Identification of a novel hypertrophic cardiomyopathy-associated mutation using targeted next-generation sequencing

Abstract

Hypertrophic cardiomyopathy (HCM), one of the most common forms of myocardial diseases, is the major cause of sudden cardiac death in young adults and competitive athletes. Analyses of gene mutations associated with HCM are valuable for its molecular diagnosis, genetic counseling, and management of familial HCM. To dissect the relationship between the clinical presentation and gene mutations of HCM, the genetic characterizations of 19 HCM-related genes in 18 patients (8 cases from 6 pedigrees with familial HCM and 10 cases without familial HCM) were detected using next-generation sequencing (NGS). As a result, 12 disease-related mutations were identified in the 18 subjects, including 6 single mutations and 3 double mutations [MYBPC3 (p.Gln998Glu) plus TNNI3 (p.Arg145Gly), PRKAG2 (p.Gly100Ser) plus MYBPC3 (p.Lys1209Serfs*28) and TNNI3 (p.Glu124Gln) plus GLA (p.Trp47*)]. The 3 heterozygous double mutations were discovered for the first time in the malignant familial HCM patients. Of the 6 single mutations, a novel mutation was found in tafazzin (TAZ, p.Ile208Val), and a mutation in β-myosin heavy chain gene (MYH7, p.Arg54Gln), which was reported as rare in the general population, was firstly found in one HCM patient. Identification of novel and rare mutations in HCM patients have added new data to the spectrum of gene mutations associated with this disease. These findings provide an essential basis for the molecular diagnosis and better management of family members at risk of familial HCM.

Clinical Interpretation of Sequence Variants

“…Zhang et al, 2017). Because approximately 15-50% of familial HCM patients harboring two heterozygous variants has been observed and speculated to result in a more severe phenotype of HCM (Emrahi, Tabrizi, Gharehsouran, Ardebili, & Estiar, 2016;Zhao et al, 2017), BP5 should not be applied in this case.…”

Heart rate variability as predictive factor for sudden cardiac death

“…SCD in young people has an estimated incidence of 0.46-3.7 events per 100000 person-years and it is more frequent in men than women as summarized in Table 1 [ 8 , 9 ]. In young people it relates to channelopathies and cardiomyopathies [ 10 – 14 ], myocarditis and substance abuse [ 15 – 20 ]. The risk of SCD increases with age due to the higher prevalence of coronary artery disease (CAD), valvular heart diseases and heart failure (HF) in older age [ 7 ].…”

Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy

“…Of these sarcomeric genes, MYH7, MYBPC3, TNNI3, and TNNT2 account for a majority of the variants [13,[16][17][18]. Identification of novel variants in these genes and other HCM-associated genes has increased dramatically due to the advancement of high throughput genome and exome sequencing technologies [19][20][21][22][23]. However, the advancement of variant identification has also increased the number of potential sequence variants that could contribute to the disease in each individual, confounding the ability to assign pathogenicity to an individual variant [24][25][26].…”

“…MYL2 encodes the Myosin regulatory light chain expressed in the ventricular heart and slow-twitch skeletal muscles [36]. Even though MYL2 is considered as a candidate gene for HCM and a handful of pathogenic variants have been described in familial cases and population screens [23,[37][38][39][40][41][42], the lack of functional testing has prevented the designation of pathogenicity in many cases [43].…”