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Nishimura A, Tamura A, Fujikawa T, Inoue S, Nakatani N, Nozu K, Yamamoto N. KMT2A-CBL fusion gene in the first reported case of T-cell acute lymphoblastic leukemia associated with Wiedemann-Steiner syndrome. Int J Hematol 2025:10.1007/s12185-025-03975-5. [PMID: 40153132 DOI: 10.1007/s12185-025-03975-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 03/30/2025]
Abstract
Wiedemann-Steiner syndrome (WSS) is a congenital malformation syndrome characterized by intellectual disability, developmental delay, and distinctive facial features, caused by germline mutations in the KMT2A gene. Despite the key role of KMT2A in hematopoiesis, leukemia has not been previously reported in WSS patients. This report presents the first documented case of acute lymphoblastic leukemia (ALL) in a WSS patient. A 16-year-old boy with developmental delay, distinct facial features, and genital abnormalities was diagnosed with WSS following the identification of a heterozygous frameshift mutation in KMT2A. At age 17, he developed T-cell ALL harboring the KMT2A-CBL fusion gene, of which only nine cases have been reported so far. cDNA sequence analysis of the KMT2A-CBL transcript at the site of the germline KMT2A pathogenic variant revealed a wild-type sequence, indicating that the KMT2A-CBL fusion occurred on the wild-type allele. While this observation suggests a potential cooperative role of the KMT2A-CBL chimeric gene and the germline KMT2A pathogenic mutation in leukemogenesis, the rarity of leukemia in WSS underscores the need for cautious interpretation. This case provides preliminary insights into a possible mechanism of leukemogenesis in WSS, but further studies are required to clarify the relationship between WSS and ALL.
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Affiliation(s)
- Akihiro Nishimura
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Akihiro Tamura
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho Chuo-ku, Kobe, Hyogo, 650-0017, Japan.
| | - Tomoko Fujikawa
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Shotaro Inoue
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Naoko Nakatani
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Kandai Nozu
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Nobuyuki Yamamoto
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho Chuo-ku, Kobe, Hyogo, 650-0017, Japan
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Al-Juraibah F, Melha M, Alromaih A, Al-Sunaid A, Alkhalaf HA. Elemental Milk Formula as a Possible Cause of Hypophosphatemic Rickets in Wiedemann-Steiner Syndrome. J Clin Res Pediatr Endocrinol 2024; 16:355-360. [PMID: 36794745 PMCID: PMC11590760 DOI: 10.4274/jcrpe.galenos.2022.2022-8-23] [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: 09/05/2022] [Accepted: 12/12/2022] [Indexed: 02/17/2023] Open
Abstract
Phosphate has a fundamental role in bone mineralization, and its chronic deficiency has multiple negative consequences in the body, including defects in bone mineralization that will manifest in children as rickets and osteomalacia. Here we present a young boy known to have Wiedemann-Steiner syndrome with multiple co-morbidities that necessitated gastric tube feeding. The child at 22 months was found to have hypophosphatemia and a high alkaline phosphatase level associated with rachitic skeletal manifestations that were attributed to low phosphate intake and/or gastrointestinal absorption, as there was no evidence of excessive phosphate wasting based on appropriate tubular renal re-absorption of phosphate. The primary nutritional source was an elemental amino acid-based milk formula (Neocate®) from 12 months of age. After switching from Neocate® to another elemental amino-acid based milk formula, all biochemical and radiological abnormalities returned to normal, indicating that the Neocate® formula was the possible cause of the patient’s low phosphate intake. However, in the literature, this formula-associated effect was only described in a limited number of patients. Whether or not some patient-related factors, such as the very rare syndrome described in our patient, could influence this effect warrants further exploration.
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Affiliation(s)
- Fahad Al-Juraibah
- King Abdullah Specialist Children’s Hospital, Clinic of Pediatrics, Riyadh, Saudi Arabia
- King Saud bin Abdul-Aziz University for Health Sciences, College of Medicine, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Maali Melha
- King Abdullah Specialist Children’s Hospital, Clinic of Pediatrics, Riyadh, Saudi Arabia
| | - Azam Alromaih
- King Saud bin Abdul-Aziz University for Health Sciences, College of Medicine, Riyadh, Saudi Arabia
| | - Areej Al-Sunaid
- King Abdullah Specialist Children’s Hospital, Clinic of Pediatrics, Riyadh, Saudi Arabia
- King Saud bin Abdul-Aziz University for Health Sciences, College of Medicine, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Hamad Abdullah Alkhalaf
- King Abdullah Specialist Children’s Hospital, Clinic of Pediatrics, Riyadh, Saudi Arabia
- King Saud bin Abdul-Aziz University for Health Sciences, College of Medicine, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
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Silveira HG, Steiner CE, Toccoli G, Angeloni LL, Heleno JL, Spineli-Silva S, dos Santos AM, Vieira TP, Melaragno MI, Gil-da-Silva-Lopes VL. Variants in KMT2A in Three Individuals with Previous Suspicion of 22q11.2 Deletion Syndrome. Genes (Basel) 2024; 15:211. [PMID: 38397201 PMCID: PMC10888166 DOI: 10.3390/genes15020211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 01/28/2024] [Accepted: 02/01/2024] [Indexed: 02/25/2024] Open
Abstract
The condition known as 22q11.2 deletion syndrome (MIM #188400) is a rare disease with a highly variable clinical presentation including more than 180 features; specific guidelines for screening individuals have been used to support clinical suspicion before confirmatory tests by Brazil's Craniofacial Project. Of the 2568 patients listed in the Brazilian Database on Craniofacial Anomalies, 43 individuals negative for the 22q11.2 deletion syndrome were further investigated through whole-exome sequencing. Three patients (6.7%) presented with heterozygous pathogenic variants in the KMT2A gene, including a novel variant (c.6158+1del) and two that had been previously reported (c.173dup and c.3241C>T); reverse phenotyping concluded that all three patients presented features of Wiedemann-Steiner syndrome, such as neurodevelopmental disorders and dysmorphic facial features (n = 3), hyperactivity and anxiety (n = 2), thick eyebrows and lower-limb hypertrichosis (n = 2), congenital heart disease (n = 1), short stature (n = 1), and velopharyngeal insufficiency (n = 2). Overlapping features between 22q11.2 deletion syndrome and Wiedemann-Steiner syndrome comprised neuropsychiatric disorders and dysmorphic characteristics involving the eyes and nose region; velopharyngeal insufficiency was seen in two patients and is an unreported finding in WDSTS. Therefore, we suggest that both conditions should be included in each other's differential diagnoses.
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Affiliation(s)
- Henrique Garcia Silveira
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo (Unifesp), São Paulo 04023-062, Brazil; (H.G.S.); (G.T.); (M.I.M.)
| | - Carlos Eduardo Steiner
- Genética Médica e Medicina Genômica, Departamento de Medicina Translacional, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas 13083-970, Brazil; (C.E.S.); (L.L.A.); (J.L.H.); (S.S.-S.); (A.M.d.S.); (T.P.V.)
| | - Giovana Toccoli
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo (Unifesp), São Paulo 04023-062, Brazil; (H.G.S.); (G.T.); (M.I.M.)
| | - Luise Longo Angeloni
- Genética Médica e Medicina Genômica, Departamento de Medicina Translacional, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas 13083-970, Brazil; (C.E.S.); (L.L.A.); (J.L.H.); (S.S.-S.); (A.M.d.S.); (T.P.V.)
| | - Júlia Lôndero Heleno
- Genética Médica e Medicina Genômica, Departamento de Medicina Translacional, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas 13083-970, Brazil; (C.E.S.); (L.L.A.); (J.L.H.); (S.S.-S.); (A.M.d.S.); (T.P.V.)
| | - Samira Spineli-Silva
- Genética Médica e Medicina Genômica, Departamento de Medicina Translacional, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas 13083-970, Brazil; (C.E.S.); (L.L.A.); (J.L.H.); (S.S.-S.); (A.M.d.S.); (T.P.V.)
| | - Ana Mondadori dos Santos
- Genética Médica e Medicina Genômica, Departamento de Medicina Translacional, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas 13083-970, Brazil; (C.E.S.); (L.L.A.); (J.L.H.); (S.S.-S.); (A.M.d.S.); (T.P.V.)
- Faculdade São Leopoldo Mandic (SLMandic), Campinas 13045-755, Brazil
| | - Társis Paiva Vieira
- Genética Médica e Medicina Genômica, Departamento de Medicina Translacional, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas 13083-970, Brazil; (C.E.S.); (L.L.A.); (J.L.H.); (S.S.-S.); (A.M.d.S.); (T.P.V.)
| | - Maria Isabel Melaragno
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo (Unifesp), São Paulo 04023-062, Brazil; (H.G.S.); (G.T.); (M.I.M.)
| | - Vera Lúcia Gil-da-Silva-Lopes
- Genética Médica e Medicina Genômica, Departamento de Medicina Translacional, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas 13083-970, Brazil; (C.E.S.); (L.L.A.); (J.L.H.); (S.S.-S.); (A.M.d.S.); (T.P.V.)
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Espinosa-Mojica AA, Varo Varo C. Determining the Linguistic Profile of Children With Rare Genetic Disorders. JOURNAL OF SPEECH, LANGUAGE, AND HEARING RESEARCH : JSLHR 2024; 67:170-186. [PMID: 38085694 DOI: 10.1044/2023_jslhr-23-00101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2024]
Abstract
PURPOSE Language studies on populations with rare genetic disorders are limited. Hence, there is little data on commonly found or expected developmental linguistic traits and cognitive mechanisms that may be impaired. Based on the hypothesis that there is a close connection between language and cognition and the relevance of specific genetic changes in the development of each, our goal was to provide linguistic data on relationships with other executive functioning mechanisms. METHOD This study assessed language skills, communicative behaviors, and executive functions in four children, aged 7-9 years, with rare genetic disorders, using standardized protocols and tests. RESULTS The findings revealed different levels of language impairment and executive functioning problems in each case. The overall executive function index performance for each of the four cases studied was clinically significantly high, indicating executive dysfunction. CONCLUSIONS The cases analyzed illustrate different types of atypical development that affect both language and other cognitive mechanisms and underscore the importance of executive skills and the various ways in which they are involved in diverse levels of language that might be affected to a greater or lesser degree in rare genetic disorders. In conclusion, we found that language dysfunction is a salient feature of the rare genetic disorders included in our study, although this is not necessarily true for all genetic disorders. Along with these conclusive results, we performed a qualitative analysis of the linguistic and cognitive components that enable functional communication in order to allow optimal interpretation of the data we have collected, laying the foundations for a more effective therapeutic approach.
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Sahly AN, Srour M, Buhas D, Scheffer IE, Myers KA. The epileptology of Wiedemann-Steiner syndrome: Electroclinical findings in five patients with KMT2A pathogenic variants. Eur J Paediatr Neurol 2023; 44:46-50. [PMID: 37075569 DOI: 10.1016/j.ejpn.2023.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 04/10/2023] [Accepted: 04/14/2023] [Indexed: 04/21/2023]
Abstract
BACKGROUND Wiedemann-Steiner Syndrome (WSTS) is a rare chromatinopathy caused by pathogenic variants in KMT2A. WSTS is characterized by neurodevelopmental disorders and distinct dysmorphic features. Epilepsy has been reported in only 33 individuals with WSTS, with only limited clinical details described. METHODS We identified patients with pathogenic KMT2A variants and epilepsy, and performed thorough phenotyping. RESULTS Five patients were identified, all of whom presented with developmental and epileptic encephalopathy (DEE). Epilepsy syndromes observed included Lennox-Gastaut syndrome [2], infantile epileptic spasms syndrome, and DEE with spike-wave activation in sleep. Seizure types observed included absence, generalized tonic-clonic, myoclonic, tonic, atonic, epileptic spasms, and focal seizures. CONCLUSIONS The spectrum of epilepsy phenotypes in patients with WSTS can be broad, but presentation is typically severe, usually involving a form of DEE.
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Affiliation(s)
- Ahmed N Sahly
- Division of Neurology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada; Department of Neurosciences, King Faisal Specialist Hospital & Research Centre, Jeddah, Saudi Arabia
| | - Myriam Srour
- Division of Neurology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada; Research Institute of the McGill University Medical Centre, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada
| | - Daniela Buhas
- Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada
| | - Ingrid E Scheffer
- Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Victoria, Australia; Murdoch Children's Research Institute and Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Victoria, Australia; The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia
| | - Kenneth A Myers
- Division of Neurology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada; Research Institute of the McGill University Medical Centre, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
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Lin Y, Chen X, Xie B, Guan Z, Chen X, Li X, Yi P, Du R, Mei H, Liu L, Zhang W, Zeng C. Novel variants and phenotypic heterogeneity in a cohort of 11 Chinese children with Wiedemann-Steiner syndrome. Front Genet 2023; 14:1085210. [PMID: 37025457 PMCID: PMC10070943 DOI: 10.3389/fgene.2023.1085210] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 03/09/2023] [Indexed: 04/08/2023] Open
Abstract
Objective: Wiedemann-Steiner syndrome (WSS) is a rare autosomal dominant disorder caused by deleterious heterozygous variants of the KMT2A gene. This study aims to describe the phenotypic and genotypic features of Chinese WSS patients, and assess therapeutic effects of recombinant human growth hormone (rhGH). Methods: Eleven Chinese children with WSS were enrolled in our cohort. Their clinical, imaging, biochemical and molecular findings were analyzed retrospectively. Moreover, the phenotypic features of 41 previously reported Chinese WSS patients were reviewed and included in our analysis. Results: In our cohort, the 11 WSS patients presented with classic clinical manifestations, but with different frequencies. The most common clinical features were short stature (90.9%) and developmental delay (90.9%), followed by intellectual disability (72.7%). The most frequent imaging features were patent ductus arteriosus (57.1%) and patent foramen ovale (42.9%) in cardiovascular system, and abnormal corpus callosum (50.0%) in the brain. In the set comprising 52 Chinese WSS patients, the most common clinical and imaging manifestations were developmental delay (84.6%), intellectual disability (84.6%), short stature (80.8%) and delayed bone age (68.0%), respectively. Eleven different variants, including three known and eight novel variants, of the KMT2A gene were identified in our 11 WSS patients without a hotspot variant. Two patients were treated with rhGH and yielded satisfactory height gains, but one developed acceleration of bone age. Conclusion: Our study adds 11 new patients with WSS, reveals different clinical characteristics in Chinese WSS patients, and extends the mutational spectrum of the KMT2A gene. Our study also shares the therapeutic effects of rhGH in two WSS patients without GH deficiency.
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Affiliation(s)
- Yunting Lin
- Department of Genetics and Endocrinology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Xiaohong Chen
- Department of Endocrinology and Metabolism, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bobo Xie
- Center for Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
- The Guangxi Health Commission Key Laboratory of Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhihong Guan
- Department of Genetics and Endocrinology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Xiaodan Chen
- Department of Genetics and Endocrinology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Xiuzhen Li
- Department of Genetics and Endocrinology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Peng Yi
- Department of Genetics and Endocrinology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Rong Du
- Department of Genetics and Endocrinology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Huifen Mei
- Department of Genetics and Endocrinology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Li Liu
- Department of Genetics and Endocrinology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Wen Zhang
- Department of Genetics and Endocrinology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Chunhua Zeng
- Department of Genetics and Endocrinology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
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Yu H, Zhang G, Yu S, Wu W. Wiedemann-Steiner Syndrome: Case Report and Review of Literature. CHILDREN (BASEL, SWITZERLAND) 2022; 9:children9101545. [PMID: 36291481 PMCID: PMC9600770 DOI: 10.3390/children9101545] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 10/04/2022] [Accepted: 10/08/2022] [Indexed: 11/07/2022]
Abstract
Wiedemann–Steiner syndrome (WDSTS) is an autosomal dominant disorder with a broad and variable phenotypic spectrum characterized by intellectual disability, prenatal and postnatal growth retardation, hypertrichosis, characteristic facial features, behavioral problems, and congenital anomalies involving different systems. Here, we report a five-year-old boy who was diagnosed with WDSTS based on the results of Trio-based whole-exome sequencing and an assessment of his clinical features. He had intellectual disability, short stature, hirsutism, and atypical facial features, including a low hairline, down-slanting palpebral fissures, hypertelorism, long eyelashes, broad and arching eyebrows, synophrys, a bulbous nose, a broad nasal tip, and dental/oral anomalies. However, not all individuals with WDSTS exhibit the classic phenotype, so the spectrum of the disorder can vary widely from relatively atypical facial features to multiple systemic symptoms. Here, we summarize the clinical and molecular spectrum, diagnosis and differential diagnosis, long-term management, and care planning of WDSTS to improve the awareness of both pediatricians and clinical geneticists and to promote the diagnosis and treatment of the disease.
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Phenotypic Variation in Two Siblings Affected with Shwachman-Diamond Syndrome: The Use of Expert Variant Interpreter (eVai) Suggests Clinical Relevance of a Variant in the KMT2A Gene. Genes (Basel) 2022; 13:genes13081314. [PMID: 35893049 PMCID: PMC9394309 DOI: 10.3390/genes13081314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/14/2022] [Accepted: 07/20/2022] [Indexed: 12/04/2022] Open
Abstract
Introduction. Shwachman-Diamond Syndrome (SDS) is an autosomal-recessive disorder characterized by neutropenia, pancreatic exocrine insufficiency, skeletal dysplasia, and an increased risk for leukemic transformation. Biallelic mutations in the SBDS gene have been found in about 90% of patients. The clinical spectrum of SDS in patients is wide, and variability has been noticed between different patients, siblings, and even within the same patient over time. Herein, we present two SDS siblings (UPN42 and UPN43) carrying the same SBDS mutations and showing relevant differences in their phenotypic presentation. Study aim. We attempted to understand whether other germline variants, in addition to SBDS, could explain some of the clinical variability noticed between the siblings. Methods. Whole-exome sequencing (WES) was performed. Human Phenotype Ontology (HPO) terms were defined for each patient, and the WES data were analyzed using the eVai and DIVAs platforms. Results. In UPN43, we found and confirmed, using Sanger sequencing, a novel de novo variant (c.10663G > A, p.Gly3555Ser) in the KMT2A gene that is associated with autosomal-dominant Wiedemann−Steiner Syndrome. The variant is classified as pathogenic according to different in silico prediction tools. Interestingly, it was found to be related to some of the HPO terms that describe UPN43. Conclusions. We postulate that the KMT2A variant found in UPN43 has a concomitant and co-occurring clinical effect, in addition to SBDS mutation. This dual molecular effect, supported by in silico prediction, could help to understand some of the clinical variations found among the siblings. In the future, these new data are likely to be useful for personalized medicine and therapy for selected cases.
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Li X, Yao R, Chang G, Li Q, Song C, Li N, Ding Y, Li J, Chen Y, Wang Y, Huang X, Shen Y, Zhang H, Wang J, Wang X. Clinical Profiles and Genetic Spectra of 814 Chinese Children With Short Stature. J Clin Endocrinol Metab 2022; 107:972-985. [PMID: 34850017 PMCID: PMC8947318 DOI: 10.1210/clinem/dgab863] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Indexed: 12/25/2022]
Abstract
CONTEXT Data and studies based on exome sequencing for the genetic evaluation of short stature are limited, and more large-scale studies are warranted. Some factors increase the likelihood of a monogenic cause of short stature, including skeletal dysplasia, severe short stature, and small for gestational age (SGA) without catch-up growth. However, whether these factors can serve as predictors of molecular diagnosis remains unknown. OBJECTIVE We aimed to explore the diagnostic efficiency of the associated risk factors and their exome sequences for screening. METHODS We defined and applied factors that increased the likelihood of monogenic causes of short stature in diagnostic genetic tests based on next-generation sequencing (NGS) in 814 patients with short stature and at least 1 other factor. RESULTS Pathogenic/likely pathogenic (P/LP) variants in genes, copy number variations, and chromosomal abnormalities were identified in 361 patients. We found P/LP variants among 111 genes, and RASopathies comprised the most important etiology. Short stature combined with other phenotypes significantly increased the likelihood of a monogenic cause, including skeletal dysplasia, facial dysmorphism, and intellectual disability, compared with simple severe short stature (<-3 SD scores). We report novel candidate pathogenic genes, KMT2C for unequivocal growth hormone insensitivity and GATA6 for SGA. CONCLUSION Our study identified the diagnostic characteristics of NGS in short stature with different risk factors. Our study provides novel insights into the current understanding of the etiology of short stature in patients with different phenotypes.
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Affiliation(s)
- Xin Li
- Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ruen Yao
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Guoying Chang
- Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qun Li
- Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Cui Song
- Department of Endocrinology and Genetic Metabolism disease, Children’s Hospital of Chongqing Medical University, Chongqing, China
| | - Niu Li
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yu Ding
- Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Juan Li
- Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yao Chen
- Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yirou Wang
- Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaodong Huang
- Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yongnian Shen
- Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hao Zhang
- Department of Cardiothoracic Surgery, Heart Center, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jian Wang
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiumin Wang
- Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Foroutan A, Haghshenas S, Bhai P, Levy MA, Kerkhof J, McConkey H, Niceta M, Ciolfi A, Pedace L, Miele E, Genevieve D, Heide S, Alders M, Zampino G, Merla G, Fradin M, Bieth E, Bonneau D, Dieterich K, Fergelot P, Schaefer E, Faivre L, Vitobello A, Maitz S, Fischetto R, Gervasini C, Piccione M, van de Laar I, Tartaglia M, Sadikovic B, Lebre AS. Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome. Int J Mol Sci 2022; 23:ijms23031815. [PMID: 35163737 PMCID: PMC8836705 DOI: 10.3390/ijms23031815] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/26/2022] [Accepted: 01/31/2022] [Indexed: 12/28/2022] Open
Abstract
Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.
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Affiliation(s)
- Aidin Foroutan
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada; (A.F.); (S.H.)
- Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada; (P.B.); (M.A.L.); (J.K.); (H.M.)
| | - Sadegheh Haghshenas
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada; (A.F.); (S.H.)
- Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada; (P.B.); (M.A.L.); (J.K.); (H.M.)
| | - Pratibha Bhai
- Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada; (P.B.); (M.A.L.); (J.K.); (H.M.)
| | - Michael A. Levy
- Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada; (P.B.); (M.A.L.); (J.K.); (H.M.)
| | - Jennifer Kerkhof
- Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada; (P.B.); (M.A.L.); (J.K.); (H.M.)
| | - Haley McConkey
- Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada; (P.B.); (M.A.L.); (J.K.); (H.M.)
| | - Marcello Niceta
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy; (M.N.); (A.C.); (M.T.)
| | - Andrea Ciolfi
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy; (M.N.); (A.C.); (M.T.)
| | - Lucia Pedace
- Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy; (L.P.); (E.M.)
| | - Evelina Miele
- Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy; (L.P.); (E.M.)
| | - David Genevieve
- Medical Genetic Department for Rare Diseases and Personalized Medicine, Reference Center AD SOOR, AnDDI-RARE, Groupe DI, Inserm U1183—Institute for Regenerative Medicine and Biotherapy, Montpellier University, Centre Hospitalier Universitaire de Montpellier, 34090 Montpellier, France;
| | - Solveig Heide
- Department of Genetics, Referral Center for Intellectual Disabilities, APHP Sorbonne University, Pitié Salpêtrière Hospital, 75013 Paris, France;
| | - Mariëlle Alders
- Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Giuseppe Zampino
- Center for Rare Diseases and Congenital Defects, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy;
- Facoltà di Medicina e Chirurgia, Università Cattolica del S. Cuore, 20123 Roma, Italy
| | - Giuseppe Merla
- Department of Molecular Medicine and Medical Biotechnology, Università di Napoli “Federico II”, 80131 Naples, Italy;
- Laboratory of Regulatory and Functional Genomics, Fondazione Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
| | - Mélanie Fradin
- Service de Génétique, CHU de Rennes, 35203 Rennes, France;
| | - Eric Bieth
- Medical Genetics Department, University of Angers, CHU Angers, 49000 Angers, France;
| | - Dominique Bonneau
- Department of genetics, CHU d’Angers, 49000 Angers, France and MitoVasc, UMR CNRS 6015-INSERM 1083, University of Angers, 49055 Angers, France;
| | - Klaus Dieterich
- CHU Grenoble Alpes, Inserm, U1209, Institute of Advanced Biosciences, Université Grenoble Alpes, 38000 Grenoble, France;
| | - Patricia Fergelot
- Medical Genetics Department, Inserm U1211, Reference Center AD SOOR, AnDDI-RARE, Bordeaux University, Centre Hospitalier Universitaire de Bordeaux, 33076 Bordeaux, France;
| | - Elise Schaefer
- Service de Génétique Médicale—Institut de Génétique Médicale d’Alsace—Hôpitaux Universitaires de Strasbourg, 67091 Strasbourg, France;
| | - Laurence Faivre
- Inserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, 15 boulevard du Maréchal de Lattre de Tassigny, 21000 Dijon, France; (L.F.); (A.V.)
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, Department of Medical Genetics, Dijon University Hospital, 21000 Dijon, France
| | - Antonio Vitobello
- Inserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, 15 boulevard du Maréchal de Lattre de Tassigny, 21000 Dijon, France; (L.F.); (A.V.)
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, Department of Medical Genetics, Dijon University Hospital, 21000 Dijon, France
| | - Silvia Maitz
- Clinical Pediatric Genetics Unit, Pediatrics Clinics, MBBM Foundation, S. Gerardo Hospital, 20900 Monza, Italy;
| | - Rita Fischetto
- Clinical Genetics Unit, Department of Pediatric Medicine, Giovanni XXIII Children’s Hospital, 02115 Bari, Italy;
| | - Cristina Gervasini
- Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy;
| | - Maria Piccione
- Department of Sciences for Health Promotion and Mother and Child Care “G. D’Alessandro”, University of Palermo, 90127 Palermo, Italy;
| | - Ingrid van de Laar
- Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands;
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy; (M.N.); (A.C.); (M.T.)
| | - Bekim Sadikovic
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada; (A.F.); (S.H.)
- Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada; (P.B.); (M.A.L.); (J.K.); (H.M.)
- Correspondence: (B.S.); (A.-S.L.)
| | - Anne-Sophie Lebre
- Team Physiopathologie des Maladies Psychiatriques, GDR3557-Institut de Psychiatrie, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Université de Paris, 75006 Paris, France
- Centre Hospitalier Universitaire de Reims, Pôle de Biologie Médicale et Pathologie, Service de GénéTique, 51100 Reims, France
- Correspondence: (B.S.); (A.-S.L.)
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11
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Wilson KD, Porter EG, Garcia BA. Reprogramming of the epigenome in neurodevelopmental disorders. Crit Rev Biochem Mol Biol 2022; 57:73-112. [PMID: 34601997 PMCID: PMC9462920 DOI: 10.1080/10409238.2021.1979457] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 07/23/2021] [Accepted: 09/08/2021] [Indexed: 02/03/2023]
Abstract
The etiology of neurodevelopmental disorders (NDDs) remains a challenge for researchers. Human brain development is tightly regulated and sensitive to cellular alterations caused by endogenous or exogenous factors. Intriguingly, the surge of clinical sequencing studies has revealed that many of these disorders are monogenic and monoallelic. Notably, chromatin regulation has emerged as highly dysregulated in NDDs, with many syndromes demonstrating phenotypic overlap, such as intellectual disabilities, with one another. Here we discuss epigenetic writers, erasers, readers, remodelers, and even histones mutated in NDD patients, predicted to affect gene regulation. Moreover, this review focuses on disorders associated with mutations in enzymes involved in histone acetylation and methylation, and it highlights syndromes involving chromatin remodeling complexes. Finally, we explore recently discovered histone germline mutations and their pathogenic outcome on neurological function. Epigenetic regulators are mutated at every level of chromatin organization. Throughout this review, we discuss mechanistic investigations, as well as various animal and iPSC models of these disorders and their usefulness in determining pathomechanism and potential therapeutics. Understanding the mechanism of these mutations will illuminate common pathways between disorders. Ultimately, classifying these disorders based on their effects on the epigenome will not only aid in prognosis in patients but will aid in understanding the role of epigenetic machinery throughout neurodevelopment.
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Affiliation(s)
- Khadija D Wilson
- Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Elizabeth G Porter
- Department of Biochemistry and Molecular Biophysics, University of Washington School of Medicine, St. Louis, MO, USA
| | - Benjamin A Garcia
- Department of Biochemistry and Molecular Biophysics, University of Washington School of Medicine, St. Louis, MO, USA
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12
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Shangguan H, Chen R. Phenotypes of Cornelia de Lange syndrome caused by non-cohesion genes: Novel variants and literature review. Front Pediatr 2022; 10:940294. [PMID: 35935361 PMCID: PMC9355708 DOI: 10.3389/fped.2022.940294] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/27/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Cornelia de Lange syndrome (CdLS) is a genetic disorder caused by variants in cohesion genes including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. According to the 2018 consensus statement, a patient with clinical scored ≥ 11 points could be diagnosed as CdLS. However, some variants in non-cohesion genes rather than cohesion genes can manifest as phenotypes of CdLS. OBJECTIVES This study describes six variants of non-cohesion genes (KDM6A, KMT2D, KMT2A ANKRD11, and UBE2A), and assesses the reliability of 11-points scale criteria in the clinical diagnosis of CdLS. METHODS Whole-exome sequencing (WES) was performed on six patients with features of CdLS. Phenotypic and genotypic spectra of 40 previously reported patients with features of CdLS caused by non-cohesion genes variants and 34 previously reported patients with NIPBL variants were summarized. Clinical score comparison among patients with NIPBL variants versus those with variants in non-cohesin genes was performed. RESULTS Variants in non-cohesion genes were found in six patients [KMT2A (n = 2), KMT2D, ANKRD11, KDM6A, and UBE2A]. Of them, four variants (KMT2A c.7789C > T, ANKRD11 c.1757_1776del, KDM6A c.655-1G > A, and UBE2A c.439C > T) were novel. Combining with previously reported cases, 46 patients with phenotypes of CdLS caused by variants in 20 non-cohesion genes are now reported. From this total cohort, the average clinical score of patients in ANKRD11 cohort, SETD5 cohort, and AFF4 cohort was statistically lower than those in NIPBL cohort (8.92 ± 1.77 vs. 12.23 ± 2.58, 7.33 ± 2.52 vs. 12.23 ± 2.58, 5.33 ± 1.53 vs. 12.23 ± 2.58; p < 0.05). The average clinical score of KMT2A cohort, EP300 cohort, and NIPBL cohort had not significantly different from (11 ± 2.19 vs. 12.23 ± 2.58, 10 ± 4.58 vs. 12.23 ± 2.58; p > 0.05). CONCLUSION We described 4 novel variants of non-cohesion genes in six Chinese patients with phenotypes of CdLS. Of note, three genes (KMT2D, KDM6A, and UBE2A) causing features of CdLS have never been reported. The proposed clinical criteria for CdLS needed to be updated and refined, insofar as WES was necessary to confirm the diagnosis of CdLS. Our study expanded the spectra of non-cohesion genetic variations in patients with features of CdLS.
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Affiliation(s)
- Huakun Shangguan
- Department of Endocrinology, Fuzhou Children's Hospital of Fujian Medical University, Fuzhou, China
| | - Ruimin Chen
- Department of Endocrinology, Fuzhou Children's Hospital of Fujian Medical University, Fuzhou, China
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13
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Buchanan K, Greenup E, Hurst ACE, Sunil B, Ashraf AP. Case report: 11-ketotestosterone may potentiate advanced bone age as seen in some cases of Wiedemann-Steiner Syndrome. Front Endocrinol (Lausanne) 2022; 13:1004114. [PMID: 36263329 PMCID: PMC9574220 DOI: 10.3389/fendo.2022.1004114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
CONTEXT Wiedemann-Steiner Syndrome (WSS) is a genetic disorder associated with an array of clinical phenotypes, including advanced bone age and short stature. 11-ketotestosterone (11KT) is a member of the group known as 11-oxygenated C19 androgens that are implicated in premature adrenarche. CASE DESCRIPTION Case 1: The patient is a 3 year and 11-month-old female diagnosed with WSS due to deletion of KMT2A detected on CGH microarray. At two years and 11 months, imaging revealed an advanced bone age. We obtained an 11KT level on this patient. 11KT in case 1 was elevated at 26.3 ng/dL, while the normal reference range is 7.3-10.9 ng/dL and the reference interval for premature adrenarche is 12.3-22.9 ng/dL, The repeat 11KT at follow up (chronological age 4 years and 6 months) was still elevated at 33.8 ng/dL Case 2: A second child with WSS and a 5kb intragenic KMT2A deletion was evaluated at 11 months of age; his 11KT was 4.5 ng/dL. CONCLUSIONS The elevated 11KT may indicate maturational changes related to increasing adrenal gland androgenic activation and may explain the advanced bone age seen in some patients with WSS. To our knowledge, this is the first case report that describes 11KT as a bioactive androgen potentially causing bone age advancement in WSS. Lack of elevation of 11KT in the second child who is an infant suggests increasing androgenic precursors and metabolites related to premature adrenarche may need to be longitudinally followed.
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Affiliation(s)
- Katherine Buchanan
- University of Alabama at Birmingham Marnix E. Heersink School of Medicine, Birmingham, AL, United States
- *Correspondence: Katherine Buchanan,
| | - Erin Greenup
- Division of Pediatric Endocrinology, Department of Pediatrics, Orlando Health Arnold Palmer Hospital for Children, Orlando, FL, United States
| | - Anna C. E. Hurst
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Bhuvana Sunil
- Division of Pediatric Endocrinology and Diabetes, Mary Bridge Children’s Hospital, Tacoma, WA, United States
| | - Ambika P. Ashraf
- Divison of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, United States
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14
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Wiedemann–Steiner Syndrome with a Pathogenic Variant in KMT2A from Taiwan. CHILDREN 2021; 8:children8110952. [PMID: 34828665 PMCID: PMC8620998 DOI: 10.3390/children8110952] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 10/17/2021] [Accepted: 10/20/2021] [Indexed: 11/17/2022]
Abstract
Wiedemann–Steiner syndrome (WSS) is a rare genetic disorder. Patients with WSS have characteristics of growth retardation, facial dysmorphism, hypertrichosis cubiti (HC), and neurodevelopmental delays. WSS is in an autosomal dominant inherited pattern caused by a mutation of the KMT2A gene (NM_001197104.2). In this article, we discuss a 5-year-old boy who has mild intellectual disability (ID), hypotonia, HC, hypertrichosis on the back, dysmorphic facies, psychomotor retardation, and growth delay. Trio-based whole-exome sequencing (trio-WES) was carried out on this patient and his parents, confirming the variants with Sanger sequencing. Trio-WES showed a de novo mutation of the KMT2A gene (NM_001197104.2: c.4696G>A, p.Gly1566Arg). On the basis of the clinical features and the results of the WES, WSS was diagnosed. Therefore, medical professionals should consider a diagnosis of WSS if patients have growth retardation and development delay as well as hirsutism, particularly HC.
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15
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Luo S, Bi B, Zhang W, Zhou R, Chen W, Zhao P, Huang Y, Yuan L, He X. Three de novo variants in KMT2A (MLL) identified by whole exome sequencing in patients with Wiedemann-Steiner syndrome. Mol Genet Genomic Med 2021; 9:e1798. [PMID: 34469078 PMCID: PMC8580087 DOI: 10.1002/mgg3.1798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 07/17/2021] [Accepted: 08/16/2021] [Indexed: 11/26/2022] Open
Abstract
Background Wiedemann–Steiner syndrome (WSS) is an autosomal dominant disorder characterized by short stature, hypertrichosis, intellectual disability, developmental delay, along with facial dysmorphism. WSS patients exhibit great phenotypic heterogeneities. Some variants in KMT2A (MLL) gene have been identified as the cause of WSS. Methods Whole exome sequencing on the probands followed by Sanger sequencing validations in the family were applied to determine genetic variants. In silico analyses were used for predicting potential effects of the variants. Results We identified three novel de novo heterozygous variants: c.883A>T (p.Lys295*), c.4171C>T (p.Gln1391*), and c.3499T>C (p.Cys1167Arg), in KMT2A gene from three unrelated Chinese WSS patients. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, these three variants were classified as pathogenic, pathogenic and likely pathogenic variant, respectively. By reviewing all the available cases with same mutated KMT2A regions as the three patients had, we found that in addition to the representative symptoms, our patients exhibited some sporadically observed symptoms, such as severe ophthalmological symptoms, endocardial fibroelastosis, cytomegalovirus infection, and feet eversion. We also revealed that variants in different KMT2A regions contribute to the phenotypic heterogeneity of WSS, highlighting challenges in the diagnosis of syndromic disorders spanning a broad phenotypic spectrum. Conclusion Our study would aid in further broadening our knowledge about the genotype–phenotype correlation of WSS.
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Affiliation(s)
- Sukun Luo
- Precision Medical Laboratory, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Bo Bi
- Rehabilitation Department, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Wenqian Zhang
- BGI Genomics, BGI-Shenzhen, Shenzhen, China.,BGI-Wuhan Clinical Laboratories, BGI-Shenzhen, Wuhan, China.,Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Rui Zhou
- BGI Genomics, BGI-Shenzhen, Shenzhen, China.,BGI-Wuhan Clinical Laboratories, BGI-Shenzhen, Wuhan, China.,State Key Laboratory of Agricultural Microbiology, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Wei Chen
- BGI Genomics, BGI-Shenzhen, Shenzhen, China.,BGI-Wuhan Clinical Laboratories, BGI-Shenzhen, Wuhan, China
| | - Peiwei Zhao
- Precision Medical Laboratory, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Yufeng Huang
- Precision Medical Laboratory, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Li Yuan
- Ultrasonography Department, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Xuelian He
- Precision Medical Laboratory, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
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16
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Sheppard SE, Campbell IM, Harr MH, Gold N, Li D, Bjornsson HT, Cohen JS, Fahrner JA, Fatemi A, Harris JR, Nowak C, Stevens CA, Grand K, Au M, Graham JM, Sanchez-Lara PA, Campo MD, Jones MC, Abdul-Rahman O, Alkuraya FS, Bassetti JA, Bergstrom K, Bhoj E, Dugan S, Kaplan JD, Derar N, Gripp KW, Hauser N, Innes AM, Keena B, Kodra N, Miller R, Nelson B, Nowaczyk MJ, Rahbeeni Z, Ben-Shachar S, Shieh JT, Slavotinek A, Sobering AK, Abbott MA, Allain DC, Amlie-Wolf L, Au PYB, Bedoukian E, Beek G, Barry J, Berg J, Bernstein JA, Cytrynbaum C, Chung BHY, Donoghue S, Dorrani N, Eaton A, Flores-Daboub JA, Dubbs H, Felix CA, Fong CT, Fung JLF, Gangaram B, Goldstein A, Greenberg R, Ha TK, Hersh J, Izumi K, Kallish S, Kravets E, Kwok PY, Jobling RK, Knight Johnson AE, Kushner J, Lee BH, Levin B, Lindstrom K, Manickam K, Mardach R, McCormick E, McLeod DR, Mentch FD, Minks K, Muraresku C, Nelson SF, Porazzi P, Pichurin PN, Powell-Hamilton NN, Powis Z, Ritter A, Rogers C, Rohena L, Ronspies C, Schroeder A, Stark Z, Starr L, Stoler J, Suwannarat P, Velinov M, Weksberg R, Wilnai Y, Zadeh N, Zand DJ, Falk MJ, et alSheppard SE, Campbell IM, Harr MH, Gold N, Li D, Bjornsson HT, Cohen JS, Fahrner JA, Fatemi A, Harris JR, Nowak C, Stevens CA, Grand K, Au M, Graham JM, Sanchez-Lara PA, Campo MD, Jones MC, Abdul-Rahman O, Alkuraya FS, Bassetti JA, Bergstrom K, Bhoj E, Dugan S, Kaplan JD, Derar N, Gripp KW, Hauser N, Innes AM, Keena B, Kodra N, Miller R, Nelson B, Nowaczyk MJ, Rahbeeni Z, Ben-Shachar S, Shieh JT, Slavotinek A, Sobering AK, Abbott MA, Allain DC, Amlie-Wolf L, Au PYB, Bedoukian E, Beek G, Barry J, Berg J, Bernstein JA, Cytrynbaum C, Chung BHY, Donoghue S, Dorrani N, Eaton A, Flores-Daboub JA, Dubbs H, Felix CA, Fong CT, Fung JLF, Gangaram B, Goldstein A, Greenberg R, Ha TK, Hersh J, Izumi K, Kallish S, Kravets E, Kwok PY, Jobling RK, Knight Johnson AE, Kushner J, Lee BH, Levin B, Lindstrom K, Manickam K, Mardach R, McCormick E, McLeod DR, Mentch FD, Minks K, Muraresku C, Nelson SF, Porazzi P, Pichurin PN, Powell-Hamilton NN, Powis Z, Ritter A, Rogers C, Rohena L, Ronspies C, Schroeder A, Stark Z, Starr L, Stoler J, Suwannarat P, Velinov M, Weksberg R, Wilnai Y, Zadeh N, Zand DJ, Falk MJ, Hakonarson H, Zackai EH, Quintero-Rivera F. Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome. Am J Med Genet A 2021; 185:1649-1665. [PMID: 33783954 DOI: 10.1002/ajmg.a.62124] [Show More Authors] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 01/29/2021] [Accepted: 01/30/2021] [Indexed: 12/19/2022]
Abstract
Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.
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Affiliation(s)
- Sarah E Sheppard
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Ian M Campbell
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Margaret H Harr
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Nina Gold
- Mass General Hospital for Children, Division of Medical Genetics and Metabolism and Harvard Medical School, Boston, Massachusetts, USA
| | - Dong Li
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Hans T Bjornsson
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Faculty of Medicine, University of Iceland, Reykjavik, Iceland.,Landspitali University Hospital, Iceland
| | - Julie S Cohen
- Division of Neurogenetics and Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, Maryland, USA.,McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jill A Fahrner
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland, USA
| | - Ali Fatemi
- Division of Neurogenetics and Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, Maryland, USA.,Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jacqueline R Harris
- Division of Neurogenetics and Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, Maryland, USA.,McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Catherine Nowak
- Division of Genetics and Genomics, Boston Children's Hospital, The Feingold Center for Children, Boston, Massachusetts, USA
| | - Cathy A Stevens
- Department of Pediatrics, University of Tennessee College of Medicine, Chattanooga, Tennessee, USA
| | - Katheryn Grand
- Division of Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, and David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Margaret Au
- Division of Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, and David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - John M Graham
- Division of Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, and David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Pedro A Sanchez-Lara
- Division of Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, and David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Miguel Del Campo
- Division of Medical Genetics, Department of Pediatrics, University of California, and Rady Children's Hospital, San Diego, California, USA
| | - Marilyn C Jones
- Division of Medical Genetics, Department of Pediatrics, University of California, and Rady Children's Hospital, San Diego, California, USA
| | - Omar Abdul-Rahman
- Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Fowzan S Alkuraya
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Jennifer A Bassetti
- Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medicine, New York, New York, USA
| | - Katherine Bergstrom
- Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medicine, New York, New York, USA
| | - Elizabeth Bhoj
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Sarah Dugan
- Division of Medical Genetics, University of Utah, Salt Lake City, Utah, USA
| | - Julie D Kaplan
- Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Nada Derar
- Department of Medical Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Karen W Gripp
- Division of Medical Genetics, Alfred I duPont Hospital for Children, Wilmington, Delaware, USA
| | - Natalie Hauser
- Division of Medical Genomics, Inova Translational Medicine Institute, Inova Fairfax Hospital, Falls Church, Virginia, USA
| | - A Micheil Innes
- Department of Medical Genetics, University of Calgary, Calgary, Canada.,Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Beth Keena
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Neslida Kodra
- Division of Medical Genomics, Inova Translational Medicine Institute, Inova Fairfax Hospital, Falls Church, Virginia, USA
| | - Rebecca Miller
- Division of Medical Genomics, Inova Translational Medicine Institute, Inova Fairfax Hospital, Falls Church, Virginia, USA
| | - Beverly Nelson
- Department of Clinical Skills, St. George's University, True Blue, Grenada
| | | | - Zuhair Rahbeeni
- Department of Medical Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Shay Ben-Shachar
- Genetic Institute, Tel-Aviv Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Joseph T Shieh
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | - Anne Slavotinek
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | - Andrew K Sobering
- Department of Biochemistry, St. George's University, True Blue, Grenada
| | - Mary-Alice Abbott
- Medical Genetics, Department of Pediatrics, University of Massachusetts Medical School - Baystate, Springfield, Massachusetts, USA
| | - Dawn C Allain
- Division of Human Genetics, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Louise Amlie-Wolf
- Division of Medical Genetics, Alfred I duPont Hospital for Children, Wilmington, Delaware, USA
| | - Ping Yee Billie Au
- Department of Medical Genetics, University of Calgary, Calgary, Canada.,Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Emma Bedoukian
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Geoffrey Beek
- Children's Hospital of Minnesota, Minneapolis, Minnesota, USA
| | - James Barry
- Division of Medical Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, Texas, USA.,Department of Pediatrics, Long School of Medicine-UT Health San Antonio, San Antonio, Texas, USA
| | - Janet Berg
- Division of Medical Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, Texas, USA.,Department of Pediatrics, Long School of Medicine-UT Health San Antonio, San Antonio, Texas, USA
| | - Jonathan A Bernstein
- Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
| | - Cheryl Cytrynbaum
- Division of Clinical and Metabolic Genetics and Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Brian Hon-Yin Chung
- Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR
| | - Sarah Donoghue
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Naghmeh Dorrani
- Department of Pediatrics, University of California Los Angeles, California, Los Angeles, USA.,UCLA Clinical Genomics Center, University of California Los Angeles, California, Los Angeles, USA
| | - Alison Eaton
- Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
| | | | - Holly Dubbs
- Division of Neurology, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Carolyn A Felix
- Division of Oncology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Chin-To Fong
- Department of Pediatrics, Division of Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Jasmine Lee Fong Fung
- Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR
| | - Balram Gangaram
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | - Amy Goldstein
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Rotem Greenberg
- Genetic Institute, Tel-Aviv Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Thoa K Ha
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | - Joseph Hersh
- Weisskopf Child Evaluation Center, Department of Pediatrics, University of Louisville, Louisville, Kentucky, USA
| | - Kosuke Izumi
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Staci Kallish
- Division of Translational Medicine and Human Genetics Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Elijah Kravets
- Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
| | - Pui-Yan Kwok
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | - Rebekah K Jobling
- Division of Clinical and Metabolic Genetics and Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | | | - Jessica Kushner
- Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA
| | - Bo Hoon Lee
- Department of Neurology, Division of Child Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Brooke Levin
- MD Anderson Cancer Center at Cooper, Cooper University Health Care, Camden, New Jersey, USA
| | | | - Kandamurugu Manickam
- Division of Human Genetics, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Rebecca Mardach
- Division of Medical Genetics, Department of Pediatrics, University of California, and Rady Children's Hospital, San Diego, California, USA
| | - Elizabeth McCormick
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - D Ross McLeod
- Department of Medical Genetics, University of Calgary, Calgary, Canada
| | - Frank D Mentch
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Kelly Minks
- Department of Neurology, Division of Child Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Colleen Muraresku
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Stanley F Nelson
- UCLA Clinical Genomics Center, University of California Los Angeles, California, Los Angeles, USA.,Department of Human Genetics, Center for Duchenne Muscular Dystrophy University of California Los Angeles, California, Los Angeles, USA
| | - Patrizia Porazzi
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Pavel N Pichurin
- Clinical Genomics Center, University of California Los Angeles, Los Angeles, California, USA
| | - Nina N Powell-Hamilton
- Division of Medical Genetics, Alfred I duPont Hospital for Children, Wilmington, Delaware, USA
| | - Zoe Powis
- Quest Diagnostics Kalamzoo, Kalamzoo, Michigan, USA
| | - Alyssa Ritter
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Caleb Rogers
- Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA
| | - Luis Rohena
- Division of Medical Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, Texas, USA.,Department of Pediatrics, Long School of Medicine-UT Health San Antonio, San Antonio, Texas, USA
| | - Carey Ronspies
- Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Audrey Schroeder
- Department of Pediatrics, Division of Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Zornitza Stark
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, Australia
| | - Lois Starr
- Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Joan Stoler
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Pim Suwannarat
- Mid-Atlantic Permanente Medical Group, Rockville, Maryland, USA
| | - Milen Velinov
- NYS Institute for Basic Research in developmental Disabilities, Staten Island, New York, USA
| | - Rosanna Weksberg
- Division of Clinical and Metabolic Genetics and Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Yael Wilnai
- Genetic Institute, Sourasky Medical Center, Te-Aviv, Tel Aviv, Israel
| | - Neda Zadeh
- Genetics Center and CHOC Children's Hospital, Orange, California, USA
| | - Dina J Zand
- Rare Disease Institute, Children's National Medical Center, Washington, District of Columbia, USA
| | - Marni J Falk
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Hakon Hakonarson
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Elaine H Zackai
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Fabiola Quintero-Rivera
- Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR.,Department of Pathology and Laboratory Medicine, University of California Los Angeles, California, Los Angeles, USA
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17
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Demir S, Gürkan H, Öz V, Yalçıntepe S, Atlı Eİ, Atlı E. Wiedemann-Steiner Syndrome as a Differential Diagnosis of Cornelia de Lange Syndrome Using Targeted Next-Generation Sequencing: A Case Report. Mol Syndromol 2021; 12:46-51. [PMID: 33776627 PMCID: PMC7983614 DOI: 10.1159/000511971] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 10/01/2020] [Indexed: 12/31/2022] Open
Abstract
Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant disorder with a variable clinical phenotype including synophrys, hypertelorism, thick eyebrows, long eyelashes, wide nasal bridge, long philtrum, hypertrichosis, growth retardation, and intellectual disability. Cornelia de Lange syndrome (CdLS) is a rare disease characterized by synophrys, long eyelashes, limb abnormalities, generalized hirsutism, growth retardation, and intellectual disability. In both WDSTS and CdLS, the malformations are due to transcriptome disturbance caused by defects in the genes encoding the components of chromatin regulation and transcription process. The overlapping features in these two syndromes may complicate the original diagnosis of a patient. Here, we report on a Wiedemann-Steiner patient found to have a de novo pathogenic KMT2A variation who had been clinically suspected as CdLS. We suggest that targeted next-generation sequencing is a feasible tool for the precise diagnosis of patients who have phenotypically and clinically overlapping features of CdLS and WDSTS.
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Affiliation(s)
- Selma Demir
- Department of Medical Genetics, Faculty of Medicine, Trakya University, Edirne, Turkey
| | - Hakan Gürkan
- Department of Medical Genetics, Faculty of Medicine, Trakya University, Edirne, Turkey
| | - Veysel Öz
- Department of Pediatric Neurology, Faculty of Medicine, Trakya University, Edirne, Turkey
| | - Sinem Yalçıntepe
- Department of Medical Genetics, Faculty of Medicine, Trakya University, Edirne, Turkey
| | - Emine İ. Atlı
- Department of Medical Genetics, Faculty of Medicine, Trakya University, Edirne, Turkey
| | - Engin Atlı
- Department of Medical Genetics, Faculty of Medicine, Trakya University, Edirne, Turkey
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18
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Nardello R, Mangano GD, Fontana A, Gagliardo C, Midiri F, Borgia P, Brighina F, Raieli V, Mangano S, Salpietro V. Broad neurodevelopmental features and cortical anomalies associated with a novel de novo KMT2A variant in Wiedemann-Steiner syndrome. Eur J Med Genet 2021; 64:104133. [PMID: 33387673 DOI: 10.1016/j.ejmg.2020.104133] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/03/2020] [Accepted: 12/27/2020] [Indexed: 11/27/2022]
Abstract
Wiedemann-Steiner syndrome (WDSTS) is a rare genetic disorder including developmental delay/intellectual disability (DD/ID), hypertrichosis cubiti, short stature, and distinctive facial features, caused by mutation in KMT2A gene, which encodes a histone methyltransferase (H3K4) that regulates chromatin-mediated transcription. Different neurodevelopmental phenotypes have been described within the WDSTS spectrum, including a peculiar Autism Spectrum Disorder (ASDs) subtype in some affected individuals. Here, we report a 9-year-old Caucasian male found by next-generation panel sequencing to carry a novel heterozygous de novo KMT2A frameshift variant (NM_001197104.2:c.4433delG; p. Arg1478LeufsTer108). This boy presented a WDSTS phenotype associated with broad neurodevelopmental features, including an unusual speech difficulty (i.e., palilalia), and brain imaging studies revealed an array of cortical anomalies (e.g., frontal simplified gyration, focal frontal cortical dysplasia). These clinical and radiological observations expand the known WDSTS-related neurodevelopmental phenotypes and further strengthen the important role of KMT2A in brain function and cortical development.
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Affiliation(s)
- Rosaria Nardello
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialities "G. D'Alessandro," University of Palermo, Palermo, Italy.
| | - Giuseppe Donato Mangano
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialities "G. D'Alessandro," University of Palermo, Palermo, Italy
| | - Antonina Fontana
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialities "G. D'Alessandro," University of Palermo, Palermo, Italy
| | - Cesare Gagliardo
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Federico Midiri
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Paola Borgia
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
| | - Filippo Brighina
- Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy
| | - Vincenzo Raieli
- Child Neuropsychiatry Department, Di Cristina - ARNAS Civico Hospital, Palermo, Italy
| | - Salvatore Mangano
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialities "G. D'Alessandro," University of Palermo, Palermo, Italy
| | - Vincenzo Salpietro
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS, Istituto "Giannina Gaslini", Genoa, Italy
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19
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Fallah MS, Szarics D, Robson CM, Eubanks JH. Impaired Regulation of Histone Methylation and Acetylation Underlies Specific Neurodevelopmental Disorders. Front Genet 2021; 11:613098. [PMID: 33488679 PMCID: PMC7820808 DOI: 10.3389/fgene.2020.613098] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 12/09/2020] [Indexed: 12/19/2022] Open
Abstract
Epigenetic processes are critical for governing the complex spatiotemporal patterns of gene expression in neurodevelopment. One such mechanism is the dynamic network of post-translational histone modifications that facilitate recruitment of transcription factors or even directly alter chromatin structure to modulate gene expression. This is a tightly regulated system, and mutations affecting the function of a single histone-modifying enzyme can shift the normal epigenetic balance and cause detrimental developmental consequences. In this review, we will examine select neurodevelopmental conditions that arise from mutations in genes encoding enzymes that regulate histone methylation and acetylation. The methylation-related conditions discussed include Wiedemann-Steiner, Kabuki, and Sotos syndromes, and the acetylation-related conditions include Rubinstein-Taybi, KAT6A, genitopatellar/Say-Barber-Biesecker-Young-Simpson, and brachydactyly mental retardation syndromes. In particular, we will discuss the clinical/phenotypic and genetic basis of these conditions and the model systems that have been developed to better elucidate cellular and systemic pathological mechanisms.
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Affiliation(s)
- Merrick S Fallah
- Division of Experimental and Translational Neuroscience, Krembil Research Institute, University Health Network, Toronto, ON, Canada.,Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
| | - Dora Szarics
- Division of Experimental and Translational Neuroscience, Krembil Research Institute, University Health Network, Toronto, ON, Canada.,Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
| | - Clara M Robson
- Division of Experimental and Translational Neuroscience, Krembil Research Institute, University Health Network, Toronto, ON, Canada.,Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
| | - James H Eubanks
- Division of Experimental and Translational Neuroscience, Krembil Research Institute, University Health Network, Toronto, ON, Canada.,Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.,Department of Surgery (Neurosurgery), University of Toronto, Toronto, ON, Canada.,Institute of Medical Science, University of Toronto, Toronto, ON, Canada.,Department of Physiology, University of Toronto, Toronto, ON, Canada
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20
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Tang Q, Zhang Y, Yang Y, Hu H, Lan X, Pan C. The KMT2A gene: mRNA differential expression in the ovary and a novel 13-nt nucleotide sequence variant associated with litter size in cashmere goats. Domest Anim Endocrinol 2021; 74:106538. [PMID: 32896800 DOI: 10.1016/j.domaniend.2020.106538] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 08/05/2020] [Accepted: 08/11/2020] [Indexed: 12/16/2022]
Abstract
A genome-wide association study had shown that lysine methyltransferase 2A (KMT2A), which encodes the histone 3 lysine 4 methyltransferase and reportedly can regulate gametogenesis, steroidogenesis, and development as well as other biological processes, is a potential candidate gene influencing litter size in the dairy goat, suggesting its key function in animal reproduction. Here, we aimed to explore the genetic effects of the KMT2A gene on litter size in females of the Chinese indigenous cashmere goat, using a large sample size (n > 1,000), based on their levels of RNA transcription and DNA variation. First, mRNA expression levels of this gene in ovarian tissues between the low-prolific group (first-born litter size = 1) and high-prolific group (first-born litter size ≥2) were significantly different, revealing the potential functioning of KMT2A in goat prolific. Moreover, a novel 13-nt nucleotide sequence variant was identified in Shaanbei white cashmere goats (n = 1,616). In accordance with the independent chi-square (χ2) analysis, the distribution of genotypes (P = 2.57 × 10-9) and allelotypes (P = 3.00 × 10-7) between the low- and high-prolific groups differed significantly, indicating the 13-nt mutation was associated with litter size. Further analysis showed that the insertion/insertion (II) genotype was significantly different with insertion/deletion (ID) (P = 1.76 × 10-9) and deletion/deletion (DD) (P = 7.00 × 10-6), with goats having the DD genotype producing an average litter size larger than the other genotypes. Taken together, these findings suggest KMT2A can serve as a candidate gene for breeding goats, which may have implications for improving the future development of the goat industry.
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Affiliation(s)
- Q Tang
- College of Animal Science and Technology, Northwest A&F University, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Key Laboratory of Animal Biotechnology, Ministry of Agriculture, No. 22 Xinong Road, Yangling, Shaanxi, 712100, PR China
| | - Y Zhang
- College of Animal Science and Technology, Northwest A&F University, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Key Laboratory of Animal Biotechnology, Ministry of Agriculture, No. 22 Xinong Road, Yangling, Shaanxi, 712100, PR China
| | - Y Yang
- College of Animal Science and Technology, Northwest A&F University, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Key Laboratory of Animal Biotechnology, Ministry of Agriculture, No. 22 Xinong Road, Yangling, Shaanxi, 712100, PR China
| | - H Hu
- College of Animal Science and Technology, Northwest A&F University, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Key Laboratory of Animal Biotechnology, Ministry of Agriculture, No. 22 Xinong Road, Yangling, Shaanxi, 712100, PR China
| | - X Lan
- College of Animal Science and Technology, Northwest A&F University, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Key Laboratory of Animal Biotechnology, Ministry of Agriculture, No. 22 Xinong Road, Yangling, Shaanxi, 712100, PR China
| | - C Pan
- College of Animal Science and Technology, Northwest A&F University, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Key Laboratory of Animal Biotechnology, Ministry of Agriculture, No. 22 Xinong Road, Yangling, Shaanxi, 712100, PR China.
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21
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Wang X, Zhang G, Lu Y, Luo X, Wu W. Trio-WES reveals a novel de novo missense mutation of KMT2A in a Chinese patient with Wiedemann-Steiner syndrome: A case report. Mol Genet Genomic Med 2020; 9:e1533. [PMID: 33325147 PMCID: PMC7963408 DOI: 10.1002/mgg3.1533] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 08/31/2020] [Accepted: 09/25/2020] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Wiedemann-Steiner Syndrome (WSS) is an autosomal dominant genetic condition caused by mutations in the KMT2A gene. Lysine methyltransferase, encoded by KMT2A, plays critical roles in the regulation of gene expression during early development. METHODS Trio-based whole exome sequencing (Trio-WES) was performed on a 15 months old Chinese girl and her two parents by MyGenostics (Beijing, China) using the Illumina HiSeq X ten system. Variants were confirmed with Sanger sequencing. She exhibited mild/moderate intellectual disability (ID), hypotonia, hypertrichosis cubiti, hypertrichosis on the back, dysmorphic facies, psychomotor retardation, growth delay, small and puffy hands, fat pads anterior to calcanei, and palmar/plantar grooves. RESULTS Trio-WES revealed a novel de novo mutation of KMT2A gene (NM_001197104.1: c.3566G>T, p.Cys1189Phe). WSS was diagnosed based on WES and clinical features. CONCLUSION Our findings expand the phenotypic and mutation spectra of WSS.
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Affiliation(s)
- Xiong Wang
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guijiao Zhang
- Department of Paediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanjun Lu
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoping Luo
- Department of Paediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Wu
- Department of Paediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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22
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Carman KB, Kaplan E, Aslan CN, Kocagil S, Cilinigr O, Yarar C. Wiedemann–Steiner Syndrome: A Rare Differential Diagnosis of Neurodevelopmental Delay and Dysmorphic Features. J Pediatr Genet 2020; 11:162-164. [DOI: 10.1055/s-0040-1716709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 08/11/2020] [Indexed: 10/23/2022]
Abstract
AbstractWiedemann–Steiner syndrome (WSS) is a rare genetic disorder characterized by dysmorphic features, neurodevelopmental delay, growth retardation, and hypertrichosis cubiti. It is caused by pathogenic variants in the KMT2A gene. Here, we report a child with WSS presented with neurodevelopmental delay. Genetic analysis revealed a heterozygous c.2312dupC (p.Ser774Valfs*11) variant at the KMT2A gene that was classified as pathogenic in dbSNP (rs1057518649). To the best of our knowledge, this is the first patient of WSS from Turkey. This case draws attention to the diagnosis of WSS in children with neurodevelopmental delay.
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Affiliation(s)
- Kursat Bora Carman
- Department of Pediatric Neurology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Emre Kaplan
- Department of Pediatric Neurology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Cefa Nil Aslan
- Department of Pediatric Neurology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Sinem Kocagil
- Department of Medical Genetics, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Oguz Cilinigr
- Department of Medical Genetics, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Coskun Yarar
- Department of Pediatric Neurology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
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23
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Di Fede E, Massa V, Augello B, Squeo G, Scarano E, Perri AM, Fischetto R, Causio FA, Zampino G, Piccione M, Curridori E, Mazza T, Castellana S, Larizza L, Ghelma F, Colombo EA, Gandini MC, Castori M, Merla G, Milani D, Gervasini C. Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann-Steiner and Rubinstein-Taybi syndromes. Eur J Hum Genet 2020; 29:88-98. [PMID: 32641752 PMCID: PMC7852672 DOI: 10.1038/s41431-020-0679-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 06/03/2020] [Accepted: 06/23/2020] [Indexed: 12/16/2022] Open
Abstract
Lysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as "writer" of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann-Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Such conditions, including WDSTS, are a group of overlapping disorders caused by mutations in genes coding for the epigenetic machinery. Among them, Rubinstein-Taybi syndrome (RSTS) is mainly caused by heterozygous pathogenic variants in CREBBP or EP300. In this work, we used next generation sequencing (either by custom-made panel or by whole exome) to identify alternative causative genes in individuals with a RSTS-like phenotype negative to CREBBP and EP300 mutational screening. In six patients we identified different novel unreported variants in KMT2A gene. The identified variants are de novo in at least four out of six tested individuals and all of them display some typical RSTS phenotypic features but also WDSTS specific signs. This study reinforces the concept that germline variants affecting the epigenetic machinery lead to a shared molecular effect (alteration of the chromatin state) determining superimposable clinical conditions.
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Affiliation(s)
- Elisabetta Di Fede
- Genetica Medica e Biologia Applicata, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy
| | - Valentina Massa
- Genetica Medica e Biologia Applicata, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy.,"Aldo Ravelli" Center for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milano, Italy
| | - Bartolomeo Augello
- Unità di Genetica Medica, IRCSS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Gabriella Squeo
- Unità di Genetica Medica, IRCSS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Emanuela Scarano
- Ambulatorio di Malattie Rare, Sindromologia ed Auxologia U.O. Pediatria AOU S.Orsola-Malpighi, Bologna, Italy
| | - Anna Maria Perri
- Ambulatorio di Malattie Rare, Sindromologia ed Auxologia U.O. Pediatria AOU S.Orsola-Malpighi, Bologna, Italy
| | - Rita Fischetto
- U.O.C. Malattie Metaboliche Genetica Medica, PO Giovanni XXIII, AOU Policlinico Consorziale, Bari, Italy
| | - Francesco Andrea Causio
- U.O.C. Malattie Metaboliche Genetica Medica, PO Giovanni XXIII, AOU Policlinico Consorziale, Bari, Italy
| | - Giuseppe Zampino
- Centro Malattie Rare e Difetti Congeniti, Fondazione Policlinico Universitario A. Gemelli, Università Cattolica, Roma, Italy
| | - Maria Piccione
- Dipartimento di scienze per la promozione della salute e la cura della madre e del bambino "G. D'Alessandro", Università di Palermo, Palermo, Italy
| | - Elena Curridori
- Dipartimento di clinica pediatrica e malattie rare, Ospedale pediatrico Antonio Cao, Cagliari, Italy
| | - Tommaso Mazza
- Unit of Bioinformatics IRCSS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Stefano Castellana
- Unit of Bioinformatics IRCSS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Lidia Larizza
- Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Filippo Ghelma
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy
| | - Elisa Adele Colombo
- Genetica Medica e Biologia Applicata, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy
| | - Maria Chiara Gandini
- Genetica Medica e Biologia Applicata, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy
| | - Marco Castori
- Unità di Genetica Medica, IRCSS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Giuseppe Merla
- Unità di Genetica Medica, IRCSS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Donatella Milani
- UOSD Pediatria ad alta intensità di cura, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milano, Milano, Italy
| | - Cristina Gervasini
- Genetica Medica e Biologia Applicata, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy. .,"Aldo Ravelli" Center for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milano, Italy.
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24
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Abstract
PURPOSE To investigate Wiedemann-Steiner syndrome (WSS), its correlation to hypotonia and developmental delay, and to determine the relative intervention strategies that may be useful during early intervention from birth to 3 years. METHODS A literature search using PEDro and PubMed was conducted using key words "Wiedemann-Steiner syndrome," "hypotonia," and "developmental delay" and a case study is presented. RESULTS A 36-month-old child with WSS received PT intervention beginning at 2 months old. Addition of orthotics and treadmill walking was added at 13 and 19 months, respectively. The child progressed through developmental sequences from rolling, sitting, standing, and walking although consistently scored with motor delay of -2 SD. CONCLUSIONS Fifty-seven percent of children diagnosed with WSS have hypotonia, and 90% have developmental delay. The diagnosis of WSS should require physical therapy services through early intervention programs due to its high correlation with motor developmental delay and disability. Determination of progress should be measured with achievement of function rather than norm-referenced outcome measures.Video Abstract: For more insights from the authors, access Supplemental Digital Content 1, available at: http://links.lww.com/PPT/A292.
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Affiliation(s)
- Carmel Mendoza
- Transitional Doctor of Physical Therapy Program, College of Saint Scholastica, Duluth, Minnesota
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25
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Fontana P, Passaretti FF, Maioli M, Cantalupo G, Scarano F, Lonardo F. Clinical and molecular spectrum of Wiedemann-Steiner syndrome, an emerging member of the chromatinopathy family. World J Med Genet 2020; 9:1-11. [DOI: 10.5496/wjmg.v9.i1.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 04/19/2020] [Accepted: 05/14/2020] [Indexed: 02/06/2023] Open
Abstract
Wiedemann-Steiner syndrome (OMIM #605130) is a rare congenital malformation syndrome characterized by hypertrichosis cubiti associated with short stature; consistent facial features, including long eyelashes, thick or arched eyebrows with a lateral flare, wide nasal bridge, and downslanting and vertically narrow palpebral fissures; mild to moderate intellectual disability; behavioral difficulties; and hypertrichosis on the back. It is caused by heterozygous pathogenic variants in KMT2A. This gene has an established role in histone methylation, which explains the overlap of Wiedemann-Steiner syndrome with other chromatinopathies, a heterogeneous group of syndromic conditions that share a common trigger: The disruption of one of the genes involved in chromatin modification, leading to dysfunction of the epigenetic machinery.
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Affiliation(s)
- Paolo Fontana
- Medical Genetics Unit, San Pio Hospital, Benevento 82100, Italy
| | | | - Marianna Maioli
- Medical Genetics Unit, San Pio Hospital, Benevento 82100, Italy
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26
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Jinxiu L, Shuimei L, Ming X, Jonathan LCS, Xiangju L, Wenyuan D. Wiedemann-steiner syndrome with a de novo mutation in KMT2A: A case report. Medicine (Baltimore) 2020; 99:e19813. [PMID: 32311999 PMCID: PMC7440326 DOI: 10.1097/md.0000000000019813] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
RATIONALE Wiedemann-Steiner syndrome (WDSTS, online mendelian inheritance in man 605130) is a rare autosomal dominant disorder characterized by hypertrichosis cubiti. Here, we report a Chinese boy who do not show the characteristic of hypertrichosis cubiti, and was misdiagnosed as blepharophimosis-ptosis-epicanthus inversus syndrome at first. We found a de novo frameshift mutation (p.Glu390Lysfs*10) in the KMT2A gene, which was not reported before. Our study increases the cohort of Chinese WDSTS patients, and expand the WDSTS phenotypic and variation spectrum. PATIENT CONCERNS The patient demonstrated typical craniofacial features of blepharophimosis-ptosis-epicanthus inversus syndrome, including small palpebral fissures, ptosis, telecanthus, and epicanthus inversus, besides he had congenital heart disease (ventricular septal defects), strabismus, hypotonia, amblyopia, delayed speech and language development, delayed psychomotor development, and amblyopia (HP:0000646) which was not reported before. DIAGNOSIS FOXL2 gene was cloned and sequenced, however, there was no mutation detected in this patient. The result of Chromosomal microarray analysis was normal. The patient was diagnosed as WDSTS by whole exome sequencing. INTERVENTIONS The patient received cardiac surgery, frontalis suspension and regular speech and occupational therapy. He also treated with growth hormone (GH). OUTCOMES The patient's symptoms are improved after cardiac surgery and frontalis suspension, he can express himself well now and had a 10 cm gain in height. LESSONS As the relationship between genotype and phenotype becomes more and more clear, WES is incredibly powerful tool to diagnose the disease of WDSTS.
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Affiliation(s)
- Liu Jinxiu
- Yinfeng Medical Laboratory, Jinan Shandong
| | | | - Xue Ming
- Genetics Diagnostic Lab, Tai’an Maternity and Child Care Hospital, Tai’an, China
| | - Liu CS. Jonathan
- SoftGenetics LLC, 100 Oakwood Ave, State College, Pennsylvania 16803, USA
| | - Liu Xiangju
- Genetics Diagnostic Lab, Tai’an Maternity and Child Care Hospital, Tai’an, China
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27
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Avagliano L, Parenti I, Grazioli P, Di Fede E, Parodi C, Mariani M, Kaiser FJ, Selicorni A, Gervasini C, Massa V. Chromatinopathies: A focus on Cornelia de Lange syndrome. Clin Genet 2020; 97:3-11. [PMID: 31721174 DOI: 10.1111/cge.13674] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/22/2019] [Accepted: 10/24/2019] [Indexed: 01/01/2023]
Abstract
In recent years, many genes have been associated with chromatinopathies classified as "Cornelia de Lange Syndrome-like." It is known that the phenotype of these patients becomes less recognizable, overlapping to features characteristic of other syndromes caused by genetic variants affecting different regulators of chromatin structure and function. Therefore, Cornelia de Lange syndrome diagnosis might be arduous due to the seldom discordance between unexpected molecular diagnosis and clinical evaluation. Here, we review the molecular features of Cornelia de Lange syndrome, supporting the hypothesis that "CdLS-like syndromes" are part of a larger "rare disease family" sharing multiple clinical features and common disrupted molecular pathways.
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Affiliation(s)
- Laura Avagliano
- Department of Health Sciences, Università degli Studi di Milano, Milano, Italy
| | - Ilaria Parenti
- Section for Functional Genetics, Institute of Human Genetics, University of Lübeck, Lübeck, Germany
- Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria
| | - Paolo Grazioli
- Department of Health Sciences, Università degli Studi di Milano, Milano, Italy
| | - Elisabetta Di Fede
- Department of Health Sciences, Università degli Studi di Milano, Milano, Italy
| | - Chiara Parodi
- Department of Health Sciences, Università degli Studi di Milano, Milano, Italy
| | | | - Frank J Kaiser
- Section for Functional Genetics, Institute of Human Genetics, University of Lübeck, Lübeck, Germany
- DZHK e.V. (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany
- Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
| | | | - Cristina Gervasini
- Department of Health Sciences, Università degli Studi di Milano, Milano, Italy
| | - Valentina Massa
- Department of Health Sciences, Università degli Studi di Milano, Milano, Italy
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28
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Gupta S, Verma P, Kapoor S, Sait H, Ghosh S. Dental phenotype of multiple impacted supernumerary teeth in Wiedemann–Steiner syndrome. JOURNAL OF CLEFT LIP PALATE AND CRANIOFACIAL ANOMALIES 2020. [DOI: 10.4103/jclpca.jclpca_12_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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29
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Wang YR, Xu NX, Wang J, Wang XM. Kabuki syndrome: review of the clinical features, diagnosis and epigenetic mechanisms. World J Pediatr 2019; 15:528-535. [PMID: 31587141 DOI: 10.1007/s12519-019-00309-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 08/07/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Kabuki syndrome (KS), is a infrequent inherited malformation syndrome caused by mutations in a H3 lysine 4 methylase (KMT2D) or an X-linked histone H3 lysine 27 demethylase (UTX/KDM6A). The characteristics in patients with KS have not yet been well recognized. DATA SOURCES We used databases including PubMed and Google Scholar to search for publications about the clinical features and the etiology of Kabuki syndrome. The most relevant articles to the scope of this review were chosen for analysis. RESULTS Clinical diagnosis of KS is challenging in initial period, because many clinical characteristics become apparent only in subsequent years. Recently, the genetic and functional interaction between KS-associated genes and their products have been elucidated. New clinical findings were reported including nervous system and intellectual performance, endocrine-related disorders and immune deficiency and autoimmune disease. Cancer risks of Kabuki syndrome was reviewed. Meanwhile, we discussed the Kabuki-like syndrome. Digital clinical genetic service, such as dysmorphology database can improve availability and provide high-quality diagnostic services. Given the significant clinical relevance of KS-associated genes and epigenetic modifications crosstalk, efforts in the research for new mechanisms are thus of maximum interest. CONCLUSIONS Kabuki syndrome has a strong clinical and biological heterogeneity. The main pathogenesis of Kabuki syndrome is the imbalance between switch-on and -off of the chromatin. The direction of drug research may be to regulate the normal opening of chromatin. Small molecule inhibitors of histone deacetylases maybe helpful in treatment of mental retardation and reduce cancer risk in KS.
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Affiliation(s)
- Yi-Rou Wang
- Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Nai-Xin Xu
- Huaxi Medical College School of Sichuan University, Sichuan, China
| | - Jian Wang
- Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Department of Genetics, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiu-Min Wang
- Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China. .,Department of Genetics, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
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30
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Grangeia A, Leão M, Moura CP. Wiedemann-Steiner syndrome in two patients from Portugal. Am J Med Genet A 2019; 182:25-28. [PMID: 31710778 DOI: 10.1002/ajmg.a.61407] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 10/17/2019] [Accepted: 10/22/2019] [Indexed: 01/28/2023]
Abstract
Wiedemann-Steiner syndrome (WSS) is a rare genetic disorder characterized by growth retardation, facial dysmorphism, hypertrichosis cubiti and neurodevelopment delay. It is caused by pathogenic variants in the KMT2A gene. This report describes two unrelated Portuguese patients, age 11 and 17 years, with a phenotype concordant with WSS and clinical and molecular diagnosis of WSS by the identification of two novel frameshift variants in the KMT2A gene. This work also highlights the presence of certain clinical features in patients with growth retardation and development delay and should draw attention to the diagnosis of WSS, when hirsutism, particularly hypertrichosis cubiti is present.
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Affiliation(s)
- Ana Grangeia
- Department of Medical Genetics, São João Hospital Center, Porto, Portugal.,i3S - Instituto de Investigação e Inovação em Saúde, Oporto University, Porto, Portugal
| | - Miguel Leão
- Department of Medical Genetics, São João Hospital Center, Porto, Portugal.,Department of Genetics, Faculty of Medicine, Oporto University, Porto, Portugal
| | - Carla P Moura
- Department of Medical Genetics, São João Hospital Center, Porto, Portugal.,i3S - Instituto de Investigação e Inovação em Saúde, Oporto University, Porto, Portugal.,Department of Genetics, Faculty of Medicine, Oporto University, Porto, Portugal
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