NEXN-mediated cardiomyopathies: Prevalence, phenotypic expression, and prognosis

Introduction Pathogenic variants in nexilin (sarcomeric protein encoded by NEXN gene) have been published as responsible of hypertrophic (HCM) and dilated cardiomyopathies (DCM), with an autosomal dominance inheritance. Despite of the few clinical data available on clinical cohort of NEXN mutation carriers, this gene has been described as gene with moderate evidence of its implication of DCM development (Jordan, 2021). Objective The objective is to evaluate the prevalence and to describe the phenotype and prognosis of patients carrying a variant of interest in the NEXN gene. Method Patients affected by cardiomyopathy have been sequenced on a custom panel of cardiomyopathy genes (>52 genes). Index cases carrying a single heterozygous class 3, 4 or 5 variant in the NEXN gene according ACMG guidelines were selected and clinical data at diagnosis and events during follow-up were collected retrospectively. Results On 4500 patients sequenced, we included 36 index cases, from whom 34 carried a single heterozygous variant in NEXN gene (18 probably pathogenic variant, 18 males, mean age at diagnosis=45±19-years-old). Regarding the genotype, 21 carried missense variants, 10 variants leading to a premature STOP codon and 3 variants affecting a consensus splice site. Regarding the phenotypes, 19 had a DCM, 6 a LVNC, 4 an HCM, 3 an idiopathic VF. Two patients suffered infant sudden death. Most patients were symptomatic at diagnosis. On 25 patients with DCM/LVNC, 17 (68%) had complete or incomplete left bundle branch block and mean left ventricle ejection fraction (LVEF) at diagnosis was 33±13%. During a median follow-up of 4 years, we reported 3 severe rhythmic events and 3 severe hemodynamic events. The LVEF improved under treatment for 17 patients (58%) with DCM/LVNC. Conclusion This work allowed to evaluate the prevalence of NEXN pathogenic variant in cardiomyopathies at 0.76% confirming that this gene is a rare cause of cardiomyopathies. This work has also permitted to better defined the clinical spectrum of NEXN mutations carriers: NEXN variants can lead to different type of cardiomyopathy, left bundle branch block is frequent, severe rhythmic or hemodynamic events can occur in follow up. Additionally, LVEF could improve in a significant number of patients under treatment.