentary organs: SATB2 is involved in α- and β-keratin gene cluster switching in the chicken. Dev Dyn 2022; 251:1490-1508. [PMID: 34240503 PMCID: PMC8742846 DOI: 10.1002/dvdy.396] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 06/30/2021] [Accepted: 06/30/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Animals develop skin regional specificities to best adapt to their environments. Birds are excellent models in which to study the epigenetic mechanisms that facilitate these adaptions. Patients suffering from SATB2 mutations exhibit multiple defects including ectodermal dysplasia-like changes. The preferential expression of SATB2, a chromatin regulator, in feather-forming compared to scale-forming regions, suggests it functions in regional specification of chicken skin appendages by acting on either differentiation or morphogenesis. RESULTS Retrovirus mediated SATB2 misexpression in developing feathers, beaks, and claws causes epidermal differentiation abnormalities (e.g. knobs, plaques) with few organ morphology alterations. Chicken β-keratins are encoded in 5 sub-clusters (Claw, Feather, Feather-like, Scale, and Keratinocyte) on Chromosome 25 and a large Feather keratin cluster on Chromosome 27. Type I and II α-keratin clusters are located on Chromosomes 27 and 33, respectively. Transcriptome analyses showed these keratins (1) are often tuned up or down collectively as a sub-cluster, and (2) these changes occur in a temporo-spatial specific manner. CONCLUSIONS These results suggest an organizing role of SATB2 in cluster-level gene co-regulation during skin regional specification.
Collapse
Affiliation(s)
- Gee-Way Lin
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan
| | - Ya-Chen Liang
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Integrative Stem Cell Center, China Medical University and Hospital, China Medical University, Taichung 40447, Taiwan
| | - Ping Wu
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Chih-Kuan Chen
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- The IEGG and Animal Biotechnology Center, National Chung Hsing University, Taichung 402204, Taiwan
| | - Yung-Chih Lai
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Integrative Stem Cell Center, China Medical University and Hospital, China Medical University, Taichung 40447, Taiwan
- Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan
| | - Ting-Xin Jiang
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Yen-Hua Haung
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan
- TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Cheng-Ming Chuong
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| |
Collapse
|
|
8
|
Zhu YY, Sun GL, Yang ZL. SATB2-associated syndrome caused by a novel SATB2 mutation in a Chinese boy: A case report and literature review. World J Clin Cases 2021; 9:6081-6090. [PMID: 34368330 PMCID: PMC8316932 DOI: 10.12998/wjcc.v9.i21.6081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/04/2021] [Accepted: 05/18/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Special AT-rich sequence binding protein 2 (SATB2)-associated syndrome (SAS; OMIM 612313) is an autosomal dominant disorder. Alterations in the SATB2 gene have been identified as causative.
CASE SUMMARY We report a case of a 13-year-old Chinese boy with lifelong global developmental delay, speech and language delay, and intellectual disabilities. He had short stature and irregular dentition, but no other abnormal clinical findings. A de novo heterozygous nonsense point mutation was detected by genetic analysis in exon 6 of SATB2, c.687C>A (p.Y229X) (NCBI reference sequence: NM_001172509.2), and neither of his parents had the mutation. This mutation is the first reported and was evaluated as pathogenic according to the guidelines from the American College of Medical Genetics and Genomics. SAS was diagnosed, and special education performed. Our report of a SAS case in China caused by a SATB2 mutation expanded the genotype options for the disease. The heterogeneous manifestations can be induced by complicated pathogenic involvements and functions of SATB2 from reviewed literatures: (1) SATB2 haploinsufficiency; (2) the interference of truncated SATB2 protein to wild-type SATB2; and (3) different numerous genes regulated by SATB2 in brain and skeletal development in different developmental stages.
CONCLUSION Global developmental delays are usually the initial presentations, and the diagnosis was challenging before other presentations occurred. Regular follow-up and genetic analysis can help to diagnose SAS early. Verification for genes affected by SATB2 mutations for heterogeneous manifestations may help to clarify the possible pathogenesis of SAS in the future.
Collapse
Affiliation(s)
- Yan-Yan Zhu
- Department of Pediatrics, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Gui-Lian Sun
- Department of Pediatrics, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Zhi-Liang Yang
- Department of Pediatrics, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| |
Collapse
|
|
9
|
Zarate YA, Bosanko KA, Thomas MA, Miller DT, Cusmano-Ozog K, Martinez-Monseny A, Curry CJ, Graham JM, Velsher L, Bekheirnia MR, Seidel V, Dedousis D, Mitchell AL, DiMarino AM, Riess A, Balasubramanian M, Fish JL, Caffrey AR, Fleischer N, Pierson TM, Lacro RV. Growth, development, and phenotypic spectrum of individuals with deletions of 2q33.1 involving SATB2. Clin Genet 2021; 99:547-557. [PMID: 33381861 DOI: 10.1111/cge.13912] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/18/2020] [Accepted: 12/28/2020] [Indexed: 02/06/2023]
Abstract
SATB2-Associated syndrome (SAS) is an autosomal dominant, multisystemic, neurodevelopmental disorder due to alterations in SATB2 at 2q33.1. A limited number of individuals with 2q33.1 contiguous deletions encompassing SATB2 (ΔSAS) have been described in the literature. We describe 17 additional individuals with ΔSAS, review the phenotype of 33 previously published individuals with 2q33.1 deletions (n = 50, mean age = 8.5 ± 7.8 years), and provide a comprehensive comparison to individuals with other molecular mechanisms that result in SAS (non-ΔSAS). Individuals in the ΔSAS group were often underweight for age (20/41 = 49%) with a progressive decline in weight (95% CI = -2.3 to -1.1, p < 0.0001) and height (95% CI = -2.3 to -1.0, p < 0.0001) Z-score means from birth to last available measurement. ΔSAS individuals were often noted to have a broad spectrum of facial dysmorphism. A composite image of ΔSAS individuals generated by automated image analysis was distinct as compared to matched controls and non-ΔSAS individuals. We also present additional genotype-phenotype correlations for individuals in the ΔSAS group such as an increased risk for aortic root/ascending aorta dilation and primary pulmonary hypertension for those individuals with contiguous gene deletions that include COL3A1/COL5A2 and BMPR2, respectively. Based on these findings, we provide additional care recommendations for individuals with ΔSAS variants.
Collapse
Affiliation(s)
- Yuri A Zarate
- Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Katherine A Bosanko
- Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Mary Ann Thomas
- Departments of Medical Genetics and Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - David T Miller
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Kristina Cusmano-Ozog
- Department of Pathology, Stanford University Medical Center, Stanford, California, USA
| | - Antonio Martinez-Monseny
- Department of Clinical Genetics and Rare Disease Paediatric Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
| | - Cynthia J Curry
- Genetic Medicine, Department of Pediatrics, University of California, San Francisco/Fresno, Fresno, California, USA
| | - John M Graham
- Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Lea Velsher
- Genetics Division, North York General, Toronto, Ontario, Canada
| | - Mir Reza Bekheirnia
- Departments of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Veronica Seidel
- Clinical Genetics, Department of Pediatrics, HGU Gregorio Marañón, Madrid, Spain
| | - Demitrios Dedousis
- Department of Genetics and Genome Sciences, University Hospitals Center for Human Genetics, Cleveland, Ohio, USA
| | - Anna L Mitchell
- Department of Genetics and Genome Sciences, University Hospitals Center for Human Genetics, Cleveland, Ohio, USA
| | - Amy M DiMarino
- Division of Pediatric Pulmonology, UH Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA
| | - Angelika Riess
- Institute of Medical Genetics and Applied Genomics, Medical faculty, University of Tuebingen, Tuebingen, Germany
| | - Meena Balasubramanian
- Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
| | - Jennifer L Fish
- Department of Biological Sciences, University of Massachusetts Lowell, Lowell, Massachusetts, United States
| | - Aisling R Caffrey
- Health Outcomes, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA
| | | | - Tyler Mark Pierson
- Departments of Pediatrics and Neurology, The Board of Governors Regenerative Medicine Institute, Cedars Sinai Medical Center, Los Angeles, California, USA
| | - Ronald V Lacro
- Department of Cardiology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
10
|
Zarate YA, Bosanko KA, Caffrey AR, Bernstein JA, Martin DM, Williams MS, Berry-Kravis EM, Mark PR, Manning MA, Bhambhani V, Vargas M, Seeley AH, Estrada-Veras JI, vanDooren MF, Schwab M, Vanderver A, Melis D, Alsadah A, Sadler L, Van Esch H, Callewaert B, Oostra A, Maclean J, Dentici ML, Orlando V, Lipson M, Sparagana SP, Maarup TJ, Alsters SIM, Brautbar A, Kovitch E, Naidu S, Lees M, Smith DM, Turner L, Raggio V, Spangenberg L, Garcia-Miñaúr S, Roeder ER, Littlejohn RO, Grange D, Pfotenhauer J, Jones MC, Balasubramanian M, Martinez-Monseny A, Blok LS, Gavrilova R, Fish JL. Mutation update for the SATB2 gene. Hum Mutat 2019; 40:1013-1029. [PMID: 31021519 PMCID: PMC11431158 DOI: 10.1002/humu.23771] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 04/10/2019] [Accepted: 04/22/2019] [Indexed: 12/20/2022]
Abstract
SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.
Collapse
Affiliation(s)
- Yuri A. Zarate
- Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Katherine A. Bosanko
- Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Aisling R. Caffrey
- Health Outcomes, College of Pharmacy, Department of Pharmacy Practice, University of Rhode Island, Kingston, Rhode Island
| | - Jonathan A. Bernstein
- Department of Pediatrics, Stanford University School of Medicine, Stanford, California
| | - Donna M. Martin
- Departments of Pediatrics and Human Genetics, The University of Michigan, Ann Arbor, Michigan
| | | | - Elizabeth M. Berry-Kravis
- Departments of Pediatrics, Neurological Sciences, Biochemistry, Rush University Medical Center, Chicago, Illinois
| | - Paul R. Mark
- Division of Medical Genetics, Spectrum Health, Grand Rapids, Michigan
| | - Melanie A. Manning
- Departments of Pathology and Pediatrics, Stanford University School of Medicine, Stanford, California
| | - Vikas Bhambhani
- Division of Genetics and Genomic Medicine, Children's Hospital and Clinics of Minnesota, Minneapolis, Minnesota
| | - Marcelo Vargas
- Division of Genetics and Genomic Medicine, Children's Hospital and Clinics of Minnesota, Minneapolis, Minnesota
| | | | - Juvianee I. Estrada-Veras
- Murtha Cancer Center Research Program, The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, Maryland
- Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland
- Pediatric subspecialty-Medical Genetics Service, Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Marieke F. vanDooren
- Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Maria Schwab
- Genetics Division, Joseph Sanzari Children's Hospital, Hackensack University Medical Center, Hackensack, New Jersey
| | - Adeline Vanderver
- Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Daniela Melis
- Department of Translational Medical Science, Section of Pediatrics, Federico II University, Naples, Italy
| | - Adnan Alsadah
- Center for Personalized Genetic Healthcare, Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio
| | - Laurie Sadler
- Division of Genetics, Oishei Children's Hospital, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, Buffalo, New York
| | - Hilde Van Esch
- Department of Human Genetics, University Hospitals Leuven, KU, Leuven, Belgium
| | - Bert Callewaert
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
| | - Ann Oostra
- Department of Pediatric Neurology, Ghent University Hospital, Ghent, Belgium
| | - Jane Maclean
- Pediatric Neurology, Palo Alto Medical Foundation, San Jose, California
| | - Maria Lisa Dentici
- Medical Genetics, Academic Department of Pediatrics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
| | - Valeria Orlando
- Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Mark Lipson
- Department of Genetics, Kaiser Permanente, Sacramento, California
| | - Steven P. Sparagana
- Department of Neurology, Texas Scottish Rite Hospital for Children, Dallas, Texas
| | | | - Suzanne IM Alsters
- Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Ariel Brautbar
- Department of Genetics, Cook Chldren's Medical Center, Fort Worth, Texas
| | | | - Sakkubai Naidu
- Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland
| | - Melissa Lees
- Department of Clinical Genetics, Great Ormond Street Hospital for Children, London, UK
| | | | - Lesley Turner
- Discipline of Genetics, Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada
| | - Víctor Raggio
- Departamento de Genética, Facultad de Medicina, Montevideo, Uruguay
| | | | - Sixto Garcia-Miñaúr
- Department of Medical Genetics, Hospital Universitario La Paz, Madrid, Spain
| | - Elizabeth R. Roeder
- Department of Pediatrics, Baylor College of Medicine, San Antonio, Texas
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Rebecca O. Littlejohn
- Department of Pediatrics, Baylor College of Medicine, San Antonio, Texas
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Dorothy Grange
- Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medcine, St Louis, Missouri
| | - Jean Pfotenhauer
- Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Marilyn C. Jones
- Division of Genetics, Department of Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, California
| | - Meena Balasubramanian
- Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Western Bank, Sheffield, UK
| | - Antonio Martinez-Monseny
- Genetics and Molecular Medicine Department, Rare Disease Pediatric Unit, Hospital Sant Joan de Déu, Barcelona, Spain
| | - Lot Snijders Blok
- Human Genetics Department, Radboud University Medical Center, Nijmegen, The Netherlands
- Language & Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands
| | - Ralitza Gavrilova
- Departments of Neurology and Clinical Genomics, Mayo Clinic, Rochester, Minnesota
| | - Jennifer L. Fish
- Department of Biological Sciences, University of Massachusetts Lowell, Lowell, Massachusetts
| |
Collapse
|
|
11
|
Qian Y, Liu J, Yang Y, Chen M, Jin C, Chen P, Lei Y, Pan H, Dong M. Paternal Low-Level Mosaicism-Caused SATB2-Associated Syndrome. Front Genet 2019; 10:630. [PMID: 31333717 PMCID: PMC6614923 DOI: 10.3389/fgene.2019.00630] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 06/17/2019] [Indexed: 12/27/2022] Open
Abstract
Mutations of SATB2 (OMIM#608148) gene at 2q33.1 have been associated with the autosomal dominant SATB2-associated syndrome (SAS), which is still short of comprehensive diagnosis technologies for small deletions and low-level mosaicism. In this Chinese Han family, single nucleotide polymorphism array identified a 4.9-kb deletion in the SATB2 gene in two consecutive siblings exhibiting obvious developmental delay and dental abnormalities but failed to find so in their parents. Prenatal diagnosis revealed that their third child carried the same deletion in SATB2 and the pregnancy was terminated. To determine the genetic causes behind the inheritance of SATB2 deletion, gap-PCR was performed on peripheral blood-derived genomic DNA of the family and semen-derived DNA from the father. Gap-PCR that revealed the deletions in the two affected siblings were inherited from the father, while the less intense mutant band indicated the mosaicism of this mutation in the father. The deletion was 3,013 bp in size, spanning from chr2: 200,191,313-200,194,324 (hg19), and covering the entire exon 9 and part of intron 8 and 9 sequences. Droplet digital PCR demonstrated mosaicism percentage of 13.2% and 16.7% in peripheral blood-derived genomic DNA and semen-derived DNA of the father, respectively. Hereby, we describe a family of special AT-rich sequence-binding protein 2-associated syndrome caused by paternal low-level mosaicism and provide effective diagnostic technologies for intragenic deletions.
Collapse
Affiliation(s)
- Yeqing Qian
- Women's Hospital, School of Medicine Zhejiang University, Hangzhou, China.,Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Jiao Liu
- Prenatal Diagnosis Center, Lishui Maternity and Child Health Care Hospital, Lishui, China
| | - Yanmei Yang
- Women's Hospital, School of Medicine Zhejiang University, Hangzhou, China.,Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Min Chen
- Women's Hospital, School of Medicine Zhejiang University, Hangzhou, China.,Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Chunlei Jin
- Prenatal Diagnosis Center, Lishui Maternity and Child Health Care Hospital, Lishui, China
| | - Penglong Chen
- Prenatal Diagnosis Center, Lishui Maternity and Child Health Care Hospital, Lishui, China
| | - Yongliang Lei
- Prenatal Diagnosis Center, Lishui Maternity and Child Health Care Hospital, Lishui, China
| | - Hangyi Pan
- Women's Hospital, School of Medicine Zhejiang University, Hangzhou, China.,Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Minyue Dong
- Women's Hospital, School of Medicine Zhejiang University, Hangzhou, China.,Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, China
| |
Collapse
|
|
12
|
Yamada M, Uehara T, Suzuki H, Takenouchi T, Yoshihashi H, Suzumura H, Mizuno S, Kosaki K. SATB2-associated syndrome in patients from Japan: Linguistic profiles. Am J Med Genet A 2019; 179:896-899. [PMID: 30848049 DOI: 10.1002/ajmg.a.61114] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 11/30/2018] [Accepted: 11/30/2018] [Indexed: 11/06/2022]
Abstract
Cleft palate can be classified as either syndromic or nonsyndromic. SATB2-associated syndrome is one example of a syndromic cleft palate that is accompanied by intellectual disability, and various dental anomalies. SATB2-associated syndrome can be caused by several different molecular mechanisms including intragenic mutations and deletions of SATB2. Here, we report two patients with SATB2 truncating mutations (p.Arg239* and p.Asp702Thrfs*38) and one with a 4.4 megabase deletion including the SATB2 locus. All three patients had cleft palate and other dysmorphic features including macrodontia wide diastema. None of the three patients had acquired any meaningful words at the age of 5 years. In a review of the linguistic natural history of presently reported three patients and 30 previously reported patients, only two patients had attained verbal skills beyond speaking a few words. This degree of delayed speech contrasts with that observed in the prototypic form of syndromic cleft palate, 22q11.2 deletion syndrome. The recognition of SATB2-associated syndrome prior to palatoplasty would be important for plastic surgeons and the families of patients because precise diagnosis should provide predictive information regarding the future linguistic and intellectual abilities of the patients. Macrodontia with a wide diastema and cleft palate is a helpful and highly suggestive sign for the diagnosis of SATB2-associated syndrome.
Collapse
Affiliation(s)
- Mamiko Yamada
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.,Health Center, Keio University, Tokyo, Japan
| | - Tomoko Uehara
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Hisato Suzuki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Toshiki Takenouchi
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
| | - Hiroshi Yoshihashi
- Department of Medical Genetics, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan
| | - Hiroshi Suzumura
- Department of Pediatrics, Dokkyo Medical University, Tochigi, Japan
| | - Seiji Mizuno
- Department of Pediatrics, Central Hospital, Aichi Human Service Center, Kasugai, Japan
| | - Kenjiro Kosaki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
13
|
Scott J, Adams C, Beetstra S, Zarate YA. SATB2-associated syndrome (SAS) and associated dental findings. SPECIAL CARE IN DENTISTRY 2019; 39:220-224. [PMID: 30648748 DOI: 10.1111/scd.12340] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 10/24/2018] [Accepted: 10/26/2018] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Identify, diagnose, and document oral clinical and radiographic evidence associated with the genetic condition known as special AT-rich sequence-binding protein 2 (SATB2)-associated syndrome. Through identifying and publishing these common dental and behavioral findings, we hope to educate oral and medical healthcare providers to identify this condition in an attempt to develop meaningful comprehensive care to this patient population. METHODS A total of 37 patients (19 female), ranging from ages 2 to 20 were evaluated at Arkansas Children's Hospital in Little Rock, Arkansas. Patient geographic distribution included: the United States, Canada, Portugal, Spain, and the Netherlands. Patients were clinically and radiographically examined for oral findings. Panoramic radiographs were obtained when patient's behavior allowed. Patient's parents or guardians were also interviewed concerning dental, medical, and behavioral histories. RESULTS Clinical findings included delayed tooth eruption, bruxism, sialorrhea, larger than normal teeth with an increased propensity for maxillary anterior tooth trauma due to unsteady ambulation. Radiographic findings included delayed permanent root formation, significantly delayed or missing second bicuspids, malformed teeth, and taurodontism. Medical and behavioral issues included: insomnia, hyperphagia, cognitive delays, and an extremely high pain threshold. CONCLUSION Patients with SATB2-associated syndrome have shown to have a consistent and unique set of dental findings both clinically and radiographically. A thorough health and dental history along with the aforementioned results of the study may facilitate a diagnosis of this syndrome. Due to the complexity of the patient's dental needs and behavior, a health practitioner with special needs care experience on a comprehensive craniofacial team would be optimal.
Collapse
Affiliation(s)
- John Scott
- Arkansas Children's Hospital, Little Rock, Arkansas, USA
| | - Chad Adams
- Arkansas Children's Hospital, Little Rock, Arkansas, USA
| | | | - Yuri A Zarate
- Arkansas Children's Hospital, Little Rock, Arkansas, USA
| |
Collapse
|
|
14
|
Kikuiri T, Mishima H, Imura H, Suzuki S, Matsuzawa Y, Nakamura T, Fukumoto S, Yoshimura Y, Watanabe S, Kinoshita A, Yamada T, Shindoh M, Sugita Y, Maeda H, Yawaka Y, Mikoya T, Natsume N, Yoshiura KI. Patients with SATB2-associated syndrome exhibiting multiple odontomas. Am J Med Genet A 2018; 176:2614-2622. [PMID: 30575289 DOI: 10.1002/ajmg.a.40670] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 09/28/2018] [Accepted: 10/02/2018] [Indexed: 01/09/2023]
Abstract
Special AT-rich sequence-binding protein 2 (SATB2)-associated syndrome (SAS) is characterized by alterations of SATB2. Its clinical features include intellectual disability and craniofacial abnormalities, such as cleft palate, dysmorphic features, and dental abnormalities. Here, we describe three previously undiagnosed, unrelated patients with SAS who exhibited dental abnormalities, including multiple odontomas. Although isolated odontomas are common, multiple odontomas are rare. Individuals in families 1 and 3 underwent whole-exome sequencing. Patient 2 and parents underwent targeted amplicon sequencing. On the basis of the hg19/GRCh37 reference and the RefSeq mRNA NM_001172517, respective heterozygous mutations were found and validated in Patients 1, 2, and 3: a splice-site mutation (chr2:g.200137396C > T, c.1741-1G > A), a nonsense mutation (chr2:g.200213750G > A, c.847C > T, p.R283*), and a frame-shift mutations (chr2:g.200188589_200188590del, c.1478_1479del, p.Q493Rfs*19). All mutations occurred de novo. The mutations in Patients 1 and 3 were novel; the mutation in Patient 2 has been described previously. Tooth mesenchymal cells derived from Patient 2 showed diminished SATB2 expression. Multiple odontomas were evident in the patients in this report; however, this has not been recognized previously as a SAS-associated phenotype. We propose that multiple odontomas be considered as an occasional manifestation of SAS.
Collapse
Affiliation(s)
- Takashi Kikuiri
- Department of Dentistry for Children and Disabled Persons, Hokkaido University Graduate School of Dental Medicine, Sapporo, Hokkaido, Japan
| | - Hiroyuki Mishima
- Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hideto Imura
- Division of Research and Treatment for Oral and Maxillofacial Congenital Anomalies, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Satoshi Suzuki
- Division of Research and Treatment for Oral and Maxillofacial Congenital Anomalies, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Yusuke Matsuzawa
- Department of Oral and Maxillofacial Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan
| | - Takashi Nakamura
- Division of Molecular Pharmacology & Cell Biophysics, Department of Oral Biology, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Satoshi Fukumoto
- Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Yoshitaka Yoshimura
- Department of Molecular Cell Pharmacology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan
| | - Satoshi Watanabe
- Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Akira Kinoshita
- Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takahiro Yamada
- Clinical Genetics Unit, Kyoto University Hospital, Kyoto, Japan
| | - Masanobu Shindoh
- Department of Oral Pathology and Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.,Tenshi College School of Nursing and Nutrition, Sapporo, Japan
| | - Yoshihiko Sugita
- Department of Oral Pathology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Hatsuhiko Maeda
- Department of Oral Pathology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Yasutaka Yawaka
- Department of Dentistry for Children and Disabled Persons, Hokkaido University Graduate School of Dental Medicine, Sapporo, Hokkaido, Japan
| | - Tadashi Mikoya
- Center for Advanced Oral Medicine, Hokkaido University Hospital, Sapporo, Japan
| | - Nagato Natsume
- Division of Research and Treatment for Oral and Maxillofacial Congenital Anomalies, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
| | - Koh-Ichiro Yoshiura
- Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| |
Collapse
|
|
15
|
Zarate YA, Smith-Hicks CL, Greene C, Abbott MA, Siu VM, Calhoun ARUL, Pandya A, Li C, Sellars EA, Kaylor J, Bosanko K, Kalsner L, Basinger A, Slavotinek AM, Perry H, Saenz M, Szybowska M, Wilson LC, Kumar A, Brain C, Balasubramanian M, Dubbs H, Ortiz-Gonzalez XR, Zackai E, Stein Q, Powell CM, Schrier Vergano S, Britt A, Sun A, Smith W, Bebin EM, Picker J, Kirby A, Pinz H, Bombei H, Mahida S, Cohen JS, Fatemi A, Vernon HJ, McClellan R, Fleming LR, Knyszek B, Steinraths M, Velasco Gonzalez C, Beck AE, Golden-Grant KL, Egense A, Parikh A, Raimondi C, Angle B, Allen W, Schott S, Algrabli A, Robin NH, Ray JW, Everman DB, Gambello MJ, Chung WK. Natural history and genotype-phenotype correlations in 72 individuals with SATB2-associated syndrome. Am J Med Genet A 2018; 176:925-935. [PMID: 29436146 DOI: 10.1002/ajmg.a.38630] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 01/16/2018] [Indexed: 11/07/2022]
Abstract
SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.
Collapse
Affiliation(s)
- Yuri A Zarate
- Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Constance L Smith-Hicks
- Division of Neurogenetics, Department of Neurology, Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Carol Greene
- Department of Pediatrics, University of Maryland Baltimore, Baltimore, Maryland
| | - Mary-Alice Abbott
- Department of Pediatrics, Baystate Medical Center, Springfield, Massachusetts
| | - Victoria M Siu
- Division of Medical Genetics, Department of Pediatrics, University of Western Ontario, London, Ontario, Canada
| | - Amy R U L Calhoun
- Division of Medical Genetics, Department of Pediatrics, University of Iowa, Iowa City, Iowa
| | - Arti Pandya
- Department of Pediatrics, Division of Genetics and Metabolism, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Chumei Li
- Clinical Genetics Program, McMaster University Medical Center, Hamilton, Ontario, Canada
| | - Elizabeth A Sellars
- Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | | | - Katherine Bosanko
- Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Louisa Kalsner
- Departments of Neurology and Pediatrics, Connecticut Children's Medical Center and University of Connecticut Health Center, Farmington, Connecticut
| | | | - Anne M Slavotinek
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California
| | - Hazel Perry
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California
| | | | - Marta Szybowska
- Clinical Genetics Program, McMaster University Medical Center, Hamilton, Ontario, Canada
| | - Louise C Wilson
- Department of Genetics, Great Ormond Street for Children NHS Foundation Trust, London, UK
| | - Ajith Kumar
- Department of Genetics, Great Ormond Street for Children NHS Foundation Trust, London, UK
| | - Caroline Brain
- Department of Endocrinology, Great Ormond Street for Children NHS Foundation Trust, London, UK
| | - Meena Balasubramanian
- Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
| | - Holly Dubbs
- Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | | | - Elaine Zackai
- Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Quinn Stein
- Divisions of Pediatric Neurology and Genetics, Sanford Children's Specialty Clinic, Sanford Children's Hospital, Sioux Falls, South Dakota
| | - Cynthia M Powell
- Department of Pediatrics, Division of Genetics and Metabolism, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Samantha Schrier Vergano
- Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, Virginia
| | - Allison Britt
- Division of Medical Genetics, Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas
| | - Angela Sun
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.,Seattle Children's Hospital, Seattle, Washington
| | - Wendy Smith
- Department of Pediatrics, The Barbara Bush Children's Hospital, Maine Medical Center, Portland, Maine
| | - E Martina Bebin
- Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama
| | | | - Amelia Kirby
- Division of Medical Genetics, SSM Health Cardinal Glennon Children's Hospital, Saint Louis, Missouri
| | - Hailey Pinz
- Division of Medical Genetics, SSM Health Cardinal Glennon Children's Hospital, Saint Louis, Missouri
| | - Hannah Bombei
- Division of Medical Genetics, Department of Pediatrics, University of Iowa, Iowa City, Iowa
| | - Sonal Mahida
- Division of Neurogenetics, Department of Neurology, Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Julie S Cohen
- Division of Neurogenetics, Department of Neurology, Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ali Fatemi
- Division of Neurogenetics, Department of Neurology, Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Hilary J Vernon
- Division of Neurogenetics, Department of Neurology, Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Rebecca McClellan
- Division of Neurogenetics, Department of Neurology, Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Leah R Fleming
- Clinical Genetics and Genomics, St. Luke's Children's Hospital, Boise, Idaho
| | - Brittney Knyszek
- Clinical Genetics and Genomics, St. Luke's Children's Hospital, Boise, Idaho
| | - Michelle Steinraths
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Cruz Velasco Gonzalez
- Biostatistics Program, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Anita E Beck
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.,Seattle Children's Hospital, Seattle, Washington
| | | | - Alena Egense
- Department of Pediatrics, University of Maryland Baltimore, Baltimore, Maryland
| | - Aditi Parikh
- University of Toledo Department of Pediatrics, Toledo, Ohio.,University Hospitals Cleveland Medical Center, Cleveland, Ohio.,Department of Genetics and Genome Sciences Case Western Reserve University School of Medicine, Cleveland, Ohio
| | | | - Brad Angle
- Advocate Children's Hospital, Park Ridge, Illinois
| | - William Allen
- Fullerton Genetics Center, Asheville, North Carolina
| | | | | | | | - Joseph W Ray
- Division of Medical Genetics, Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas
| | | | | | - Wendy K Chung
- Department of Pediatrics and Medicine, Columbia University, New York, New York
| |
Collapse
|
|
16
|
Gao K, Zhang Y, Zhang L, Kong W, Xie H, Wang J, Wu Y, Wu X, Liu X, Zhang Y, Zhang F, Yu ACH, Jiang Y. Large De Novo Microdeletion in Epilepsy with Intellectual and Developmental Disabilities, with a Systems Biology Analysis. ADVANCES IN NEUROBIOLOGY 2018; 21:247-266. [DOI: 10.1007/978-3-319-94593-4_9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
|
|
17
|
Zarate YA, Fish JL. SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations. Am J Med Genet A 2016; 173:327-337. [PMID: 27774744 PMCID: PMC5297989 DOI: 10.1002/ajmg.a.38022] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 09/29/2016] [Indexed: 12/11/2022]
Abstract
The SATB2‐associated syndrome is a recently described syndrome characterized by developmental delay/intellectual disability with absent or limited speech development, craniofacial abnormalities, behavioral problems, dysmorphic features, and palatal and dental abnormalities. Alterations of the SATB2 gene can result from a variety of different mechanisms that include contiguous deletions, intragenic deletions and duplications, translocations with secondary gene disruption, and point mutations. The multisystemic nature of this syndrome demands a multisystemic approach and we propose evaluation and management guidelines. The SATB2‐associated syndrome registry has now been started and that will allow gathering further clinical information and refining the provided surveillance recommendations. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Yuri A Zarate
- Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Jennifer L Fish
- Department of Biological Sciences, University of Massachusetts Lowell, Lowell, Massachusetts
| |
Collapse
|
|
18
|
Yoon AJ, Pham BN, Dipple KM. Genetic Screening in Patients with Craniofacial Malformations. J Pediatr Genet 2016; 5:220-224. [PMID: 27895974 DOI: 10.1055/s-0036-1592423] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 02/14/2016] [Indexed: 01/28/2023]
Abstract
Craniofacial malformations include a variety of anomalies, including cleft lip with or without cleft palate, craniosynostosis, microtia, and hemifacial microsomia. All of these anomalies can be either isolated or part of a defined genetic syndrome. A clinical geneticist or genetic counselor should be a member of the craniofacial team to help determine which patients have isolated anomalies and which are likely to have a syndrome. They would then arrange for the appropriate genetic testing to confirm the diagnosis of the specific syndrome. The identification of the specific syndrome is important for the overall care of the patient (as it identifies risk for other medical problems such as congenital heart defect) that will have to be taken into account in the care of the craniofacial malformation. In addition, knowing the specific syndrome will allow the family to understand how this happened to their child and the recurrence risk for future pregnancies. With the advent of new technologies, there are now many types of genetic testing available (including, karyotype, fluorescence in situ hybridization, chromosomal microarrays, and next generation sequencing) and the medical geneticist and genetic counselor can determine which specific testing is needed for a given patient.
Collapse
Affiliation(s)
- Amanda J Yoon
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Binh N Pham
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Katrina M Dipple
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California
| |
Collapse
|
|
19
|
Papoulidis I, Paspaliaris V, Papageorgiou E, Siomou E, Dagklis T, Sotiriou S, Thomaidis L, Manolakos E. Deletion of 4.4 Mb at 2q33.2q33.3 May Cause Growth Deficiency in a Patient with Mental Retardation, Facial Dysmorphic Features and Speech Delay. Cytogenet Genome Res 2015; 145:19-24. [PMID: 25925190 DOI: 10.1159/000381568] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/03/2015] [Indexed: 11/19/2022] Open
Abstract
A patient with a rare interstitial deletion of chromosomal band 2q33.2q33.3 is described. The clinical features resembled the 2q33.1 microdeletion syndrome (Glass syndrome), including mental retardation, facial dysmorphism, high-arched narrow palate, growth deficiency, and speech delay. The chromosomal aberration was characterized by whole genome BAC aCGH. A comparison of the current patient and Glass syndrome features revealed that this case displayed a relatively mild phenotype. Overall, it is suggested that the deleted region of 2q33 causative for Glass syndrome may be larger than initially suggested.
Collapse
Affiliation(s)
- Ioannis Papoulidis
- Access To Genome - ATG P.C., Clinical Laboratory Genetics, Thessaloniki, Greece
| | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Zhao X, Qu Z, Tickner J, Xu J, Dai K, Zhang X. The role of SATB2 in skeletogenesis and human disease. Cytokine Growth Factor Rev 2013; 25:35-44. [PMID: 24411565 DOI: 10.1016/j.cytogfr.2013.12.010] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 12/15/2013] [Indexed: 02/06/2023]
Abstract
Since the discovery of SATB2 (special AT-rich sequence binding protein 2) a decade ago, its pivotal roles in development and tissue regeneration have emerged, particularly in craniofacial patterning and development, palate formation, and osteoblast differentiation and maturation. As a member of the special AT-rich binding proteins family that bind to nuclear matrix-attachment regions (MAR), it also displays functional versatility in central nervous development, especially corpus callosum and pons formation, cancer development and prognosis, as well as in immune regulation. At the molecular level, Satb2 gene expression appears to be tissue and stage-specific, and is regulated by several cytokines and growth factors, such as BMP2/4/7, insulin, CNTF, and LIF via ligand receptor signaling pathways. SATB2 mainly performs a twofold role as a transcription regulator by directly binding to AT-rich sequences in MARs to modulate chromatin remodeling, or through association with other transcription factors to modulate the cis-regulation elements and thus to regulate the expression of down-stream target genes and a wide range of biological processes. This contemporary review provides an exploration of the molecular characteristics and function of SATB2; including its expression and cytokine regulation, its involvement in human disease, and its potential roles in skeletogenesis.
Collapse
Affiliation(s)
- Xiaoying Zhao
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, China
| | - Zhihu Qu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 200031, China
| | - Jennifer Tickner
- School of Pathology and Laboratory Medicine, The University of Western Australia (M504), 35 Stirling Highway, Crawley WA 6009, Australia
| | - Jiake Xu
- School of Pathology and Laboratory Medicine, The University of Western Australia (M504), 35 Stirling Highway, Crawley WA 6009, Australia.
| | - Kerong Dai
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, China; Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Xiaoling Zhang
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, China; Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
| |
Collapse
|
|
21
|
Small deletions of SATB2 cause some of the clinical features of the 2q33.1 microdeletion syndrome. PLoS One 2009; 4:e6568. [PMID: 19668335 PMCID: PMC2719055 DOI: 10.1371/journal.pone.0006568] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2009] [Accepted: 04/23/2009] [Indexed: 12/16/2022] Open
Abstract
Recurrent deletions of 2q32q33 have recently been reported as a new microdeletion syndrome. Clinical features of this syndrome include severe mental retardation, growth retardation, dysmorphic features, thin and sparse hair, feeding difficulties and cleft or high palate. The commonly deleted region contains at least seven genes. Haploinsufficiency of one of these genes, SATB2, a DNA-binding protein that regulates gene expression, has been implicated as causative in the cleft or high palate of individuals with 2q32q33 microdeletion syndrome. In this study we describe three individuals with smaller microdeletions of this region, within 2q33.1. The deletions ranged in size from 173.1 kb to 185.2 kb and spanned part of SATB2. Review of clinical records showed similar clinical features among these individuals, including severe developmental delay and tooth abnormalities. Two of the individuals had behavioral problems. Only one of the subjects presented here had a cleft palate, suggesting reduced penetrance for this feature. Our results suggest that deletion of SATB2 is responsible for several of the clinical features associated with 2q32q33 microdeletion syndrome.
Collapse
|
|
22
|
Urquhart J, Black GCM, Clayton-Smith J. 4.5 Mb microdeletion in chromosome band 2q33.1 associated with learning disability and cleft palate. Eur J Med Genet 2009; 52:454-7. [PMID: 19576302 DOI: 10.1016/j.ejmg.2009.06.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2009] [Accepted: 06/27/2009] [Indexed: 10/20/2022]
Abstract
We report a 4.5 Mb deletion of 2q33.1 in an individual with developmental delay and cleft palate. There have been various previous reports of deletions of 2q3, all with varying breakpoints and all larger than the current case. Whilst there is some variation in the phenotypes of patients with 2q3 deletions all share a commonly deleted region within 2q33.1 which includes SATB2, a gene previously shown to be associated with cleft palate. The phenotypic features of our patient are milder than those reported so far.
Collapse
Affiliation(s)
- Jill Urquhart
- Genetic Medicine, University of Manchester, Manchester Academic Heath Science Centre, Central Manchester University Hospital, NHS Foundation Trust, Oxford Road, Manchester, M13 9WL, UK.
| | | | | |
Collapse
|
|
23
|
Van Buggenhout G, Van Ravenswaaij-Arts C, Mc Maas N, Thoelen R, Vogels A, Smeets D, Salden I, Matthijs G, Fryns JP, Vermeesch JR. The del(2)(q32.2q33) deletion syndrome defined by clinical and molecular characterization of four patients. Eur J Med Genet 2005; 48:276-89. [PMID: 16179223 DOI: 10.1016/j.ejmg.2005.05.005] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2004] [Indexed: 01/30/2023]
Abstract
We report four patients with an interstitial deletion of chromosome 2q32-->2q33. They presented similar clinical findings including pre- and postnatal growth retardation, distinct facial dysmorphism, thin and sparse hair and fair built, micrognathia, cleft or high palate, relative macroglossia, dacrocystitis, persisting feeding difficulties, inguinal hernia and broad based gait. All were severely mentally retarded. Three patients had a specific behavioral phenotype with hyperactivity and motor restlessness, chaotic behavior, happy-personality but with periods of aggression and anxiety, sleeping problems and self-mutilation. (head-banging). Array CGH and fluorescence in situ hybridization (FISH) allowed us to delineate the deletion size and showed that the four patients share a 8.1 Mb minimal deleted region. Reviewing additional nine case reports of patients with similar deletions showed striking phenotypic similarities which enabled the delineation of the 2q32.2q33 syndrome. Deletion of 2q32 has been also associated with the wrinkly skin syndrome (WWS) and isolated cleft palate. Although the patients presented here shared many aspects of WWS, they did not had the wrinkly skin. All patients had a cleft or high palate, most likely as a result of hemizygosity for SATB2. A potential commonly deleted interval of the three patients with behavioral problems, excluding the deletion in the patient without behavioral problems, is at most 0.5 Mb in size harboring only two genes.
Collapse
Affiliation(s)
- G Van Buggenhout
- Center for Human Genetics, University of Leuven, Heresraat 49, 3000 Leuven, Belgium.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Aijaz S, Allen J, Tregidgo R, van Heyningen V, Hanson I, Clark BJ. Expression analysis of SIX3 and SIX6 in human tissues reveals differences in expression and a novel correlation between the expression of SIX3 and the genes encoding isocitrate dehyhrogenase and cadherin 18. Genomics 2005; 86:86-99. [PMID: 15953543 DOI: 10.1016/j.ygeno.2005.03.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2004] [Revised: 02/22/2005] [Accepted: 03/03/2005] [Indexed: 11/22/2022]
Abstract
SIX3 and SIX6 are transcription factors expressed during early stages of eye development. Limited expression data for SIX3 and SIX6 are available in the literature but, to date, there are no reports of the relative levels of expression of these genes throughout the human body and in adult tissues in particular. In this paper, we report extensive real-time quantitative PCR analyses of SIX3 and SIX6 expression in many different tissues of the adult human body, including ocular tissues, and a comparison of expression data with that of many other genes to identify similarity in expression. Using this powerful technique, we have detected a novel statistical correlation between the spatial distribution and the quantitative expression of SIX3 and 5 other transcripts including IDH1, the gene encoding the NADP(+)-dependent enzyme isocitrate dehydrogenase, and cadherin 18, type 2 (CDH14). Our data demonstrate that this novel technique can be used to generate hypotheses by comparison of gene expression profiles to identify possible interactions between genes or gene products.
Collapse
Affiliation(s)
- Saima Aijaz
- Institute of Ophthalmology, University College London, Bath Street, London EC1V 9EL, UK
| | | | | | | | | | | |
Collapse
|
|
25
|
Singh R, Gardner RJM, Crossland KM, Scheffer IE, Berkovic SF. Chromosomal abnormalities and epilepsy: a review for clinicians and gene hunters. Epilepsia 2002; 43:127-40. [PMID: 11903458 DOI: 10.1046/j.1528-1157.2002.19498.x] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
PURPOSE We analyzed databases on chromosomal anomalies and epilepsy to identify chromosomal regions where abnormalities are associated with clinically recognizable epilepsy syndromes. The expectation was that these regions could then be offered as targets in the search for epilepsy genes. METHODS The cytogenetic program of the Oxford Medical Database, and the PubMed database were used to identify chromosomal aberrations associated with seizures and/or EEG abnormalities. The literature on selected small anomalies thus identified was reviewed from a clinical and electroencephalographic viewpoint, to classify the seizures and syndromes according to the current International League Against Epilepsy (ILAE) classification. RESULTS There were 400 different chromosomal imbalances described with seizures or EEG abnormalities. Eight chromosomal disorders had a high association with epilepsy. These comprised: the Wolf-Hirschhorn (4p-) syndrome, Miller-Dieker syndrome (del 17p13.3), Angelman syndrome (del 15q11-q13), the inversion duplication 15 syndrome, terminal deletions of chromosome 1q and 1p, and ring chromosomes 14 and 20. Many other segments had a weaker association with seizures. The poor quality of description of the epileptology in many reports thwarted an attempt to make precise karyotype-phenotype correlations. CONCLUSIONS We identified certain chromosomal regions where aberrations had an evident association with seizures, and these regions may be useful targets for gene hunters. New correlations with specific epilepsy syndromes were not revealed. Clinicians should continue to search for small chromosomal abnormalities associated with specific epilepsy syndromes that could provide important clues for finding epilepsy genes, and the epileptology should be rigorously characterized.
Collapse
Affiliation(s)
- Rita Singh
- Department of Medicine (Neurology), The University of Melbourne, Austin and Repatriation Medical Centre, Australia
| | | | | | | | | |
Collapse
|
|
26
|
Riegel M, Morava E, Czakó M, Kosztolányi G, Schinzel A. Distal deletion, del(2)(q33.3q33.3), in a patient with severe growth deficiency and minor anomalies. AMERICAN JOURNAL OF MEDICAL GENETICS 2001; 102:227-30. [PMID: 11484198 DOI: 10.1002/ajmg.1455] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
We report on an 18-month-old boy with a 2q33.3 deletion. The clinical findings observed in the propositus included minor anomalies of face and distal limbs, intrauterine and postnatal growth retardation, microcephaly and, so far, moderate developmental delay. Conventional GTG banded chromosome analysis indicated a small deletion in distal 2q. Subsequent analysis by fluorescent in situ hybridization (FISH) using different probes allowed us to narrow down the deletion to most or all of segment 2q33.3. This case shows the importance of the application of different YAC probes for a precise determination of breakpoints in small interstitial deletions.
Collapse
Affiliation(s)
- M Riegel
- Institute of Medical Genetics, University of Zürich, Zürich, Switzerland
| | | | | | | | | |
Collapse
|
|
27
|
Slavotinek A, Schwarz C, Getty JF, Stecko O, Goodman F, Kingston H. Two cases with interstitial deletions of chromosome 2 and sex reversal in one. AMERICAN JOURNAL OF MEDICAL GENETICS 1999; 86:75-81. [PMID: 10440834 DOI: 10.1002/(sici)1096-8628(19990903)86:1<75::aid-ajmg15>3.0.co;2-j] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
We present two children with de novo interstitial deletions of the long arm of chromosome 2 (karyotypes 46,XY, del(2)(q31.1q31.3) and 46,XY, del(2)(q24.3q31.3), respectively). The first child had severe learning difficulties, growth retardation, unilateral ptosis, small palpebral fissures, a cleft uvula, and bilateral cutaneous syndactyly of the second and third toes. Despite her male karyotype, she had female external genitalia with hypoplasia of the clitoris and labia minora. This is the first reported case of feminization of the external genitalia in a genotypic male with an interstitial deletion of chromosome 2q31 and adds to the growing amount of evidence for a gene involved in sex determination in this chromosome region. The second child had severe mental and growth retardation, ptosis, down-slanting palpebral fissures, low-set ears, micrognathia, finger camptodactyly, and brachysyndactyly of the second to fifth toes. The clinical manifestations associated with deletions of 2q31 to 2q33 are similar to those found with proximal deletions at 2q24 to 2q31 and of band 2q24, suggesting that the phenotype may result from haploinsufficiency for one or more genes located at 2q31. Microsatellite marker studies showed that both children had paternally derived deletions that included the HOXD gene cluster and the EVX2, DLX1, and DLX2 genes known to be important in limb development.
Collapse
Affiliation(s)
- A Slavotinek
- University Department of Medical Genetics, St Mary's Hospital, Manchester, United Kingdom
| | | | | | | | | | | |
Collapse
|
|
28
|
Courtens W, Speleman F, Messiaen L, Bormans J, Roy NV, Vamos E. Interstitial deletion 2q33.3-q34 in a boy with a phenotype resembling the Seckel syndrome. ACTA ACUST UNITED AC 1997. [DOI: 10.1002/(sici)1096-8628(19970905)71:4<479::aid-ajmg21>3.0.co;2-c] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
|
|
29
|
Chinen Y, Tohma T, Izumikawa Y, Iha T, Goya Y, Naritomi K. Small interstitial deletion of the long arm of chromosome 2 (2q24.3): further delineation of 2q medial monosomy syndrome. THE JAPANESE JOURNAL OF HUMAN GENETICS 1996; 41:323-8. [PMID: 8996968 DOI: 10.1007/bf01913175] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
We report on a female infant with an interstitial deletion involving 2q24.3. She had multiple congenital anomalies similar to those in patients with del(2)(q31q33) except for an occipital encephalocele. As a result of comparison of clinical findings among interstitial 2q deletions, a distinct 2q medial monosomy syndrome may be delineable in association with a deletion of 2q31.
Collapse
Affiliation(s)
- Y Chinen
- Department of Pediatrics, University of the Ryukyus School of Medicine, Okinawa, Japan
| | | | | | | | | | | |
Collapse
|
|
30
|
Boles RG, Pober BR, Gibson LH, Willis CR, McGrath J, Roberts DJ, Yang-Feng TL. Deletion of chromosome 2q24-q31 causes characteristic digital anomalies: case report and review. AMERICAN JOURNAL OF MEDICAL GENETICS 1995; 55:155-60. [PMID: 7717414 DOI: 10.1002/ajmg.1320550204] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
We describe a newborn boy with multiple anomalies, including bilateral split foot and an interstitial deletion of chromosome 2 (q24.2-q31.1). Four additional cases in 2 families involving similar deletions have been reported. Bilateral digital anomalies of hands and feet were seen in all 5 cases, including a wide cleft between the first and second toes, wide halluces, brachysyndactyly of the toes, and camptodactyly of the fingers. Other common manifestations have included postnatal growth and mental retardation, microcephaly, down-slanting palpebral fissures, micrognathia, and apparently low-set ears. Bilateral digital anomalies were reported in 22 of 24 cases with deletions including at least part of region 2q24-q31. Digital anomalies were not prevalent in 18 patients with deletions of chromosome 2q not overlapping 2q24-q31. 2q31.1 appears to be the common deleted segment in all cases with significant digital anomalies, which implies the existence of one or more genes involved in distal limb morphogenesis in this region. HOXD13 and EVX2, located in the proximity of 2q31, were not deleted in our patient by Southern analysis. Bilateral digital malformations of the hands and feet associated with other anomalies should be evaluated by chromosome analysis focused at the 2q24-q31 region.
Collapse
Affiliation(s)
- R G Boles
- Childrens Hospital Los Angeles, CA 90027, USA
| | | | | | | | | | | | | |
Collapse
|
|
31
|
Weaver RG, Rao N, Thomas IT, Pettenati MJ. De novo inv(2)(p21q31) associated with isolated bilateral microphthalmia and cataracts. AMERICAN JOURNAL OF MEDICAL GENETICS 1991; 40:509-12. [PMID: 1746620 DOI: 10.1002/ajmg.1320400428] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
We report on a patient with bilateral microphthalmia and unusual cataracts with a de novo pericentric inversion of chromosome (2)(p21q31). A literature review of previous associations of eye abnormalities and anomalies of chromosome 2 suggests probable gene locations for eye development.
Collapse
Affiliation(s)
- R G Weaver
- Department of Ophthalmology, Bowman Gray School of Medicine, Wake Forest University Medical Center, Winston-Salem, North Carolina 27103
| | | | | | | |
Collapse
|
|
32
|
Wamsler C, Müller B, Freyberger G, Schmid M. Interstitial deletion del(2)(q24q31) with a phenotype similar to del(2)(q31q33). AMERICAN JOURNAL OF MEDICAL GENETICS 1991; 39:204-6. [PMID: 2063926 DOI: 10.1002/ajmg.1320390217] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
A 3 3/12-year-old girl with multiple anomalies is reported. An interstitial deletion del(2)(q24q31) was demonstrated. There is considerable overlap of symptoms in cases with del(2)(q31q33), which are reviewed.
Collapse
Affiliation(s)
- C Wamsler
- Department of Human Genetics, University of Würzburg, Germany
| | | | | | | |
Collapse
|
|
33
|
Spano LM, Opitz JM. Bibliography on X-linked mental retardation, the fragile X, and related subjects V (1991). AMERICAN JOURNAL OF MEDICAL GENETICS 1991; 38:173-85. [PMID: 2018055 DOI: 10.1002/ajmg.1320380203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- L M Spano
- Department of Medical Genetics, Shodair Children's Hospital, Helena, Montana 59604
| | | |
Collapse
|
|
34
|
Asher JH, Morell R, Friedman TB. Waardenburg syndrome (WS): the analysis of a single family with a WS1 mutation showing linkage to RFLP markers on human chromosome 2q. Am J Hum Genet 1991; 48:43-52. [PMID: 1670751 PMCID: PMC1682754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Waardenburg syndrome type I (WS1; MIM 19350) is caused by a pleiotropic, autosomal dominant mutation with variable penetrance and expressivity. Of individuals with this mutation, 20%-25% are hearing impaired. A multilocus linkage analysis of RFLP data from a single WS1 family with 11 affected individuals indicates that the WS1 mutation in this family is linked to the following four marker loci located on the long arm of chromosome 2: ALPP (alkaline phosphatase, placental), FN1 (fibronectin 1), D2S3 (a unique-copy DNA segment), and COL6A3 (collagen VI, alpha 3). For the RFLP marker loci, a multilocus linkage analysis using MLINK produced a peak lod (Z) of 3.23 for the following linkage relationships and recombination fractions (theta i): (ALPP----.000----FN1)----.122----D2S3----.267----CO L6A3. A similar analysis produced a Z of 6.67 for the following linkage relationships and theta i values among the markers and WS1: (FN1----.000----WS1----.000----ALPP)----.123----D2S 3----.246----COL6A3. The data confirm the conclusion of Foy et al. that at least some WS1 mutations map to chromosome 2q.
Collapse
Affiliation(s)
- J H Asher
- Department of Zoology, Michigan State University, East Lansing 48824
| | | | | |
Collapse
|
|
35
|
Abstract
Four different Waardenburg syndromes have been defined based upon observed phenotypes. These syndromes are responsible for approximately 2% of subjects with profound congenital hearing loss. At present, Waardenburg syndromes have not been mapped to particular human chromosomes. One or more of the mouse mutant alleles, Ph (patch), s (piebald), Sp (splotch), and Mior (microphthalmia-Oak Ridge) and the hamster mutation Wh (anophthalmic white) may be homologous to mutations causing Waardenburg syndromes. In heterozygotes, phenotypic effects of these four mouse mutations and the hamster mutation are similar to the phenotypes produced by different Waardenburg syndrome mutations. The chromosomal locations and syntenic relationships associated with three of the four mouse mutant genes have been used to predict human chromosomal locations for Waardenburg syndromes: (1) on chromosome 2q near FN1 (fibronectin 1), (2) on chromosome 3p near the proto-oncogene RAF1 or 3q near RHO (rhodopsin), and (3) on chromosome 4p near the proto-oncogene KIT. Waardenburg syndromes show extensive intrafamilial phenotypic variability. Results of our studies with the hamster mutation Wh suggest that this variability may be explained in part by modifier genes segregating within families.
Collapse
Affiliation(s)
- J H Asher
- Department of Zoology, Michigan State University, East Lansing 48824
| | | |
Collapse
|
|
36
|
Palmer CG, Heerema N, Bull M. Deletions in chromosome 2 and fragile sites. AMERICAN JOURNAL OF MEDICAL GENETICS 1990; 36:214-8. [PMID: 2368809 DOI: 10.1002/ajmg.1320360215] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
We report on 2 patients with de novo deletions of 2q and chromosome constitutions of 46,XY,del(2)(q32.3q33.3) and 46,XX,del(2) (q21q23.2), respectively. Comparisons of breakpoints of interstitial deletions show frequent correspondence to common fragile sites.
Collapse
Affiliation(s)
- C G Palmer
- Department of Medical Genetics, Indiana University, Indianapolis
| | | | | |
Collapse
|
|
37
|
Sybert VP, Pagon RA, Donlan M, Bradley CM. Pigmentary abnormalities and mosaicism for chromosomal aberration: association with clinical features similar to hypomelanosis of Ito. J Pediatr 1990; 116:581-6. [PMID: 2319405 DOI: 10.1016/s0022-3476(05)81606-3] [Citation(s) in RCA: 88] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Thirteen patients with hypopigmentation of the skin characteristic of hypomelanosis of Ito, and with developmental disabilities or structural malformations, or both, were examined at our center. Eight were found to have abnormal karyotypes in lymphocytes, fibroblasts, or both. No single clinical feature was predictive of chromosome imbalance in this group of patients. Cytogenetic findings included a balanced de novo X-autosome translocation; ring 10; 45,X/46,X,+ring; mosaic del 13q11 (fibroblasts); mosaic triploidy (fibroblasts); mosaic tetrasomy 12p (fibroblasts); mosaic apparently balanced 15;22 translocation (peripheral blood); and mosaic trisomy 18 (peripheral blood). Hypomelanosis of Ito is characterized by swirly hypopigmentation or depigmentation of the skin with or without other malformations. Autosomal dominant, autosomal recessive, and X-linked dominant inheritance have been suggested but not confirmed. Chromosomal aneuploidy has also been reported. We believe that hypomelanosis of Ito is an etiologically heterogeneous physical finding, and recommend karyotyping of multiple tissues of all patients with abnormal cutaneous pigmentation associated with developmental delay or structural malformations.
Collapse
Affiliation(s)
- V P Sybert
- Department of Pediatrics, Children's Hospital and Medical Center, Seattle, WA 98105
| | | | | | | |
Collapse
|