ABCC9 – Brugada Syndrome Susceptibility

Brugada syndrome (BrS) is an autosomal dominant cardiac channelopathy characterized by coved-type ST-segment elevation in the right precordial leads and an increased risk of sudden cardiac death. The ABCC9 gene encodes the sulfonylurea receptor 2 (SUR2) regulatory subunit of ATP-sensitive potassium (KATP) channels, which modulate cardiac repolarization. Evidence from targeted resequencing and functional studies implicates heterozygous ABCC9 variants as novel susceptibility alleles in BrS.

In a cohort of 150 BrS probands, eight distinct ABCC9 mutations were identified in 11 unrelated male patients (11 probands) by direct sequencing of all known BrS/early repolarization genes (PMID:24439875). Among these, the recurrent c.2200G>A (p.Val734Ile) variant was found in four probands with overlapping early repolarization syndrome. No large pedigrees with segregation of ABCC9 variants have been described.

BrS associated with ABCC9 follows an autosomal dominant inheritance pattern, but familial segregation data are limited; no additional affected relatives carrying ABCC9 variants have been reported (affected_relatives: 0). The absence of clear cosegregation underscores the incompleteness of genetic linkage for SUR2 variants in BrS.

Functional electrophysiological analyses demonstrate that the p.Val734Ile and p.Ser1402Cys SUR2A variants reduce ATP sensitivity of KATP channels, increasing MgATP IC₅₀ by ~5-fold and enhancing channel open probability in TSA201 cells, consistent with gain-of-function mechanisms that can abbreviate action potential duration (PMID:24439875). These aberrant biophysical properties align with altered repolarization substrates observed in BrS.

A rare ABCC9 variant (c.437T>A (p.Ile146Asn)) was reported in a single BrS‐affected individual and his asymptomatic mother, without segregation with disease, highlighting a potential false positive association (PMID:25341504). No studies have refuted the broader involvement of SUR2 variants in BrS.

Taken together, 11 BrS probands harbour heterozygous ABCC9 variants with supportive in vitro gain-of-function data but lack familial segregation, placing the gene–disease relationship in the ClinGen “Moderate” category. Additional large families and in vivo models are needed to confirm pathogenicity. Key take-home: ABCC9 should be considered in genetic testing panels for Brugada syndrome, with functional characterization essential for variant interpretation.

References

• Basic research in cardiology • 2014 • Complex Brugada syndrome inheritance in a family harbouring compound SCN5A and CACNA1C mutations. PMID:25341504
• International journal of cardiology • 2014 • ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene. PMID:24439875

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