Congenital dilated cardiomyopathy caused by biallelic mutations in Filamin C

Abstract

In the vast majority of pediatric patients with dilated cardiomyopathy, the specific etiology is unknown. Studies on families with dilated cardiomyopathy have exemplified the role of genetic factors in cardiomyopathy etiology. In this study, we applied wholeexome sequencing to members of a non-consanguineous family affected by a previously unreported congenital dilated cardiomyopathy syndrome necessitating early-onset heart transplant. Exome analysis identified compound heterozygous variants in the FLNC gene. Histological analysis of the cardiac muscle demonstrated marked sarcomeric and myofibrillar abnormalities, and immunohistochemical staining demonstrated the presence of Filamin C aggregates in cardiac myocytes. We conclude that biallelic variants in FLNC can cause congenital dilated cardiomyopathy. As the associated clinical features of affected patients are mild, and can be easily overlooked, testing for FLNC should be considered in children presenting with dilated cardiomyopathy.

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

“…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., ). Remarkably, one of the typical morphological features in patients with the A1186V mutation was the absence of filamin C regular staining in the areas of intercalated discs, a sign previously reported in association with FLNC ‐caused cardiomyopathies (Brodehl et al., ; Reinstein et al., ).…”

“…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.…”

“…Notably, RCM myocardial dysfunction, as well as other types of cardiomyopathies, can manifest concomitant with skeletal muscle system pathology, highlighting the involvement of genes expressed both in cardiac and skeletal muscle (Janin et al., ; Konersman et al., ; Kostareva, Sejersen, & Sjoberg, ). One such gene recently associated with several types of cardiomyopathies is FLNC (MIM# 102565) (Begay et al., ; Brodehl et al., ; Gomez et al., ; Ortiz‐Genga et al., ; Reinstein et al., ; Valdes‐Mas et al., ). FLNC encodes filamin C, an actin cross‐linking protein abundant both in cardiomyocytes and skeletal muscle cells.…”

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

“…None of these reports indicated any observed cardiac phenotype. More recently, the impact of FLNC variation on the heart has been recognized, including reports on dilated cardiomyopathy, 34–36 hypertrophic cardiomyopathy, 37,38 atrial fibrillation, 37,39 and restrictive cardiomyopathy. 9 The phenotypic spectrum associated with FLNC variation is intriguing, suggesting that variants act through divergent and tissue specific manner and/or that variants are modified by other genetic factors present in the given family.…”

Cardiomyopathies and Related Changes in Contractility of Human Heart Muscle

“…The end-diastolic volume increase causes a decrease in left ventricular ejection fraction [91]. A decrease in myofibril density was also observed in the case of end-stage pediatric cardiomyopathy [58] and congenital dilated cardiomyopathy with mutation in the structural protein filamin-C [92]. …”