Lifeng Wang1, Lei Zuo2, Jing Hu3, Hong Shao4, Changhui Lei5, Wei Qi2, Ying Liu2, Yunbo Miao6, Xuan Ma6, Christopher L-H Huang7, Bo Wang2, Xiaodong Zhou8, Yanmin Zhang9, Liwen Liu8. 1. Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an, China Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China. 2. Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an, China. 3. Department of Stomatology, the Military General Hospital of Beijing PLA, Beijing, China. 4. Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an, China Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. 5. Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an, China Department of Ultrasound, Ningxia Medical University, Yinchuan, China. 6. Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China. 7. Physiological Laboratory, University of Cambridge, Cambridge, UK. 8. Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an, China zhouxd@fmmu.edu.cn zhangym@mail.xjtu.edu.cn. 9. Heart Center, Northwest Women's and Children's Hospital, Xi'an, China zhouxd@fmmu.edu.cn zhangym@mail.xjtu.edu.cn.
Abstract
AIMS: Hypertrophic cardiomyopathy (HCM) mainly results from autosomal-dominant inherited single heterozygous mutations in cardiac sarcomere genes. Contributions of multiple gene mutations to disease heterogeneity in a three-generation family were investigated. METHODS: Clinical, electrocardiographic (ECG), and echocardiographic examination in members of a three-generation Chinese family was followed by exon and boarding intron analysis of 96 genes in the proband using second-generation sequencing. The identified mutations were confirmed by bi-directional Sanger sequencing in all family members and 300 healthy controls. RESULTS: Four missense mutations were detected in the family. These were two novel MYH7-H1717Q and MYLK2-K324E mutations accompanied by the KCNQ1-R190W and TMEM70-I147T mutations. The proband carried all four mutations and showed overlapping HCM and LQT1 phenotypes. Five family members each carried two mutations. Subject II-2 only carried TMEM70-I147T. MYH7-H1717Q and TMEM70-I147T came from the paternal side, whereas KCNQ1-R190W and MYLK2-K324E came from the maternal side. Left ventricle mass indices in MYH7-H1717Q carriers were significantly higher than in non-H1717Q carriers (90.05 ± 7.33 g/m(2), 63.20 ± 4.53 g/m(2), respectively, P < 0.01). Four KCNQ1-R190W carriers showed QTc intervals that were significantly more prolonged than those in non-R190W carriers (472.25 ± 16.18 and 408.50 ± 7.66 ms, respectively, P < 0.05). All MYLK2-K324E carriers showed inverted ECG T waves. The subject with only a TMEM70-I147T mutation showed normal ECG and echocardiographs, suggesting that this had less pathological effects at least in this family. CONCLUSIONS: We demonstrate dual LQT1 and HCM phenotypes in this multiple LQT1- and HCM-related gene mutation carrier family for the first time and suggest that LQT-related gene mutations associate with QT interval prolongation and/or arrhythmia in HCM patients. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Hypertrophic cardiomyopathy (HCM) mainly results from autosomal-dominant inherited single heterozygous mutations in cardiac sarcomere genes. Contributions of multiple gene mutations to disease heterogeneity in a three-generation family were investigated. METHODS: Clinical, electrocardiographic (ECG), and echocardiographic examination in members of a three-generation Chinese family was followed by exon and boarding intron analysis of 96 genes in the proband using second-generation sequencing. The identified mutations were confirmed by bi-directional Sanger sequencing in all family members and 300 healthy controls. RESULTS: Four missense mutations were detected in the family. These were two novel MYH7-H1717Q and MYLK2-K324E mutations accompanied by the KCNQ1-R190W and TMEM70-I147T mutations. The proband carried all four mutations and showed overlapping HCM and LQT1 phenotypes. Five family members each carried two mutations. Subject II-2 only carried TMEM70-I147T. MYH7-H1717Q and TMEM70-I147T came from the paternal side, whereas KCNQ1-R190W and MYLK2-K324E came from the maternal side. Left ventricle mass indices in MYH7-H1717Q carriers were significantly higher than in non-H1717Q carriers (90.05 ± 7.33 g/m(2), 63.20 ± 4.53 g/m(2), respectively, P < 0.01). Four KCNQ1-R190W carriers showed QTc intervals that were significantly more prolonged than those in non-R190W carriers (472.25 ± 16.18 and 408.50 ± 7.66 ms, respectively, P < 0.05). All MYLK2-K324E carriers showed inverted ECG T waves. The subject with only a TMEM70-I147T mutation showed normal ECG and echocardiographs, suggesting that this had less pathological effects at least in this family. CONCLUSIONS: We demonstrate dual LQT1 and HCM phenotypes in this multiple LQT1- and HCM-related gene mutation carrier family for the first time and suggest that LQT-related gene mutations associate with QT interval prolongation and/or arrhythmia in HCM patients. Published on behalf of the European Society of Cardiology. All rights reserved.
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 Journal: Mol Med Rep Date: 2019-10-16 Impact factor: 2.952