Dataset Information

Retrospective analysis of a clinical exome sequencing cohort reveals the mutational spectrum and identifies candidate disease-associated loci for BAFopathies.

ABSTRACT:

Purpose

BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex that plays a critical role in gene regulation. Defects in the genes encoding BAF subunits lead to BAFopathies, a group of neurodevelopmental disorders with extensive locus and phenotypic heterogeneity.

Methods

We retrospectively analyzed data from 16,243 patients referred for clinical exome sequencing (ES) with a focus on the BAF complex. We applied a genotype-first approach, combining predicted genic constraints to propose candidate BAFopathy genes.

Results

We identified 127 patients carrying pathogenic variants, likely pathogenic variants, or de novo variants of unknown clinical significance in 11 known BAFopathy genes. Those include 34 patients molecularly diagnosed using ES reanalysis with new gene-disease evidence (n = 21) or variant reclassifications in known BAFopathy genes (n = 13). We also identified de novo or predicted loss-of-function variants in 4 candidate BAFopathy genes, including ACTL6A, BICRA (implicated in Coffin-Siris syndrome during this study), PBRM1, and SMARCC1.

Conclusion

We report the mutational spectrum of BAFopathies in an ES cohort. A genotype-driven and pathway-based reanalysis of ES data identified new evidence for candidate genes involved in BAFopathies. Further mechanistic and phenotypic characterization of additional patients are warranted to confirm their roles in human disease and to delineate their associated phenotypic spectrums.

SUBMITTER: Chen CA

PROVIDER: S-EPMC8957292 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

Retrospective analysis of a clinical exome sequencing cohort reveals the mutational spectrum and identifies candidate disease-associated loci for BAFopathies.

Chen Chun-An CA Lattier John J Zhu Wenmiao W Rosenfeld Jill J Wang Lei L Scott Tiana M TM Du Haowei H Patel Vipulkumar V Dang Anh A Magoulas Pilar P Streff Haley H Sebastian Jessica J Svihovec Shayna S Curry Kathryn K Delgado Mauricio R MR Hanchard Neil A NA Lalani Seema S Marom Ronit R Madan-Khetarpal Suneeta S Saenz Margarita M Dai Hongzheng H Meng Linyan L Xia Fan F Bi Weimin W Liu Pengfei P Posey Jennifer E JE Scott Daryl A DA Lupski James R JR Eng Christine M CM Xiao Rui R Yuan Bo B

Genetics in medicine : official journal of the American College of Medical Genetics 20211130 2

<h4>Purpose</h4>BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex that plays a critical role in gene regulation. Defects in the genes encoding BAF subunits lead to BAFopathies, a group of neurodevelopmental disorders with extensive locus and phenotypic heterogeneity.<h4>Methods</h4>We retrospectively analyzed data from 16,243 patients referred for clinical exome sequencing (ES) with a focus on the BAF complex. We applied a genotype-first approach, combining predicted gen ...[more]

PMID: 34906496

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Dataset Information

Retrospective analysis of a clinical exome sequencing cohort reveals the mutational spectrum and identifies candidate disease-associated loci for BAFopathies.

Purpose

Methods

Results

Conclusion

Publications

Retrospective analysis of a clinical exome sequencing cohort reveals the mutational spectrum and identifies candidate disease-associated loci for BAFopathies.

Similar Datasets

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