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

Abstract

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 genotypedriven 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.

Complex Diagnostics of Non-Specific Intellectual Developmental Disorder

“…Notably, these patients lacked dysmorphic features or specific manifestations of any of the above-mentioned syndromes and could not be suggested for targeted gene analysis. Our findings support the idea of looking for the cause of undiagnosed non-specific IDD among other genes associated with the BAF complex but not previously associated with IDD [ 37 ].…”

Elucidating the clinical and molecular spectrum ofSMARCC2-associated NDD in a cohort of 65 affected individuals

“…14,15 To date, reports of SMARCC2 variants have been mostly part of individual case reports or large NDD studies with limited clinical information. [9][10][11][12][13]16 In an attempt to better characterize the clinical and molecular spectrum of SMARCC2-associated NDD, a large cohort of 65 cases was collected, including 41 novel individuals with de novo or inherited variants, whose clinical and molecular findings were systematically described, and 24 previously published individuals, whose data were thoroughly curated. Additionally, Human Phenotype Ontology (HPO) and automated facial recognition were used to investigate genotype-phenotype correlations between nontruncating and LGD variants, and structural modeling as well as functional assays to investigate missense variants.…”

“…[2][3][4][5][6][7] Recent studies reporting affected individuals with mainly de novo missense/in-frame and a few likely gene-disrupting (LGD) pathogenic variants in another BAF-subunit, SMARCC2 (BAF170, MIM *601734), expanded the spectrum of BAF-related NDDs. [8][9][10][11][12][13] Machol et al described a cohort of 15 cases with variable clinical manifestations resembling CSS and NCBRS. 8 The Online Mendelian Inheritance in Man (OMIM) database now classifies the SMARCC2-associated phenotype as Coffin-Siris syndrome 8 (MIM #601734).…”

Epilepsy in Coffin–Siris syndrome: A report from the international CSS registry and review of the literature

“…Tsurusaki et al (2012) and Santen et al (2012) first described genes in the BRG‐1 associated factors (BAF) chromatin remodeling complex to be causative for CSS, while other groups have identified BAF‐related genes as causing similar pathology [ SOX11 (Tsurusaki, Okamoto, et al, 2014; Tsurusaki, Koshimizu, et al, 2014) and DPF2 (Vasileiou et al, 2018)]. The term “BAFopathies” has been proposed previously to better summarize these disorders (Chen et al, 2022).…”

“…BAF-related genes as causing similar pathology [SOX11 Tsurusaki, Koshimizu, et al, 2014) and DPF2 (Vasileiou et al, 2018)]. The term "BAFopathies" has been proposed previously to better summarize these disorders (Chen et al, 2022).…”