RRAD and Brugada syndrome

This evaluation summarizes the association between RRAD (HGNC:10446) and Brugada syndrome (MONDO_0015263). The evidence is derived from a comprehensive familial study that identified a rare non‑synonymous substitution in RRAD, providing a strong basis for its role in disease predisposition. The findings are significant for diagnostic decision‑making, commercial assay development, and future genetic publications. The clinical report focused on a three‑generation pedigree with clear segregation and was further supported by additional unrelated index cases. The description spans both genetic and functional domains and has been scrutinized through published evidence. This multi‑layered approach enhances the clinical validity of the association (PMID:31114854).

The genetic evidence is robust. Whole‑exome sequencing of a three‑generation family with five affected members led to the identification of the c.632G>A (p.Arg211His) variant in RRAD. Moreover, three additional unrelated index cases presenting with Brugada syndrome were found to carry rare missense variants in the same gene. Such recurrence and segregation across multiple families provide compelling evidence for a genetic contribution. These data are aligned with ClinGen’s criteria, placing the gene‑disease association in the strong category. Each piece is referenced with consistent support from the published report (PMID:31114854).

Segregation analysis within the single family revealed that four additional affected relatives, beyond the index case, shared the identified variant, underscoring the inheritance of the alteration in an autosomal dominant manner. Notably, the variant c.632G>A (p.Arg211His) has been verified using stringent sequencing criteria and is reported in a clinically relevant context. The precise definition of the coding alteration, following HGVS nomenclature with three‑letter amino acid codes throughout, adds to the technical validity of the report. The observed familial pattern contributed to strong genetic evidence accumulation. Such findings are essential when counseling families and considering genetic testing protocols. All genetic details are critical for both molecular diagnostics and translational research (PMID:31114854).

Functional evidence has been equally influential in substantiating the association. Detailed electrophysiological studies in iPSC‑derived cardiomyocytes demonstrated hallmark Brugada syndrome features such as decreased Na+ peak current amplitude and structural cytoskeletal abnormalities. Genome editing experiments that introduced the RRAD variant into control cells recapitulated the abnormal phenotypes observed in patient‑derived cells. These experimental assays confirm that the pathogenic mechanism arises from a direct effect of the variant on ion channel function and cytoskeletal organization. The reproducibility of these cellular and molecular findings reinforces the clinical relevance of the variant. The functional assays therefore provide a complementary layer of evidence that bridges genetic findings with cardiac electrophysiological manifestations (PMID:31114854).

Integration of both genetic and experimental evidence has led to a coherent narrative. The segregation of the RRAD c.632G>A (p.Arg211His) variant among multiple affected individuals, along with its recurrence in additional unrelated cases, anchors the role of RRAD in disease etiology. Functional assays confirm that the variant disrupts critical electrophysiological properties and cytoskeletal integrity, which are known to contribute to the Brugada syndrome phenotype. Although additional studies could further expand upon this association, the current body of evidence robustly supports its strong clinical utility. The convergence of data from distinct approaches provides a high level of confidence in the association and informs the design of diagnostic assays and therapeutic strategies. This integrated perspective is vital for translational applications in precision cardiology.

Key take‑home message: The robust genetic segregation of the RRAD c.632G>A (p.Arg211His) variant across multiple families, together with comprehensive functional validations, confirms its strong association with Brugada syndrome, making it a clinically actionable target for diagnostic and therapeutic interventions.

References

• European heart journal • 2019 • RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome PMID:31114854

Evidence Based Scoring (AI generated)