title: Dual LQT1 and HCM phenotypes associated with tetrad heterozygous mutations in KCNQ1, MYH7, MYLK2, and TMEM70 genes in a three-generation Chinese family.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zuo
authors.affiliation: Department of Stomatology, the Military General Hospital of Beijing PLA, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an, China Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Shao
authors.affiliation: Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an, China Department of Ultrasound, Ningxia Medical University, Yinchuan, China.
authors.forename: Changhui
authors.initials: C
authors.lastname: Lei
authors.affiliation: Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qi
authors.affiliation: Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Yunbo
authors.initials: Y
authors.lastname: Miao
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Ma
authors.affiliation: Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Christopher L-H
authors.initials: CL
authors.lastname: Huang
authors.affiliation: Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an, China zhouxd@fmmu.edu.cn zhangym@mail.xjtu.edu.cn.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Heart Center, Northwest Women's and Children's Hospital, Xi'an, China zhouxd@fmmu.edu.cn zhangym@mail.xjtu.edu.cn.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi'an, China zhouxd@fmmu.edu.cn zhangym@mail.xjtu.edu.cn.
authors.forename: Liwen
authors.initials: L
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D024722:Cardiac Myosins / Q000235:genetics*; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D016022:Case-Control Studies; D002648:Child; D002681:China; D004252:DNA Mutational Analysis; D004452:Echocardiography; D004562:Electrocardiography; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006579:Heterozygote; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000235:genetics*; D009219:Myosin-Light-Chain Kinase / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D029597:Romano-Ward Syndrome / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult
chemical_list: D005819:Genetic Markers; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C501641:MYH7 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C533106:TMEM70 protein, human; D009219:Myosin-Light-Chain Kinase; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains
keywords: Hypertrophic cardiomyopathy; Multiple mutations; Overlap phenotypes; Second-generation sequencing