Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy

Abstract

Mutations in different genes encoding sarcomeric proteins are responsible for 50-60% of familial cases of hypertrophic cardiomyopathy (HCM); however, the genetic alterations causing the disease in one-third of patients are currently unknown. Here we describe a case with familial HCM of unknown cause. Whole-exome sequencing reveals a variant in the gene encoding the sarcomeric protein filamin C (p.A1539T) that segregates with the disease in this family. Sequencing of 92 HCM cases identifies seven additional variants segregating with the disease in eight families. Patients with FLNC mutations show marked sarcomeric abnormalities in cardiac muscle, and functional analysis reveals that expression of these FLNC variants resulted in the formation of large filamin C aggregates. Clinical studies indicate that FLNC-mutated patients have higher incidence of sudden cardiac death. On the basis of these findings, we conclude that mutations in the gene encoding the sarcomeric protein filamin C cause a new form of familial HMC.

Congenital dilated cardiomyopathy caused by biallelic mutations in Filamin C

“…Only recently, a direct connection between dominant variants in FLNC to isolated hypertrophic and restrictive cardiomyopathies has been proposed. 4,12 Interestingly, none of the reported patients had symptoms or clinical findings of myopathy. It was shown previously that disruption of the desmin gene in mice work in a dominant-negative mechanism to compromise myofibril alignment and leads to the appearance of aggregates that are characteristic of desmin-related cardiomyopathy.…”

“…Blocks were sectioned (3 μm) and histochemical techniques including H&E and Masson trichrome were performed following the manufacturer's instructions and as described previously. 4 Immunohistochemistry was performed on paraffin 3-μm-thick sections, previously heated at 60°C, then cleared and dehydrated in xylene and graded alcohols. Antigen retrieval was performed by heating in with a Tris borate EDTA buffer (pH 8.4).…”

Primary distal renal tubular acidosis: novel findings in patients studied by next-generation sequencing

“…The amplicons covered 99% of the target sequence (Supplementary Table S1 online). Each DNA pool was amplified with the Ion Ampliseq Library Kit 2.0 in conjunction with Ion Ampliseq Custom Primer Pool protocols, followed by template preparation by Ion PGM Template OT2 200 kit, and sequenced in a PGM sequencer using Ion PGM Sequencing 200 kit v2 according to the manufacturer procedures (Life Technologies) (29). Template-positive spheres were recovered using Dynabeads MyOne Streptavidin C1 beads and quantified using the Ion Sphere quality control assay with the Qubit 2.0 fluorometer (Life Technologies).…”

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

“…FLNC residue 1546 is in the 14th (out of 24) Ig-like domain of filamin C, close to a recently identified RCM missense mutation S1624L 17 and an HCM-related mutation, A1539T 25 . The Clustal alignment of this 14th domain peptide sequence, containing c.4636G>A G1546S, showed perfect conservation at the Gly 1546 residue among phylogenetically diverse organisms and filamin C isoforms [ Figure 4].…”