NEXN Gene in Cardiomyopathies and Sudden Cardiac Deaths: Prevalence, Phenotypic Expression, and Prognosis

Author:

Hermida Alexis1234ORCID,Ader Flavie567ORCID,Millat Gilles8ORCID,Jedraszak Guillaume92ORCID,Maury Phillipe10ORCID,Cador Romain11,Antoine Catalan Pierre12ORCID,Clerici Gaël13ORCID,Combes Nicolas14ORCID,De Groote Pascal15ORCID,Dupin-Deguine Delphine16,Eschalier Romain12ORCID,Faivre Laurence17ORCID,Garcia Patricia18,Guillon Benoit19,Janin Alexandre8ORCID,Kugener Beatrice20ORCID,Lackmy Marylin21,Laredo Mikael37,Le Guillou Xavier22ORCID,Lesaffre François23ORCID,Lucron Hugues24ORCID,Milhem Antoine25ORCID,Nadeau Gwenaël26ORCID,Nguyen Karine27,Palmyre Aurélien28ORCID,Perdreau Elodie29,Picard François30ORCID,Rebotier Nicolas31,Richard Pascale67ORCID,Rooryck Caroline32ORCID,Seitz Julien33,Verloes Alain34ORCID,Vernier Agathe35,Winum Pierre36,Yabeta Grace-A-Dieu37,Bouchot Océane38,Chevalier Philippe39ORCID,Charron Philippe34728ORCID,Gandjbakhch Estelle347ORCID

Affiliation:

1. Cardiology, Arrhythmia, and Cardiac Stimulation Service (A.H.), Amiens-Picardie University Hospital.

2. EA4666 HEMATIM, University of Picardie-Jules Verne, Amiens (A.H., G.J.).

3. Institute of Cardiology and ICAN Institute for Cardiometabolism and Nutrition (A.H., M. Laredo, P. Charron, E.G.).

4. Department of Genetics, Department of Cardiology, and Referral center for hereditary cardiac diseases, APHP, Pitié-Salpêtrière Hospital (A.H., P. Charron, E.G.).

5. Unité Pédagogique de Biochimie, Département des Sciences Biologiques et Médicales, UFR de Pharmacie-Faculté de Santé, Université Paris Cité (F.A.).

6. Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, DMU Biogem, Service de Biochimie Métabolique, AP-HP-Sorbonne Université, Pitié-Salpêtrière -Charles Foix (F.A., P.R.).

7. Sorbonne Université, INSERM 1166, Paris (F.A., M. Laredo, P.R., P. Charron, E.G.).

8. Service de Génétique Moléculaire, Hospices Civils de Lyon (G.M., A.J.).

9. Molecular Genetics Laboratory (G.J.), Amiens-Picardie University Hospital.

10. Service de Cardiologie (P.M.), CHU Toulouse.

11. Service de Cardiologie, Hôpital Saint Joseph, Paris (R.C.).

12. Service de Cardiologie, CHU Clermont Ferrand (P.A.C., R.E.).

13. Service de Cardiologie, Centre hospitalier universitaire, Saint Pierre, La Réunion (G.C.).

14. Service de Cardiologie, Clinique Pasteur, Toulouse (N.C.).

15. France CHU Lille, Service de Cardiologie & Inserm U1167, Institut Pasteur de Lille (P.D.G.).

16. Service de Génétique (D.D.-D.), CHU Toulouse.

17. Centre de Génétique, CHU Dijon (L.F.).

18. Unité Mort Inattendue du Nourrisson, Hôpital de la Conception, APHM, Marseille (P.G.).

19. Service de Cardiologie, CHU Besançon (B.G.).

20. Urgences Pédiatriques (B.K.), Hôpital Louis Pradel, HCL, Lyon.

21. Unité de Génétique Clinique, CHU de Guadeloupe, Pointe à Pitre (M. Lackmy).

22. Service de Génétique Clinique, CHU Poitiers, Poitiers (X.L.G.).

23. Service de Cardiologie, CHU Reims (F.L.).

24. Service de Cardiologie pédiatrique, CHU Martinique, Fort-de-France (H.L.).

25. Service de Cardiologie, CH La Rochelle (A.M.).

26. Service de génétique clinique CH Métropole Savoie, Chambéry (G.N.).

27. Service de Génétique, APHM, Marseille (K.N.).

28. APHP, Ambroise Paré Hospital, Department of Genetics and Referral center for cardiac hereditary cardiac diseases, Boulogne-Billancourt (A.P., P. Charron).

29. Département médico chirurgical de cardiologie pédiatrique (E.P.), Hôpital Louis Pradel, HCL, Lyon.

30. Service de Cardiologie, Hôpital Cardiologique Haut Leveque, Bordeaux (F.P.).

31. Service de Cardiologie, CH Basse-Terre (N.R.).

32. CHU Bordeaux, Service de Génétique Médicale (C.R.).

33. Service de Cardiologie, Hôpital Saint Joseph, Marseille (J.S.).

34. Departement de génétique, Hôpital Robert Debré, APHP (A. Verloes).

35. Service de Cardiologie, CH Compiègne (A. Vernier).

36. Service de Cardiologie, CHU Nîmes (P.W.).

37. Service de Cardiologie, CH Ouest Guyane, Saint-Laurent-du-Maroni (G.-A.-D.Y.).

38. Service de Cardiologie, CH Annecy Genevois, Annecy, France (O.B.).

39. Service de Cardiologie (P. Chevalier), Hôpital Louis Pradel, HCL, Lyon.

Abstract

BACKGROUND: Few clinical data are available on NEXN mutation carriers, and the gene’s involvement in cardiomyopathies or sudden death has not been fully established. Our objectives were to assess the prevalence of putative pathogenic variants in NEXN and to describe the phenotype and prognosis of patients carrying the variants. METHODS: DNA samples from consecutive patients with cardiomyopathy or sudden cardiac death/sudden infant death syndrome/idiopathic ventricular fibrillation were sequenced with a custom panel of genes. Index cases carrying at least one putative pathogenic variant in the NEXN gene were selected. RESULTS: Of the 9516 index patients sequenced, 31 were carriers of a putative pathogenic variant in NEXN only, including 2 with double variants and 29 with a single variant. Of the 29 unrelated probands with a single variant (16 males; median age at diagnosis, 32.0 [26.0–49.0] years), 21 presented with dilated cardiomyopathy (prevalence, 0.33%), and 3 presented with hypertrophic cardiomyopathy (prevalence, 0.14%). Three patients had idiopathic ventricular fibrillation, and there were 2 cases of sudden infant death syndrome (prevalence, 0.46%). For patients with dilated cardiomyopathy, the median left ventricle ejection fraction was 37.5% (26.25–50.0) at diagnosis and improved with treatment in 13 (61.9%). Over a median follow-up period of 6.0 years, we recorded 3 severe arrhythmic events and 2 severe hemodynamic events. CONCLUSIONS: Putative pathogenic NEXN variants were mainly associated with dilated cardiomyopathy; in these individuals, the prognosis appeared to be relatively good. However, severe and early onset phenotypes were also observed—especially in patients with double NEXN variants. We also detected NEXN variants in patients with hypertrophic cardiomyopathy and sudden infant death syndrome/idiopathic ventricular fibrillation, although a causal link could not be established.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

General Medicine

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