Dual LQT1 and HCM phenotypes associated with tetrad heterozygous mutations in KCNQ1, MYH7, MYLK2, and TMEM70 genes in a three-generation Chinese family

Europace. 2016 Apr;18(4):602-9. doi: 10.1093/europace/euv043. Epub 2015 Mar 29.

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.

Keywords: Hypertrophic cardiomyopathy; Multiple mutations; Overlap phenotypes; Second-generation sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Asian People / genetics
  • Cardiac Myosins / genetics*
  • Cardiomyopathy, Hypertrophic, Familial / diagnosis
  • Cardiomyopathy, Hypertrophic, Familial / ethnology
  • Cardiomyopathy, Hypertrophic, Familial / genetics*
  • Cardiomyopathy, Hypertrophic, Familial / physiopathology
  • Case-Control Studies
  • Child
  • China
  • DNA Mutational Analysis
  • Echocardiography
  • Electrocardiography
  • Female
  • Genetic Association Studies
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Heredity
  • Heterozygote*
  • Humans
  • KCNQ1 Potassium Channel / genetics*
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Mitochondrial Proteins / genetics*
  • Mutation, Missense*
  • Myosin Heavy Chains / genetics*
  • Myosin-Light-Chain Kinase / genetics*
  • Pedigree
  • Phenotype
  • Romano-Ward Syndrome / diagnosis
  • Romano-Ward Syndrome / ethnology
  • Romano-Ward Syndrome / genetics*
  • Romano-Ward Syndrome / physiopathology
  • Young Adult

Substances

  • Genetic Markers
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • MYH7 protein, human
  • Membrane Proteins
  • Mitochondrial Proteins
  • TMEM70 protein, human
  • Myosin-Light-Chain Kinase
  • Cardiac Myosins
  • Myosin Heavy Chains