Evidence map›Paper›PMID 40680702›Full record

ArticleJACC. Heart failure2025

Genetic and Phenotypic Characterization of Nexilin (NEXN)-Related Cardiomyopathy: Results From a Multicentric Study.

Maria Perotto, Alessia Paldino, Francesco Mazzarotto, Giulia Barbati, Sophie L V M Stroeks, Job A J Verdonschot, Mohammed Akhtar, Perry Elliott, Juan Pablo Ochoa, Pablo Garcia-Pavia and 30 more

Abstract readMulticenter Study
PubMed Full text at PMC Publisher
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Article in JACC. Heart failure, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

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1 · What the graph read from it

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2 · The registry

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3 · Its place in the literature

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1 citing paper in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

40 authors.

Maria PerottoCardiovascular 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.
Alessia PaldinoCardiovascular 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.
Francesco MazzarottoDepartment of Molecular and Translational Medicine, University of Brescia, Italy; National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Giulia BarbatiBiostatistics Unit, University of Trieste, Italy.
Sophie L V M StroeksDepartment of Cardiology, Cardiovascular Research Institute (member of the European Reference Network for Rare, Low-Prevalence, or Complex Diseases of the Heart), Maastricht University Medical Center, Maastricht, the Netherlands.
Job A J VerdonschotDepartment of Cardiology, Cardiovascular Research Institute (member of the European Reference Network for Rare, Low-Prevalence, or Complex Diseases of the Heart), Maastricht University Medical Center, Maastricht, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
Mohammed AkhtarSt Bartholomew's Hospital, Barts Heart Centre, London, United Kingdom.
Perry ElliottSt Bartholomew's Hospital, Barts Heart Centre, London, United Kingdom.
Juan Pablo OchoaHeart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro (member of the European Reference Network for Rare, Low-Prevalence, or Complex Diseases of the Heart), Madrid, Spain.
Pablo Garcia-PaviaHeart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro (member of the European Reference Network for Rare, Low-Prevalence, or Complex Diseases of the Heart), Madrid, Spain; Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
Fernando de FrutosHeart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro (member of the European Reference Network for Rare, Low-Prevalence, or Complex Diseases of the Heart), Madrid, Spain; Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
Robert SeppCardiology Center, Department of Medicine, University of Szeged (member of the European Reference Network for Rare, Low-Prevalence, or Complex Diseases of the Heart), Szeged, Hungary.
Lidia HateganCardiology Center, Department of Medicine, University of Szeged (member of the European Reference Network for Rare, Low-Prevalence, or Complex Diseases of the Heart), Szeged, Hungary.
Sanjay PrasadRoyal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Momina YazdaniRoyal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Deborah Morris-RosendahlRoyal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Eszter Dalma PalinkasCardiology Unit, Meyer University Hospital IRCCS, Florence, Italy; Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary.
Francesca GirolamiCardiology Unit, Meyer University Hospital IRCCS, Florence, Italy.
Iacopo OlivottoCardiology Unit, Meyer University Hospital IRCCS, Florence, Italy; Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy.
Victoria N ParikhStanford Center for Inherited Cardiovascular Disease, California, USA.
Diane FatkinMolecular Cardiology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney, Kensington, New South Wales, Australia; Cardiology Department, St Vincent's Hospital, Darlinghurst, New South Wales, Australia.
Neal LakdawalaDepartment of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
William J McKennaInstitute of Cardiovascular Science, University College London, London, United Kingdom.
Davide StolfoCardiovascular 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; Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Marta GigliCardiovascular 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.
Francesca BrunCardiovascular 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.
Chiara CollesiDepartment of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy; International Center for Genetic Engineering and Biotechnology, Trieste, Italy.
Mauro GiaccaInternational Center for Genetic Engineering and Biotechnology, Trieste, Italy; British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, King's College London, London, United Kingdom.
Serena ZacchignaDepartment of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy; International Center for Genetic Engineering and Biotechnology, Trieste, Italy.
Giovanni Maria SeveriniDivision of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Stefania LenarduzziInstitute for Maternal and Child Health-IRCCS, Burlo Garofolo, Trieste, Italy.
Beatrice SpedicatiDepartment of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
Aurora SantinDepartment of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
Giorgia GirottoDepartment of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy; Institute for Maternal and Child Health-IRCCS, Burlo Garofolo, Trieste, Italy.
Paolo GaspariniDepartment of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy; Institute for Maternal and Child Health-IRCCS, Burlo Garofolo, Trieste, Italy.
Matthew R G TaylorCardiovascular Institute and Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Luisa MestroniCardiovascular Institute and Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Marco MerloCardiovascular 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 Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
Gianfranco SinagraCardiovascular 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 Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
Matteo Dal FerroCardiovascular 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. Electronic address: matteo.dalferro@asugi.sanita.fvg.it.

Funding

Systematically mapping variant effects for cardiovascular genesR01HL164675 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI ASHLEY, EUAN A, RODEN, DAN M · 2022 to 2025
$8.1M
NHLBI NIH HHS R01 HL164675
6 · The paper itself

Abstract

backgroundNexilin (NEXN)-related cardiomyopathies (CMPs) are largely unexplored.

objectivesThis study investigated the causative role of NEXN in CMPs, examining its phenotypic expression and prognostic profile.

methodsTwelve 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.

resultsInvolving 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.

conclusionsNEXNtvs 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.

Indexed as

CardiomyopathiesCardiomyopathy, DilatedAdultConnectinFemaleGenotypeHumansLongitudinal StudiesMaleMiddle AgedPhenotypePrognosisRetrospective StudiesConnectinTTN protein, humanarrhythmiascardiac fibrosisDCMgeneticsinherited cardiac diseasesNDLVC

Identifiers

PMID40680702
PMCPMC12405182

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