Reduced Penetrance and Variable Expression of SCN5A Mutations and the Importance of Co-inherited Genetic Variants: Case Report and Review of the Literature

Abstract

Mutations in the SCN5A gene are responsible for multiple phenotypical presentations including Brugada syndrome, long QT syndrome, progressive familial heart block, sick sinus syndrome, dilated cardiomyopathy, lone atrial fibrillation and multiple overlap syndromes. These different phenotypic expressions of a mutation in a single gene can be explained by variable expression and reduced penetrance. One of the possible explanations of these phenomena is the co-inheritance of genetic variants. We describe a family where the individuals exhibit a compound heterozygosity in the SCN5A gene including a mutation (R1632H) and a new variant (M858L). Individuals with both the mutation and new variant present with a more severe phenotype including spontaneous atrial tachyarrhythmia at young age. We give an overview of the different phenotypes of "SCN5A disease" and discuss the importance of co-inherited genetic variants in the expression of SCN5A disease.

Keywords: Brugada syndrome; SCN5A disease; genetic variants.

Figure 1

ECG of sibling 3; A: at admission atrial flutter with variable conduction 4/1-3/1; B: after cardioversion showing sinus bradycardia and arrhythmia. (25mm/s; 10mm/mV)

Figure 2

ECG of mother before (A) and after (B) ajmaline infusion with induction of typical Brugada type 1 pattern. (25mm/s; 10mm/mV)

Figure 3

ECG of sibling 4 during exercise test on a treadmill provoking transition to broad QRS tachycardia due to 1/1 conduction of atrial flutter with aberration. There is diffuse intraventricular conduction slowing due to the SCN5A mutation resulting in a tracing resembling ventricular fibrillation. (25mm/s; 10mm/mV)