Investigation of Pathogenic Genes in Chinese sporadic Hypertrophic Cardiomyopathy Patients by Whole Exome Sequencing

Abstract

Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease with high heterogeneity. Limited knowledge concerning the genetic background of nearly 40% HCM cases indicates there is a clear need for further investigation to explore the genetic pathogenesis of the disease. In this study, we undertook a whole exome sequencing (WES) approach to identify novel candidate genes and mutations associated with HCM. The cohort consisted of 74 unrelated patients with sporadic HCM (sHCM) previously determined to be negative for mutations in eight sarcomere genes. The results showed that 7 of 74 patients (9.5%) had damaging mutations in 43 known HCM disease genes. Furthermore, after analysis combining the Transmission and De novo Association (TADA) program and the ToppGene program, 10 putative genes gained priority. A thorough review of public databases and related literature revealed that there is strong supporting evidence for most of the genes playing roles in various aspects of heart development. Findings from recent studies suggest that the putative and known disease genes converge on three functional pathways: sarcomere function, calcium signaling and metabolism pathway. This study illustrates the benefit of WES, in combination with rare variant analysis tools, in providing valuable insight into the genetic etiology of a heterogeneous sporadic disease.

Rare Genetic Variants in Gata Transcription Factors in Patients with Hypertrophic Cardiomyopathy

“…Furthermore, polymorphisms in genes of the renin–angiotensin system,6 7 in the resistin gene,8 and in the MEF2C gene,9 among others, have been described as modifiers in HCM features, with controversial results in some cases 10. These findings support the search for additional genes implicated in the pathophysiology of HCM or in the interindividual variability 11. Likely candidates are cardiac transcription factors that regulate the expression of cardiac genes involved in the hypertrophic response 12.…”

Novel obscurins mediate cardiomyocyte adhesion and size via the PI3K/AKT/mTOR signaling pathway

“…Recently, obscurins were linked to the development of heart failure [11,12]. Accordingly, up-regulation of obscurins was reported in a mouse model of myocardial hypertrophy and a canine model of ventricular tachycardia [13,14], and missense and frameshift mutations in the OBSCN gene were linked to the development of cardiomyopathies [11,12,15,16]. …”

Obscure functions: the location–function relationship of obscurins

“…A possible pathogenic mechanism for the R4344Q variant of obscurin is decreased stability and integrity of sarcomeric structure at the Z-disc through disruption of the obscurin-titin complex; however, it cannot be denied that the R4344Q mutation of obscurin is involved in the development of HCM through an alternative mechanism. More recently, six additional variants of OBSCN were identified in HCM patients (Xu et al 2015). Specifically, missense variants R5215H and G7500R map to one of the Ig domains between the IQ motif and SH3 domain and to the Ig domain just upstream of SK2, respectively.…”

“…Specifically, genomic linkage analysis has identified several variants of the OBSCN gene that are directly linked with the development of hypertrophic (HCM) and dilated (DCM) cardiomyopathy as well as left ventricular noncompaction (Fig. 4) (Arimura et al 2007;Marston et al 2015;Rowland et al 2016;Xu et al 2015). While the impact of these mutations on obscurin protein function is unknown, plausible consequences on the protein function can be speculated.…”

“…The functional significance of these regions and therefore of these variants is as yet undefined. In addition, four frameshift variants, namely, A966fs, A1640fs, A1088fs, and A1272fs, occurring prior to Ig domain 20 result in truncated proteins devoid of the signaling motifs and are classified as loss-of-function mutations (Xu et al 2015).…”