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.

Bioinformatics method identifies potential biomarkers of dilated cardiomyopathy in a human induced pluripotent stem cell-derived cardiomyocyte model

“…Reportedly, DCM is associated with mutations in several genes, such as DES, LMNA, SCN5A and TNNT2 (6)(7)(8). Among them, TNNT2 is the gene that encodes for cardiac troponin T, one of the subunits of the troponin complex that regulates muscle contraction and sarcomere assembly (9).…”

A common polymorphism in the SCN5A gene is associated with dilated cardiomyopathy

“…For example, the loss-of sodium channel function mutations result in BrS subtype-1, idiopathic ventricular fibrillation, cardiac conduction diseases and congenital sick sinus syndrome, whereas gain-of-function mutations are mainly associated with congenital LQTS type 3 and atrial fibrillation. 18 , 19 , 31 In addition, SCN5A mutations related to both loss and gain function have also been linked to DCM, which suggests that dysfunction in electrical excitability, caused by disturbance of sodium channel function, also leads to dilation remodelling. 32 – 34 It has been suggested that deranged functioning of the SCN5A channel may cause dysfunction of cytoskeletal protein binding partners and so result in DCM.…”

“…SCN5A gene mutations are associated with various cardiac disorders, including arrhythmogenic syndromes, namely, long QT syndrome (LQTS), Brugada syndrome (BrS), familial atrial fibrillation, sick sinus syndrome (SSS), paroxysmal familial ventricular fibrillation and progressive familial heart block type IA (PFHB1A), as well as with the structural cardiomyopathies such as DCM. 18 , 19 …”

Compound Heterozygous SCN5A Mutations in a Toddler - Are they Associated with a More Severe Phenotype?

“…8-10 Medeiros-Domingos et al 8 described a child with progressive cardiac conduction system disease, monomorphic ventricular tachycardia in a febrile state, compound mutation inherited from the mother ( SCN5A gene, mutation p.R34fs*62), and a prolonged QT interval inherited from the father ( SCN5A gene, mutation p.R1195H), revealed by the functional analysis. Robyns et al 9 showed a compound mutation also in the SCN5A gene, which was actually a combination of a mutation and a new variant that seemed to evoke a severe phenotype, including spontaneous atrial tachyarrhythmia at young age.…”