Caveolin 3 Variant T78M in a Large Family With Brugada Syndrome: Clinical Features and Coexistence of ADRB1 and GRK5...

Genetic mutations involving sodium channel Nav 1.5 have been linked with Brugada Syndrome (BrS). Caveolin-3(CAV-3) is a protein that could modulate Nav1.5 function. Aim of the study is to characterize a multi-generational family with BrS and CAV-3 gene mutation.

Clinical and genetic investigations were performed. Genetic testing was performed with whole-exome sequencing (WES). Variants found by WES were evaluated in all family members by bidirectional capillary Sanger resequencing. The effect of the mutation was investigated by using in silico prediction of pathogenicity. Index case was a 58-year-old man with BrS, that needed an implantable cardioverter defibrillator (ICD) due to resuscitated cardiac arrest. WES of the index case identified a missense mutation p.(Thr78Met) of the CAV3 gene and two additionally variants: ADRB1 p.(Leu353Met) and GRK5 p.(Thr129Met). Six out of 11 family members had BrS ECG and were all CAV-3 mutation carriers. Three family members had CAV-3 mutation and ADRB1 and GRK5 variants. ICD implant was needed in four family members. All patients with CAV-3, ADRB1 and GRK5 gene mutations underwent ICD implant due to cardiac arrest or arrhythmic syncope. Another patient with CAV-3 mutation only, had and ICD implant due to spontaneous BrS type 1 ECG and positive electrophysiological study.

Caveolin 3 p.(Thr78Met) gene mutation could be associated with BrS. This mutation if combined with other susceptible BrS gene variations as ADRB1 p.(Leu353Met) and GRK5 p.(Thr129Met), could have an increased arrhythmic risk.