TY - JOUR
T1 - Genetic and Phenotypic Characterization of Nexilin (NEXN)–Related Cardiomyopathy
T2 - Results From a Multicentric Study
AU - Perotto, Maria
AU - Paldino, Alessia
AU - Mazzarotto, Francesco
AU - Barbati, Giulia
AU - Stroeks, Sophie L.V.M.
AU - Verdonschot, Job A.J.
AU - Akhtar, Mohammed
AU - Elliott, Perry
AU - Ochoa, Juan Pablo
AU - Garcia-Pavia, Pablo
AU - de Frutos, Fernando
AU - Sepp, Robert
AU - Hategan, Lidia
AU - Prasad, Sanjay
AU - Yazdani, Momina
AU - Morris-Rosendahl, Deborah
AU - Palinkas, Eszter Dalma
AU - Girolami, Francesca
AU - Olivotto, Iacopo
AU - Parikh, Victoria N.
AU - Fatkin, Diane
AU - Lakdawala, Neal
AU - McKenna, William J.
AU - Stolfo, Davide
AU - Gigli, Marta
AU - Brun, Francesca
AU - Collesi, Chiara
AU - Giacca, Mauro
AU - Zacchigna, Serena
AU - Severini, Giovanni Maria
AU - Lenarduzzi, Stefania
AU - Spedicati, Beatrice
AU - Santin, Aurora
AU - Girotto, Giorgia
AU - Gasparini, Paolo
AU - Taylor, Matthew R.G.
AU - Mestroni, Luisa
AU - Merlo, Marco
AU - Sinagra, Gianfranco
AU - Dal Ferro, Matteo
N1 - Funding Information:
Prof Rossana Bussani, Associate Professor of Pathological Anatomy, University of Trieste, is gratefully acknowledged for her expert review of endomyocardial biopsies. The authors are grateful to the patients and family members for their participation in these studies.
Publisher Copyright:
© 2025 The Authors
PY - 2025/9/1
Y1 - 2025/9/1
N2 - Background: Nexilin (NEXN)–related cardiomyopathies (CMPs) are largely unexplored. 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.
AB - Background: Nexilin (NEXN)–related cardiomyopathies (CMPs) are largely unexplored. 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.
KW - arrhythmias
KW - cardiac fibrosis
KW - DCM
KW - genetics
KW - inherited cardiac diseases
KW - NDLVC
U2 - 10.1016/j.jchf.2025.102529
DO - 10.1016/j.jchf.2025.102529
M3 - Article
SN - 2213-1779
VL - 13
JO - JACC: Heart Failure
JF - JACC: Heart Failure
IS - 9
M1 - 102529
ER -