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

TitleRetrospective analysis of a clinical exome sequencing cohort reveals the mutational spectrum and identifies candidate disease-associated loci for BAFopathies.
Publication TypeJournal Article
Year of Publication2022
AuthorsChen, C-A, Lattier, J, Zhu, W, Rosenfeld, J, Wang, L, Scott, TM, Du, H, Patel, V, Dang, A, Magoulas, P, Streff, H, Sebastian, J, Svihovec, S, Curry, K, Delgado, MR, Hanchard, NA, Lalani, S, Marom, R, Madan-Khetarpal, S, Saenz, M, Dai, H, Meng, L, Xia, F, Bi, W, Liu, P, Posey, JE, Scott, DA, Lupski, JR, Eng, CM, Xiao, R, Yuan, B
JournalGenet Med
Date Published2022 Feb
KeywordsAbnormalities, Multiple, Actins, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins, Exome, Hand Deformities, Congenital, Humans, Micrognathism, Retrospective Studies

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.

Alternate JournalGenet Med
PubMed ID34906496
PubMed Central IDPMC8957292
Grant ListK08 HG008986 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States

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