KCNQ1 and GJA1 Variants Associated With Arrhythmogenic Right Ventricular Cardiomyopathy With a Lethal Outcome

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is mainly caused by desmosomal variants. Nondesmosomal ARVC is rare.

A 31-year-old athlete experienced sudden cardiac death. Autopsy revealed ARVC and syndactyly. Genetic testing identified a heterozygous pathogenic KCNQ1 variant associated with long QT syndrome, and a heterozygous likely pathogenic GJA1 variant encoding connexin-43, a gap junction protein. No relative had ARVC or prolonged QTc interval; however, GJA1-positive relatives had either syndactyly or a gait disorder; both of these pathologies are associated with GJA1.

Connexin-43 is essential for desmosomal function; however, ARVC causation has not been established. Cascade genetic and clinical testing suggests that the combination of both variants and lifelong endurance exercise may have precipitated the ARVC phenotype.

This is the first documented case linking GJA1 and KCNQ1 variants to ARVC. Comprehensive genetic and clinical family screening is vital for assessing the individual contribution of each variant to the diagnosis and arrhythmic risk.