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Brugada syndrome (BrS) is an autosomal dominant primary cardiac channelopathy associated with sudden cardiac death, traditionally linked to SCN5A mutations. Emerging evidence implicates ion channel–interacting proteins as minor susceptibility factors, including the MAGUK scaffold SAP97 encoded by DLG1, which organizes Nav1.5 and Kv channels in cardiomyocytes (PMID:32196358).
In an Italian BrS pedigree, whole-exome sequencing identified a heterozygous DLG1 c.1556G>A (p.Arg519His) variant that co-segregated with spontaneous or drug-induced type 1 BrS ECG and syncope in 6 of 12 family members, consistent with autosomal dominant inheritance and segregation in 6 affected relatives (PMID:36833354). The p.Arg519His change lies adjacent to a PDZ domain, with in silico modeling predicting disruption of an H-bond network and altered SAP97 conformation.
Functional assessment in a murine cardiac-specific Sap97 knockout model demonstrated ECG abnormalities, action potential prolongation, high incidence of arrhythmogenic afterdepolarizations, and perturbation of Nav and Kv currents, recapitulating key BrS features and highlighting SAP97’s role in channel trafficking and modulation (PMID:32196358).
Mechanistically, impaired SAP97 scaffolding is expected to mislocalize Nav1.5 and Kv4.3 channels at the intercalated disc, supported by human data showing gain-of-function DLG1 variants augmenting Ito current in BrS patients.
No conflicting human genetic data have been reported to date.
Taken together, the co-segregation of c.1556G>A (p.Arg519His) in a multigenerational BrS family, concordant murine arrhythmia phenotypes, and mechanistic plausibility support a moderate level of clinical validity for DLG1 as a Brugada syndrome susceptibility gene. Further studies across diverse cohorts are warranted to strengthen this association.
Key Take-home: Incorporation of DLG1 into BrS genetic testing panels may enhance molecular diagnosis and guide risk stratification.
Gene–Disease AssociationModerateSingle-family segregation (6 carriers) and functional concordance in murine model and human assays Genetic EvidenceModerateHeterozygous variant c.1556G>A segregating with BrS in one pedigree Functional EvidenceModerateCardiac-specific Sap97 ablation in mice and mechanistic modeling of human variant support arrhythmogenic mechanism |