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

Abstract

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.

A mutation update for the FLNC gene in myopathies and cardiomyopathies

“…Conversely, muscular problems in cardiomyopathy patients have also been described (Limongelli et al, 2013), showing the strong molecular link between hereditary muscular dystrophies and cardiomyopathies. In line with this, cardiac involvement is not uncommon in FLNC-associated myopathy ( Figure 5), but muscle involvement has not been described (yet) at the moment of diagnosis in FLNC-associated cardiomyopathy (Ader et al, 2019). A single patient with DCM developed distal myopathy during follow-up (Ortiz-Genga et al, 2016).…”

“…Missense variants are mainly associated with HCM with a varying prevalence from 1.3% to 8.7% in HCM cohorts (Ader et al, 2019;Cui et al, 2018;Gomez et al, 2017;Valdes-Mas et al, 2014; Figure 1; Table 2). Two studies did not detect an excess of rare missense variants between HCM patients and controls, questioning the importance of FLNC missense variants in HCM (Cui et al, 2018;Walsh et al, 2019).…”

“…Two studies did not detect an excess of rare missense variants between HCM patients and controls, questioning the importance of FLNC missense variants in HCM (Cui et al, 2018;Walsh et al, 2019). Only 13 of the 54 missense variants are supported to be (likely) pathogenic by additional evidence such as functional studies (n = 4) and/or segregation (n = 13; Ader et al, 2019;Cui et al, 2018;Gomez et al, 2017;Valdes-Mas et al, 2014). Based on current diagnostic classification criteria, all other missense variants would individually be classified as VUS (Table 2).…”

“…DCM ranges from 1% to 4.5% (Ader et al, 2019;Begay et al, 2018;Janin et al, 2017;Ortiz-Genga et al, 2016; Table 1).…”

Clinical Implications of the Genetic Architecture of Dilated Cardiomyopathy

“…Functional studies supported FLNC haploinsufficiency as the mechanism driving arrhythmogenic DCM [68,69]. Multiple groups have reported FLNCtvs in probands and families with DCM and ventricular arrhythmias [68][69][70][71][72][73][74], which provides strong evidence for FLNCtv pathogenicity in arrhythmogenic DCM.…”