Isolated X-Linked Hypertrophic Cardiomyopathy Caused by a Novel Mutation of the Four-and-a-Half LIM Domain 1 Gene

Abstract

We identified a novel FHL1 mutation causing isolated hypertrophic cardiomyopathy with X-chromosomal inheritance.

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

“…These findings, together with previous reports showing that different mutations within the filamin C molecule result in different myopathological features 16 [19][20][21] . Similarly, mutations in FHL1, which usually cause skeletal muscle disease, have been shown to cause HCM with left ventricular diastolic dysfunction without skeletal muscle affection 22,23 . This situation is closely parallel to that of the FLNC mutations described in the present work, which are mainly clustered on the N-and C-terminal parts of the protein, but none of them overlap with previously described mutations causing myofibrillar myopathy 16 .…”

Expanding the Genetic Spectrum of Hypertrophic Cardiomyopathy: X Marks the Spot

“…In the current study by Hartmannova et al, 6 the likely X-linked transmission, based on the family history alone, played a major role in refining the DNA variant list to those changes present on the X-chromosome. As shown in Table I in the online-only Data Supplement in the current study, 6 the FHL1 variant was the only one that fulfilled both the pathogenic criteria and was present on the X-chromosome! Significant advances have been made in defining the genetic basis of HCM.…”

“…The study by Hartmannova et al 6 presents several interesting insights. To date, HCM has been considered an autosomal dominant disorder.…”

“…Significant advances have been made in defining the genetic basis of HCM. The study by Hartmannova et al 6 provides additional evidence for an X-linked form of isolated HCM caused by a mutation in the FHL1 gene. The study reminds us of the importance of taking a detailed family history, which may provide clues about the disease transmission pattern as well as the diversity of the clinical phenotype.…”

“…In the cardiovascular field, several studies have already emerged demonstrating the use of exome sequencing in genetic discoveries in both primary arrhythmogenic disorders and inherited cardiomyopathies. [15][16][17][18] Using an appropriate bioinformatics pipeline and analysis, Hartmannova et al 6 performed exome sequencing on only 3 affected individuals. Looking for potential pathogenic variants common to all 3 affected individuals, the vast list of variants was narrowed down to 51 rare coding variants, with the variant in the FHL1 gene emerging as the most likely pathogenic variant.…”