Mutations in SCN5A gene have been associated with different cardiac manifestations, so it is frequently tested in familial cardiovascular diseases. Our objective was to analyze the prevalence of pathogenic mutations (PM) in SCN5A in hereditary cardiovascular diseases and to describe the clinical characteristics of genetic carriers.
SCN5A gene (NM_198056.2) was sequenced by NGS in panels of genes directed to each cardiac phenotype. We studied 219 index cases with theses phenotypes: 144 dilated/arrhythmogenic cardiomyopathy (DCM), 34 Brugada syndrome (BS), 19 idiopathic ventricular fibrillation (IVF), 10 long QT syndrome (LQTS), 9 sudden death with nondiagnostic necropsy and 3 advanced conduction system abnormalities.
We identified 8 PM in 9 families, two of them have not been previously described: deletion of exons 1–16 of SCN5A and 15_27 in SCN10A and c.2665C>G. The prevalence of PM according to phenotypes was: 3 DCM (2%), 1 IVF (5%), 4 BS (12%) and 1 advanced conduction system abnormalities (33%). Additionally, we identified 4 variants of uncertain pathogenicity, two of them in the same patient with LQTS (compound heterozygosis). The index cases description is developed in Table 1.
In our cohort the prevalence of PM in SCN5A is similar to those described in literature. The majority are associated with a combined phenotype (overlap syndrome of cardiac sodium channelopathy) which is characterized by supraventricular and ventricular arrhythmias and conduction system abnormalities, and some of them with DCM. Patients with BS had no additional manifestations, apart from ventricular arrhythmias in follow up.
Table 1 Family number SCN5A Mutation Other mutations Sex/Age at diagnosis of index case (years) Phenotype of index case Devices (Age, years) Number of studied relatives (+ Genotype) Phenotypes in the family (Age, years) Family history 1 Deletion in exons 1_16 of SCN5A, y 15_27 of SCN10A SCN5A:c.3068G>T (VUS) Female/38 SCD due to nocturnal VF, Brugada syndrome Secondary prevention ICD (38) 2 (0) – SCD at paternal line 2 c.2254G>A LMNA:c.986G>A (VUS) Female/64 DCM Primary prevention ICD (69) 3 (1) Daughter PM (39) and atrial flutter SCD in first degree family members 3 c.2665C>G – Male/46 AF (27), AVB (36), VF (46) PM (36), secondary prevention ICD (46) 6 (3) Father PM (47) and atrial flutter Paternal grandfather SCD (53), cousin SCD (26) 4 c.2665C>G SCN5A:c.4057G>A (VUS) Male/ 64 DCM, VT, AF, atrial flutter (64) Secondary prevention (64), cardiac resynchronization therapy (68) 15 (7) Sister PM (26) None 5 c.3823G>A – Male/48 BS Primary prevention ICD (48) 0 (0) – SCD. Cousin with BS and ICD. Maternal grandmother with pacemaker. 6 c.4297G>T – Male/42 BS NO 4 (2) Sister Type 2 BS None 7 c.4783G>A – Male/14 Bifascicular heart block (right bundle branch block and left anterior division block), VT, atrial flutter. Primary prevention ICD (15) 3 (0) – None (de novo mutation) 8 c.4876C>T MYH7:c.4763G>A (VUS) Male/38 DCM, AVB, VF Secondary prevention ICD (38) 0 (0) – SCD in sibling (39 years) 9 c.4981G>A – Female/23 BS Primary prevention ICD (25), appropriate therapy in follow up 3 (0) – None (de novo mutation) AF: atrial fibrillation; AVB: atrioventricular block; BS: Brugada syndrome; DCM: dilated cardiomyopathy; ICD: implantable cardioverter defibrillator; PM: pacemaker; SCD: sudden cardiac death; VF: ventricular fibrillation; VT: ventricular tachycardia; VUS: Variant of uncertain significance.
Funding Acknowledgement
Type of funding source: None
