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Three de novo variants in KMT2A (MLL) identified by whole exome sequencing in patients with Wiedemann–Steiner syndrome
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 be...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8580087/ https://www.ncbi.nlm.nih.gov/pubmed/34469078 http://dx.doi.org/10.1002/mgg3.1798 |
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author | Luo, Sukun Bi, Bo Zhang, Wenqian Zhou, Rui Chen, Wei Zhao, Peiwei Huang, Yufeng Yuan, Li He, Xuelian |
author_facet | Luo, Sukun Bi, Bo Zhang, Wenqian Zhou, Rui Chen, Wei Zhao, Peiwei Huang, Yufeng Yuan, Li He, Xuelian |
author_sort | Luo, Sukun |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8580087 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85800872021-11-17 Three de novo variants in KMT2A (MLL) identified by whole exome sequencing in patients with Wiedemann–Steiner syndrome Luo, Sukun Bi, Bo Zhang, Wenqian Zhou, Rui Chen, Wei Zhao, Peiwei Huang, Yufeng Yuan, Li He, Xuelian Mol Genet Genomic Med Original Articles 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. John Wiley and Sons Inc. 2021-09-01 /pmc/articles/PMC8580087/ /pubmed/34469078 http://dx.doi.org/10.1002/mgg3.1798 Text en © 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Luo, Sukun Bi, Bo Zhang, Wenqian Zhou, Rui Chen, Wei Zhao, Peiwei Huang, Yufeng Yuan, Li He, Xuelian Three de novo variants in KMT2A (MLL) identified by whole exome sequencing in patients with Wiedemann–Steiner syndrome |
title | Three de novo variants in KMT2A (MLL) identified by whole exome sequencing in patients with Wiedemann–Steiner syndrome |
title_full | Three de novo variants in KMT2A (MLL) identified by whole exome sequencing in patients with Wiedemann–Steiner syndrome |
title_fullStr | Three de novo variants in KMT2A (MLL) identified by whole exome sequencing in patients with Wiedemann–Steiner syndrome |
title_full_unstemmed | Three de novo variants in KMT2A (MLL) identified by whole exome sequencing in patients with Wiedemann–Steiner syndrome |
title_short | Three de novo variants in KMT2A (MLL) identified by whole exome sequencing in patients with Wiedemann–Steiner syndrome |
title_sort | three de novo variants in kmt2a (mll) identified by whole exome sequencing in patients with wiedemann–steiner syndrome |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8580087/ https://www.ncbi.nlm.nih.gov/pubmed/34469078 http://dx.doi.org/10.1002/mgg3.1798 |
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