纽蛋白（NEXN）相关心肌病的遗传学和表型特征：一项多中心研究的结果
Genetic and Phenotypic Characterization of Nexilin (NEXN)-Related Cardiomyopathy: Results From a Multicentric Study.
作者信息
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
机构信息
Cardiovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina (member of the European Reference Network for Rare, Low-Prevalence, or Complex Diseases of the Heart), University of Trieste, Italy.
Department of Molecular and Translational Medicine, University of Brescia, Italy; National Heart and Lung Institute, Imperial College London, London, United Kingdom.
出版信息
JACC Heart Fail. 2025 Sep;13(9):102529. doi: 10.1016/j.jchf.2025.102529. Epub 2025 Jul 18.
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.
背景
与Nexilin（NEXN）相关的心肌病（CMP）在很大程度上尚未得到充分研究。
目的
本研究调查了NEXN在CMP中的致病作用，研究其表型表达和预后特征。
方法
12个转诊中心收集了携带NEXN变异患者的表型/基因型数据。根据gnomAD中CMP的等位基因频率确定变异的罕见性。针对gnomAD非芬兰欧洲人（NFE），对肥厚型心肌病（HCM）和扩张型心肌病（DCM）/非扩张型左心室心肌病（NDLVC）CMP中的罕见NEXN变异进行负担富集测试。详细阐述了已验证变异的结果，并与与肌联蛋白（TTN）和细丝蛋白C（FLNC）相关的CMP队列进行预后比较。
结果
纳入60名携带罕见的、可改变蛋白质的变异的NEXN携带者，在DCM/NDLVC队列中发现NEXN截短变异（tv）显著富集（gnomAD NFE中为0.39%对0.09%；P = 0.0001），而未观察到与HCM相关。患有DCM/NDLVC且携带NEXNtv的患者（n = 17；中位年龄：45岁[四分位间距：36 - 55岁]，88%为先证者，53%为男性）表现出轻度左心室扩张（舒张末期容积指数69 mL[四分位间距：46 - 87 mL]）、左心室射血分数轻度降低（44%[四分位间距：31% - 53%]）和心肌纤维化（64%）。纽约心脏协会（NYHA）心功能I级常见（71%）。在中位随访45个月（四分位间距：11 - 130个月）期间，53%的患者植入了植入式心脏复律除颤器，25%发生了恶性室性心律失常（MVA）。与TTN - CMP相比，NEXN - CMP在较高射血分数时表现出更早且更频繁的MVA，与FLNC - CMP相比未发现显著差异。
结论
NEXNtv与DCM/NDLVC显著相关，其特征为轻度心脏异常、心力衰竭不常见、纤维化常见和心律失常。这个迄今为止最大的NEXN变异携带者队列有助于确定这种罕见基因型及其相关表型的致病作用。
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