Genetic and phenotypic characterization of Nexilin (NEXN) related cardiomyopathy

Abstract Background Clinical and genetic features of Nexilin (NEXN) related cardiomyopathies (CMPs) are largely uncharacterized. At present, the strength of the gene-disease association for NEXN is currently moderate for Dilated Cardiomyopathy (DCM), limited for Hypertrophic Cardiomyopathy (HCM), and unevaluated for Arrhythmogenic Cardiomyopathy (ACM). More evidence is needed to establish a definite genotype-phenotype association. Purpose We sought to investigate 1) the causative role of NEXN gene in CMPs, and 2) its phenotypic expression and prognostic profile. Methods All patients carrying NEXN variants, recruited in 11 international referral centres, were classified according to reported phenotype and genetic variant. Variants were considered rare if below GnomAD Popmax Filtering Allele Frequency of 8x10-5. Burden enrichment testing of rare NEXN variants was performed in our case-cohort of patients with DCM/ACM (n=3053), in comparison with the GnomAD population of non-Finnish Europeans (NFE). Clinical phenotypes and outcomes of patients carrying validated variants were described. A previously established cohort of patients with Titin-related CMP was used for prognostic comparison. Results Data from 87 patients were collected. Forty patients were excluded due to being carriers of non-rare NEXN variants (n=22) and/or pathogenic variants in other genes (n=18). Of the remaining patients, only 2 had HCM diagnosis, precluding any further analysis on this phenotype. NEXN truncating variants (tv) resulted significantly enriched in DCM/ACM disease-cohort with a prevalence of 0.39% vs 0.09% in GnomAD NFE (p=0.0001), whereas non-truncating ones were not. Patients carrying NEXNtv (n=16), plus a further patient carrying a homozygous p.G650del variant were thus considered affected by NEXN-related CMP (NEXN-CMP). Out of 17 patients with NEXN-CMP, 82% were probands, 53% were males and median age at diagnosis was 46 (IQR 35-55). At baseline, the most prevalent phenotypes were DCM (53%) and ACM (41%) and NYHA I class was common (71%). Left ventricular (LV) indexed End Diastolic Volume was mildly increased (75mL, IQR 43-87) and ejection fraction mildly reduced (LVEF 41%±15). Myocardial fibrosis was reported for up to 67% of patients, median ventricular ectopic beats were 515/24h (IQR 43-5071). During a median follow of 42 months, 8 patients were implanted with ICD, 1 patient died and 3 (21%) had malignant ventricular arrythmias (MVA). When compared to a cohort of patients with TTN-CMP, patients with NEXN-CMP showed MVA earlier, and with higher LVEF. Conclusions NEXNtv showed significant disease association with DCM/ACM phenotypes. NEXN-CMP seems to be characterized by mild LV dilation and dysfunction, uncommon heart failure, but frequent myocardial fibrosis and ventricular arrythmias. These findings from the largest cohort of NEXN variants carriers strongly contribute to defining the causative role of this rare genotype and its related phenotype.