Genetic and Phenotypic Characterization of Nexilin (NEXN)-Related Cardiomyopathy: Results From a Multicentric Study.
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Perotto Maria, Paldino Alessia, Mazzarotto Francesco, Barbati Giulia, Stroeks Sophie L V M, Verdonschot Job A J, Akhtar Mohammed, Elliott Perry, Ochoa Juan Pablo, Garcia-Pavia Pablo, de Frutos Fernando, Sepp Robert, Hategan Lidia, Prasad Sanjay, Yazdani Momina, Morris-Rosendahl Deborah, Palinkas Eszter Dalma, Girolami Francesca, Olivotto Iacopo, Parikh Victoria N, Fatkin Diane, Lakdawala Neal, McKenna William J, Stolfo Davide, Gigli Marta, Brun Francesca, Collesi Chiara, Giacca Mauro, Zacchigna Serena, Severini Giovanni Maria, Lenarduzzi Stefania, Spedicati Beatrice, Santin Aurora, Girotto Giorgia, Gasparini Paolo, Taylor Matthew R G, Mestroni Luisa, Merlo Marco, Sinagra Gianfranco, Dal Ferro Matteo
Аннотация
OBJECTIVES: This study investigated the causative role of NEXN in CMPs, examining its phenotypic expression and prognostic profile.
METHODS: Twelve referral centers collected phenotypic/genotypic data of patients with NEXN variants. Variant rarity was determined according to gnomAD allele frequency in CMPs. Burden enrichment tested rare NEXN variants in hypertrophic (HCM) and dilated cardiomyopathy (DCM)/nondilated left ventricular cardiomyopathy (NDLVC) CMPs against gnomAD non-Finnish Europeans (NFE). Outcomes of validated variants were detailed, with prognostic comparisons to Titin (TTN)- and Filamin C (FLNC)-related CMP cohorts.
RESULTS: Involving 60 NEXN carriers with rare, protein-altering variants, a significant enrichment of NEXN-truncating variants (tvs) was found in the DCM/NDLVC cohort (0.39% vs 0.09% in gnomAD NFE; P = 0.0001), whereas no association was observed with HCM. Patients with DCM/NDLVC with NEXNtv (n = 17; median age: 45 years [Q1-Q3: 36-55 years], 88% probands, 53% male) showed mild left ventricular dilatation (indexed end-diastolic volume 69 mL [Q1-Q3: 46-87 mL]), mildly reduced left ventricular ejection fraction (44% [Q1-Q3: 31%-53%]), and myocardial fibrosis (64%). NYHA functional class I was common (71%). During a 45-month median follow-up (Q1-Q3: 11-130 months), 53% of patients were implanted with an implantable cardioverter-defibrillator and 25% had malignant ventricular arrhythmias (MVAs). Compared with TTN-CMP, NEXN-CMP exhibited earlier and more frequent MVAs at higher ejection fractions, and no significant differences were found against FLNC-CMP.
CONCLUSIONS: NEXNtvs were significantly associated with DCM/NDLVC, characterized by mild cardiac abnormalities, infrequent heart failure, common fibrosis, and arrhythmias. This largest NEXN variant carrier cohort to date contributes to defining the causative role of this rare genotype and its associated phenotype.