Submission Details

There is limited evidence that SCN5A is associated with ARVC. Screening of ARVC patient cohorts for SCN5A mutations has been performed in four studies (2589161, 24388542, 18375968, 28069705). The first study (2589161) reported the investigation on 6 young patients who were electrically resuscitated after ventricular fibrillation. One of these patients died suddenly during a four years follow-up and autopsy revealed fibrofatty changes in the right ventricle, a decrease number of myocardial cells as typical features of ARVC. Genetic screening revealed a variant on SCN5A, however no further information about genomic localization and classification of the variant was present. The second study (24388542) reported the case of a 50 year old female patient presenting an enlarged right ventricle with structural myocardial changes. Right ventricular angiography showed sacculations in the so-called triangle of dysplasia resembling ARVC structural changes. Genetic testing identified a loss-of-function variant on SCN5A, however no further information about genomic localization and classification of the variant was present. The third study (18375968) reported the case of 58 years old man presenting monomorphic and polymorphic non-sustained ventricular tachycardias, chest pain and dyspnea at rest, complete RBBB, mild dilatation and hypokinesia of the right ventricular and bioptic investigation revealed cardiac hypertrophy and fibrosis, but no myocardial tissue degeneration. Genetic screening identified a splice error on intron 21 of SCN5A gene c.3840+1 G>A, which results in a loss of function of the sodium channel. However, no segregation data were available and patient’s phenotype does not fulfil a definite ARVC diagnosis. The most recent study (28069705) investigated the entire exome for pathogenic variants among a ‘discovery cohort’ of six unrelated Caucasian patients with a clinical diagnosis of ARVC. Genetic screening identified a heterozygous SCN5A missense variant in a female patient causing the aminoacid substitution Arg1898His. Subsequently, authors analysed a ‘validation cohort’ of 281 unrelated patients for SCN5A variants. Authors identified 5 different variants in 5 patients; among these a missense variant causing the aminoacid substitution Ser1787Asn was excluded due its high frequency in the general population. Two patients were digenic variants carriers, both presenting a different pathogenic variant on PKP2 and an additional variant on SCN5A. Another patient carried a heterozygous in frame deletion (Leu729del), however cascade genetic screening revealed that family members carrying this variants did not fulfill definite ARVC criteria. Finally genetic screening identified a missense variant Tyr416Cys in a 55 years old female but segregation study in the family don’t demonstrate the link of this variant with the clinical phenotype. Experimental data from this last study (28069705) analyzed the role of SCN5A Arg1898His variant. Authors generated an induced pluripotent stem cell-derived cardiomyocytes and then corrected them by using CRISP/Cas9 technology. Whole-cell patch clamping revealed a 36% reduction in peak sodium current and super-resolution and fluorescence microscopy showed reduced abundance of both SCN5A and CDH2 clusters at the intercalated disc. However, experimental data do not showed the link of electrical abnormalities to structural changes typical of ARVC alterations such as myocardial fibrotic replacement. In summary, there is limited evidence to support gene-disease association. There is no clear evidence that the identified SCN5A variants contribute to the ARVC phenotype and there is no known disease mechanism that would link SCN5A with ARVC.