Key result
MYH7-H1717Q and KCNQ1-R190W mutations were associated with significantly higher left ventricle mass indices (P<0.01) and prolonged QTc intervals (P<0.05) compared to non-carriers in a Chinese family.
Why the study?
Do multiple gene mutations contribute to the overlapping phenotypes of HCM and LQT1 in a single family?
Observational
Do multiple gene mutations contribute to the overlapping phenotypes of HCM and LQT1 in a single family?
p-value: p=<0.01
The study identifies a complex genetic basis for overlapping HCM and LQT1 phenotypes in a single family, highlighting the role of multiple mutations in disease heterogeneity.
Multiple mutations may explain mixed HCM-LQT phenotypes in families; leaves open oligogenic contributions to heterogeneity.
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.
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Wang et al. (2015) conducted an observational in Hypertrophic cardiomyopathy and LQT1. Heterozygous mutations in KCNQ1, MYH7, MYLK2, and TMEM70 genes vs. Non-carriers was evaluated on Left ventricle mass index and QTc interval (p=<0.01). MYH7-H1717Q and KCNQ1-R190W mutations were associated with significantly higher left ventricle mass indices (P<0.01) and prolonged QTc intervals (P<0.05) compared to non-carriers in a Chinese family.
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