Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy

Abstract

Background Restrictive cardiomyopathy (RCM) is a rare cardiomyopathy characterized by impaired diastolic ventricular function resulting in a poor clinical prognosis. Rarely, heritable forms of RCM have been reported and mutations underlying RCM have been identified in genes that govern the contractile function of the cardiomyocytes. Methods and Results We evaluated 8 family members across four generations by history, physical examination, electrocardiography and echocardiography. Affected individuals presented with a pleitropic syndrome of progressive RCM, atrioventricular septal defects, and a high prevalence of atrial fibrillation. Exome sequencing of 5 affected members identified a single novel missense variant in a highly conserved residue of FLNC (p.V2297M). FLNC encodes Filamin C, a protein that acts as both a scaffold for the assembly and organization of the central contractile unit of striated muscle, and also as a mechanosensitive signaling molecule during cell migration and shear stress. Immunohistochemical analysis of Filamin C localization in cardiac tissue from an affected family member revealed a diminished localization at the z-disk, whereas traditional localization at the intercalated disk was preserved. Stem-cell derived cardiomyocytes mutated to carry the effect allele had diminished contractile activity when compared to controls. Conclusion We have identified a novel variant in FLNC as pathogenic variant for familial RCM, a finding that further expands upon the genetic basis of this rare and morbid cardiomyopathy.

Novel pathogenic variants in filamin C identified in pediatric restrictive cardiomyopathy

“…The pattern of HCM variants falling in the C‐terminal half of the protein is also seen with RCM variants: the two we report here fall in filamin repeats 20 and 23, a neighboring RCM variant to p.Pro2298Leu (p.Val2297Met) was recently reported by Tucker et al. (), and variants published by Brodehl et al. () localize in repeats 14 and 19.…”

De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy

“…One such gene is FLNC , known for a long time exclusively in association with distal and myofibrillar myopathies (Kley et al., ), and only more recently described in connection to cardiac phenotypes (Kley et al., ; Valdes‐Mas et al., ; Vorgerd et al., ). After the first description of FLNC mutation in a familial case of HCM in 2014, the number of reports documenting its role in the development of cardiac disorders has rapidly grown, making FLNC one of the most common genes associated with cardiomyopathies causing about 10% of HCM and up to 5% of DCM (Begay et al., ; Brodehl et al., ; Dal Ferro et al., ; Gomez et al., ; Janin et al., ; Ortiz‐Genga et al., ; Reinstein et al., ; Tucker et al., ; Valdes‐Mas et al., ). Similar to titin , FLNC is linked to all types of cardiomyopathies, including arrhythmogenic cardiomyopathy.…”

“…The aggregate formation at the developmental stage studied, however, did not result in disruption of muscle force generation (data not shown), which may be due to the expression of variable amounts of the transgene in the skeletal muscle which, in a wild‐type background, may not result in clear muscle function impairment. Given the presence of filamin C aggregates in patient 22, who was the oldest at the time of examination, and their absence in patient 25 despite the same genetic background, suggests that the FLNC aggregates might reflect the efficacy of the intracellular protein degradation system rather than an obligatory condition for clinical manifestation of filaminopathies (Kley et al., ; Ruparelia et al., ; Tucker et al., ). This is well in line with the fact that clinical presentation of filaminopathies does not always depend on the presence of intracellular aggregates (Janin et al., ; Ortiz‐Genga et al., ; Reinstein et al., ; Tucker et al., ; van den Bogaart et al., ).…”

“…In the past decade, FLNC mutations have been described in connection to several different inherited neuromuscular disorders such as myofibrillar myopathy and distal myopathy, and recently also as a frequent cause of cardiomyopathy (Begay et al, 2016;Brodehl et al, 2016;Gomez et al, 2017;Ortiz-Genga et al, 2016;Reinstein et al, 2016;Valdes-Mas et al, 2014). However, even though FLNC mutations can be a frequent cause of hypertrophic (HCM), dilated (DCM), and arrhythmogenic cardiomyopathy (ACM), little is still known about the association of FLNC with RCM (Brodehl et al, 2016;Tucker et al, 2017). Importantly, among all the reported FLNC-caused cardiomyopathies there are only a few cases with a combined cardiac and muscle phenotype, none of which included arthrogryposis (Gomez et al, 2017;Ortiz-Genga et al, 2016).…”

Exome sequencing identifies FLNC and ADD3 variants in a family with cardiomyopathy

“…The power and efficiency of WES is demonstrated in the identification of the FLNC mutation in this family, and other pathogenic genes in other RCM pedigrees [8,11,28] , dilated cardiomyopathy [37] , and in disease-gene discovery in general [38] . Although there are commercially available panels to test for mutations in known cardiomyopathy genes, WES is an unbiased search for such mutations and has the power to identify new cardiomyopathy genes.…”