RESUMEN
BACKGROUND: Few clinical data are available on NEXN mutation carriers, and the gene's involvement in cardiomyopathies or sudden death has not been fully established. Our objectives were to assess the prevalence of putative pathogenic variants in NEXN and to describe the phenotype and prognosis of patients carrying the variants. METHODS: DNA samples from consecutive patients with cardiomyopathy or sudden cardiac death/sudden infant death syndrome/idiopathic ventricular fibrillation were sequenced with a custom panel of genes. Index cases carrying at least one putative pathogenic variant in the NEXN gene were selected. RESULTS: Of the 9516 index patients sequenced, 31 were carriers of a putative pathogenic variant in NEXN only, including 2 with double variants and 29 with a single variant. Of the 29 unrelated probands with a single variant (16 males; median age at diagnosis, 32.0 [26.0-49.0] years), 21 presented with dilated cardiomyopathy (prevalence, 0.33%), and 3 presented with hypertrophic cardiomyopathy (prevalence, 0.14%). Three patients had idiopathic ventricular fibrillation, and there were 2 cases of sudden infant death syndrome (prevalence, 0.46%). For patients with dilated cardiomyopathy, the median left ventricle ejection fraction was 37.5% (26.25-50.0) at diagnosis and improved with treatment in 13 (61.9%). Over a median follow-up period of 6.0 years, we recorded 3 severe arrhythmic events and 2 severe hemodynamic events. CONCLUSIONS: Putative pathogenic NEXN variants were mainly associated with dilated cardiomyopathy; in these individuals, the prognosis appeared to be relatively good. However, severe and early onset phenotypes were also observed-especially in patients with double NEXN variants. We also detected NEXN variants in patients with hypertrophic cardiomyopathy and sudden infant death syndrome/idiopathic ventricular fibrillation, although a causal link could not be established.
Asunto(s)
Cardiomiopatías , Cardiomiopatía Dilatada , Cardiomiopatía Hipertrófica , Muerte Súbita del Lactante , Fibrilación Ventricular , Masculino , Lactante , Humanos , Adulto , Persona de Mediana Edad , Cardiomiopatía Dilatada/genética , Prevalencia , Cardiomiopatías/diagnóstico , Fenotipo , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/complicaciones , Muerte Súbita Cardíaca/etiología , Pronóstico , Proteínas de Microfilamentos/genéticaRESUMEN
BACKGROUND: SCN5A variants are associated with a spectrum of cardiac electrical disorders with clear phenotypes. However, they may also be associated with complex phenotypic traits like overlap syndromes, or pleiotropy, which have not been systematically described. Additionally, the involvement of SCN5A in dilated cardiomyopathies (DCM) remains controversial. OBJECTIVE: We aimed to (1) evaluate the different phenotypes associated with pathogenic (P)/likely pathogenic (LP) SCN5A variants and (2) determine the prevalence of pleiotropy in a large multicentric cohort of P/LP SCN5A variant carriers. METHODS: The DNA of 13,510 consecutive probands (9960 with cardiomyopathies) was sequenced using a custom panel of genes. Individuals carrying a heterozygous single P/LP SCN5A variant were selected and phenotyped. RESULTS: The study included 170 P/LP variants found in 495 patients. Among them, 119 (70%) were exclusively associated with a single well-established phenotype: 91 with Brugada syndrome, 15 with type 3 long QT syndrome, six with progressive cardiac conduction disease, four with multifocal ectopic Purkinje-related premature contraction, and three with sick sinus syndrome. Thirty-two variants (19%) were associated with overlap syndromes and/or pleiotropy. The 19 remaining variants (11%) were associated with atypical or unclear phenotypes. Among those, eight were carried by eight patients presenting with DCM with a debatable causative genotype/phenotype link. CONCLUSION: Most P/LP SCN5A variants were found in patients with primary electrical disorders, mainly Brugada syndrome. Nearly 20% were associated with overlap syndromes or pleiotropy, underscoring the need for comprehensive phenotypic evaluation. The concept of SCN5A variants causing DCM is extremely rare (8/9960), if not questionable.