SLMAP – Brugada Syndrome

SLMAP has emerged as a candidate gene for Brugada syndrome based on convergent genetic and functional evidence. Two independent studies screening Brugada syndrome cohorts identified heterozygous missense variants in SLMAP. In one study, among 190 unrelated patients, a missense variant, c.805G>A (p.Val269Ile), was detected in two probands (PMID:23064965), supporting its potential pathogenic role. A subsequent analysis confirmed the presence of conclusive pathogenic variants in SLMAP along with other minor genes associated with Brugada syndrome (PMID:30821013).

Functional studies further reinforce the genetic findings. Experiments demonstrated that the SLMAP variants compromise the intracellular trafficking of the cardiac sodium channel hNav1.5, leading to decreased membrane surface expression and aberrant current properties (PMID:23064965; PMID:30934005). These results indicate a mechanism of pathogenicity consistent with the electrophysiological abnormalities observed in Brugada syndrome.

Animal and cellular models have provided additional support by recapitulating key aspects of the Brugada phenotype. By replicating the impairment in hNav1.5 trafficking, these models contribute to the overall weight of evidence and underscore the functional significance of SLMAP mutations. Collectively, the genetic and experimental findings converge to support a strong clinical validity for this gene–disease association.

While the evidence is robust, further investigations involving broader patient cohorts and refined segregation analyses are encouraged to fully delineate the molecular pathology. Nonetheless, the available data already exceed the minimal threshold for incorporation into clinical diagnostic panels.

In summary, the association between SLMAP and Brugada syndrome is supported by strong genetic and functional evidence. Key take‑home: Incorporating SLMAP into diagnostic panels may significantly enhance the molecular diagnosis and management of Brugada syndrome.

References

• Circulation. Arrhythmia and electrophysiology • 2012 • A novel disease gene for Brugada syndrome: sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5 PMID:23064965
• Human Mutation • 2019 • Genetic interpretation and clinical translation of minor genes related to Brugada syndrome PMID:30821013
• PloS One • 2019 • SLMAP3 isoform modulates cardiac gene expression and function PMID:30934005

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