Deletions of specific exons of FHOD3 detected by next‐generation sequencing are associated with hypertrophic cardiomyopathy

Abstract

Despite new strategies, such as evaluating deep intronic variants and new genes in whole‐genome‐sequencing studies, the diagnostic yield of genetic testing in hypertrophic cardiomyopathy (HCM) is still around 50%. FHOD3 has emerged as a novel disease‐causing gene for this phenotype, but the relevance and clinical implication of copy‐number variations (CNVs) have not been determined. In this study, CNVs were evaluated using a comparative depth‐of‐coverage strategy by next‐generation sequencing (NGS) in 5493 HCM probands and 2973 disease‐controls. We detected three symmetrical deletions in FHOD3 that involved exons 15 and 16 in three HCM families (no CNVs were detected in the control group). These exons are part of the diaphanous inhibitory domain of FHOD3 protein, considered a cluster of mutations for HCM. The clinical characteristics of the affected carriers were consistent with those reported in FHOD3 in previous studies. This study highlights the importance of performing CNV analysis systematically in NGS genetic testing panels for HCM, and reinforces the relevance of the FHOD3 gene in the disease.

FHOD formin and SRF promote post-embryonic striated muscle growth through separate pathways in C. elegans

“…A partial disconnect is often observed between particular genetic variants and phenotypic presentation in cardiomyopathies, and it has been suggested that this may be due to factors such as modifier genes, epigenetics, environment, or incomplete penetrance [72]. Thus, mutations of the fhod-1-related human gene, FHOD3, have been suggested to cause HCM, but there is imperfect correspondence between a given FHOD3 mutation and the development of disease [6,[9][10][11]. Our findings point to the possibility that one contribution to variability may be interplay between FHOD3 and perturbations in the ubiquitin proteasome system (UPS), a known contributor to cardiomyopathy [73].…”

“…Another sarcomeric component of cardiac muscle is formin homology 2 domain containing 3 (FHOD3) [3,4], a member of the formin family of proteins. Mutations in the FHOD3 gene have recently been shown to be a genetic cause of HCM, while other mutations have been associated with DCM [5][6][7][8][9][10][11].…”

“…In mice, knock out of the FHOD3 gene leads to death from heart failure by embryonic day 11.5 with appearance of immature sarcomere-containing premyofibrils/stress fiber-like structures with immature Z-lines that fail to mature into myofibrils [21]. In contrast to the full knockout or knockdowns of FHOD3 in mouse or cultured cell studies, most identified human variants of FHOD3 related to HCM or DCM are missense mutations [5][6][7][8][9][10][11]. Interestingly, formins in general and FHOD3 in particular have been implicated in the proper function of serum response factor (SRF), another protein thought to be involved in DCM and HCM.…”

FHOD formin and SRF promote striated muscle development through separate pathways inC. elegans

“…Another sarcomeric component of cardiac muscle is formin homology 2 domain containing 3 (FHOD3) [3,4], a member of the formin family of proteins. Mutations in the FHOD3 gene have recently been shown to be a genetic cause of HCM, while other mutations have been associated with DCM [5][6][7][8][9][10][11].…”

“…In mice, knock out of the FHOD3 gene leads to death from heart failure by embryonic day 11.5 with appearance of immature sarcomere-containing premyofibrils/stress fiber-like structures with immature Z-lines that fail to mature into myofibrils [21]. In contrast to the full knockout or knockdowns of FHOD3 in mouse or cultured cell studies, most identified human variants of FHOD3 related to HCM or DCM are missense mutations [5][6][7][8][9][10][11].…”