Whole‐Exome Sequencing Identifies a Rare CSRP3 Variant Associated With Familial Brugada Syndrome in a Lebanese Family

INTRODUCTION: Brugada syndrome (BrS) is an inherited arrhythmia associated with an increased risk of sudden cardiac death. Although traditionally regarded as a primary cardiac channelopathy, pathogenic variants in SCN5A account for only 20%-30% of clinically diagnosed cases, leaving most patients genetically unresolved. Emerging evidence suggests that structural cardiac genes may also contribute to BrS susceptibility. We investigated the genetic basis of BrS in a consanguineous Lebanese family with three affected brothers. METHODS AND RESULTS: Whole-exome sequencing was performed in all affected individuals, followed by variant calling, annotation, and phenotype-driven prioritization using Franklin (Genoox). Candidate variants were evaluated according to allele frequency, inheritance model, segregation, and ACMG/AMP classification. Evolutionary conservation, AlphaMissense prediction, protein domain annotation, and structural modeling were performed to assess the potential functional impact of the prioritized variant. Whole-exome sequencing identified a rare homozygous CSRP3 missense variant (NM_003476.5:c.56 A > G; p.His19Arg) shared by all three affected siblings. Following exome-wide filtering under a recessive inheritance model, CSRP3 represented the only rare homozygous coding variant, while no pathogenic or likely pathogenic variants were identified in established Brugada syndrome-associated genes. The variant was absent from public population databases and an internal cohort of Lebanese exomes. His19 was highly conserved across vertebrate species, AlphaMissense classified the variant as likely pathogenic (score = 0.942), and structural modeling predicted alterations within the N-terminal LIM domain that may affect protein stability and local residue interactions. CONCLUSIONS: Our findings nominate CSRP3 as a candidate susceptibility gene for Brugada syndrome and support the emerging role of structural cardiac genes in inherited arrhythmia syndromes. Although functional validation is required to establish causality, this study highlights the value of whole-exome sequencing in consanguineous and underrepresented populations for identifying rare candidate variants contributing to BrS susceptibility.