FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype‐phenotype correlations

Flavie Ader (1, 2, 3, 3, 4) , Pascal de Groote (5) , Patricia Réant (6) , Caroline Rooryck-Thambo (7) , Delphine Dupin-Deguine (8) , Caroline Rambaud (9) , Diala Khraiche , Claire Perret (1) , Jean-François Pruny (3) , Michèle Mathieu‐dramard (10) , Marion Gérard (11) , Yann Troadec (11) , Laurent Gouya (12) , Xavier Jeunemaitre (13) , Lionel van Maldergem , Albert A. Hagège (14) , Eric Villard (1, 2) , Philippe Charron (1, 2) , Pascale Richard (3, 1, 2, 3)

1 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
2 SU - Sorbonne Université
3 CHU Pitié-Salpêtrière [AP-HP]
4 UPD5 - Université Paris Descartes - Paris 5
5 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
6 Adaptation cardiovasculaire à l'ischemie
7 CHU Bordeaux
8 Service Génétique Médicale [CHU Toulouse]
9 SADV - Stress Abiotiques et Différenciation des Végétaux Cultivés
10 Unité de génétique médicale et oncogénétique [CHU Amiens Picardie]
11 Service de Génétique [CHU Caen]
12 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation
13 PARCC - UMR-S U970 - Paris-Centre de Recherche Cardiovasculaire
14 UMR_S 633 - Therapie Cellulaire en Pathologie Cardio-Vasculaire

Pathogenic variants in FLNC encoding filamin C have been firstly reported to cause myopathies, and were recently linked to isolated cardiac phenotypes. Our aim was to estimate the prevalence of FLNC pathogenic variants in subtypes of cardiomyopathies and to study the relations between phenotype and genotype. DNAs from a cohort of 1150 unrelated index-patients with isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non-compactions) have been sequenced on a custom panel of 51 cardiomyopathy disease-causing genes. An FLNC pathogenic variant was identified in 28 patients corresponding to a prevalence ranging from 1% to 8% depending on the cardiomyopathy subtype. Truncating variants were always identified in patients with dilated cardiomyopathy, while missense or in-frame indel variants were found in other phenotypes. A personal or family history of sudden cardiac death (SCD) was significantly higher in patients with truncating variants than in patients carrying missense variants (P = .01). This work reported the first observation of a left ventricular non-compaction associated with a unique probably causal variant in FLNC which highlights the role of FLNC in cardiomyopathies. A correlation between the nature of the variant and the cardiomyopathy subtype was observed as well as with SCD risk.

Mots clés: cardiomyopathies; FLNC; Genotype-phenotype correlation; myopathy; next generation sequencing

Domaines: Génétique

Flavie Ader, Pascal de Groote, Patricia Réant, Caroline Rooryck-Thambo, Delphine Dupin-Deguine, et al.. FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype‐phenotype correlations. Clinical Genetics, 2019, 96 (4), pp.317-329. ⟨10.1111/cge.13594⟩. ⟨hal-02268422⟩