Mutation profile of FLNC gene and its prognostic relevance in patients with hypertrophic cardiomyopathy

Abstract

BackgroundFilamin C (FLNC) mutation was reported as a cause of HCM, with a high probability of sudden cardiac death. However, the mutation profile of FLNC, and its relationship with phenotypic expression in HCM, remains to be elucidated.MethodsIn this study, FLNC gene was sequenced in 540 HCM patients and 307 healthy controls.ResultsWe found that 39 (7.2%) patients carried FLNC mutations, with a similar frequency to that of controls (4.2%, p = 0.101). Pedigree analysis showed that mutations were not well segregated with HCM. The baseline characteristics between HCM patients, with and without mutations, were comparable. FLNC mutations did not increase the risk for either all‐cause mortality (HR 0.746, 95% CI 0.222–2.295, p = 0.575) or cardiac mortality (HR 0.615, 95% CI 0.153–1.947, p = 0.354) in HCM patients during a follow‐up of 4.7 ± 3.2 years. Moreover, there was no significant difference in survival free from sudden cardiac arrest (HR 0.721, 95% CI 0.128–3.667, p = 0.660) and heart failure (HR 0.757, 95% CI 0.318–1.642, p = 0.447).Conclusions FLNC mutations were common in both HCM patients and healthy population. The pathogenicity of FLNC mutations detected in HCM patients and its association with the clinical outcomes should be cautiously interpreted.

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

“…However, the implication of missense variants in HCM is questioned and need to be confirmed. Mainly, two publications did not detect significant excess of rare missense variants between HCM cases and controls . One limitation discussed by Walsh et al is an insufficient size of the cohort .…”

“…One limitation discussed by Walsh et al is an insufficient size of the cohort . Additionally, in the publication of Cui et al, at least three differences could be noticed: (a) the ethnic origin of the cohort, (b) the threshold of variant frequency and (c) the fact that 33% of their patients were carriers of a second mutation in a major gene which could induce a bias in the expression of the disease …”

“…Mainly, two publications did not detect significant excess of rare missense variants between HCM cases and controls. 20,21 One limitation discussed by Walsh et al is an insufficient size of the cohort. 21 concluded to a haploinsufficiency model.…”

Clinical and pathological characterization of FLNC‐related myofibrillar myopathy caused by founder variant c.8129G>A in Hong Kong Chinese

“…At the time of writing, the Hong Kong variant is absent from controls in the Exome Sequencing Project, 1000 Genomes Project and Genome Aggregation Database, as well as the ethnic‐specific Chinese Millionome Database, Genome Variation Map, and Virtual Chinese Genome Database . It has not been detected in FLNC ‐related myofibrillar myopathy Chinese patients from other areas, or cohorts of Chinese patients tested for FLNC ‐related cardiomyopathies, even when the neighboring c.8130G>A had been described in one ethnic Chinese family . Indeed, to our knowledge the Hong Kong variant has not been reported in any other populations including ethnic Chinese residing in other areas.…”

Structure and Function of Filamin C in the Muscle Z-Disc

“…This is far higher than HCM prevalence (0.2%) in the general population. In addition, FLNC-CM patients rarely have skeletal myopathy, suggesting that the genotype-phenotype relationship of some FLNC mutations might be uncertain and needs to be further evaluated [97].…”