Genetic analysis of monoallelic double MYH7 mutations responsible for familial hypertrophic cardiomyopathy

Wang,Bo; Wang,Jing; Wang,Li‑Feng; Yang,Fan; Xu,Lei; Li,Wen‑Xia; He,Yang; Zuo,Lei; Yang,Qian‑Li; Shao,Hong; Hu,Dan; Liu,Li‑Wen

doi:10.3892/mmr.2019.10754

Genetic analysis of monoallelic double MYH7 mutations responsible for familial hypertrophic cardiomyopathy

Authors:
- Bo Wang
- Jing Wang
- Li‑Feng Wang
- Fan Yang
- Lei Xu
- Wen‑Xia Li
- Yang He
- Lei Zuo
- Qian‑Li Yang
- Hong Shao
- Dan Hu
- Li‑Wen Liu
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Affiliations: Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China, Department of General Surgery, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China, Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
Published online on: October 16, 2019 https://doi.org/10.3892/mmr.2019.10754
Pages: 5229-5238
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

β‑myosin heavy chain (MHC) 7 (MYH7) is the dominant pathogenic gene that harbors mutations in 20‑30% of cases of familial hypertrophic cardiomyopathy (HCM). The aim of this study was to elucidate the distribution and type of genetic variations among Chinese HCM families. From 2013 to 2017, the clinical data of 387 HCM probands and their families were collected. Targeted exome‑sequencing technology was used in all probands, and the selected mutations were subsequently verified by Sanger sequencing in the probands, family members and 300 healthy ethnic‑matched volunteers. Three‑dimensional models were created using Swiss‑PdbViewer 4.1, and further genetic analyses were performed to determine sequence conservation and frequency of the mutations. Among the 5 probands with double MYH7 mutations, 4 carried compound heterozygous mutations, and 1 carried monoallelic double mutations (A934V and E1387K). Four family members of the proband with monoallelic double mutations had the same mutation as the proband. Echocardiography and 12‑lead electrocardiography revealed abnormalities in the proband and 3 of the 4 carriers. The probands with compound heterozygous mutation had a higher left ventricular mass as revealed by echocardiography and higher QRS, SV1 and RV5+SV1 amplitudes than those with monoallelic double mutations (P<0.05). Simulation of the 3D structure of mutated proteins showed that the replacement of alanine by valine affected the flexibility of the MHC neck domain in case of the A934V mutation, whereas reactivity of the MHC rod domain was affected in the case of the E1387K mutation. In conclusion, we identified several novel HCM‑causing MYH7 mutations. More importantly, this is the first study to report a rare HCM family with monoallelic double mutations.

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