An NGS-based genotyping in LQTS; minor genes are no longer minor

Mutations in KCNQ1, KCNH2, and SCN5A are the major cause of long QT syndrome (LQTS). More than 90% of the genotyped patients have been reported to carry mutations in any of these three genes. Thanks to increasing popularity of next generation sequencer (NGS), novel CACNA1C mutations have been identi...

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Bibliographic Details
Published in:Journal of human genetics 2020-12, Vol.65 (12), p.1083-1091
Main Authors: Ohno, Seiko, Ozawa, Junichi, Fukuyama, Megumi, Makiyama, Takeru, Horie, Minoru
Format: Article
Language:English
Subjects:
Asymptomatic
Genetic analysis
Genetic screening
Genotypes
Genotyping
Heart
KCNQ1 protein
Kinases
Long QT syndrome
Mutation
Phenotypes
Potassium channels (voltage-gated)
Ryanodine receptors
Syncope
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Summary:Mutations in KCNQ1, KCNH2, and SCN5A are the major cause of long QT syndrome (LQTS). More than 90% of the genotyped patients have been reported to carry mutations in any of these three genes. Thanks to increasing popularity of next generation sequencer (NGS), novel CACNA1C mutations have been identified among LQTS patients without extra-cardiac phenotypes. We aimed to clarify the frequency of genotypes in LQTS patients in the era of NGS. The study comprised 160 congenital LQTS patients (71 males) registered from November 2015 to September 2018. Inclusion criteria was QTc > 460 ms and Schwartz score ≥ 3. We performed genetic analysis using target gene method by NGS and confirmed the mutations by Sanger method. The median age for genetic screening was 13 (0–68) years. Sixteen patients suffered cardiac arrest, 47 syncope, and 97 were asymptomatic. We identified genetic mutations in 111 (69.4%) patients including 6 CACNA1C (5.4% of the genotyped patients) with 4 asymptomatic patients. Five (3.1%) patients carried double mutations; three out of them with RYR2 and KCNQ1 or KCNH2. In conclusion, CACNA1C screening would be recommended even if the patient is asymptomatic to elucidate the genetic background of the LQTS patients.
ISSN:1434-5161
1435-232X
DOI:10.1038/s10038-020-0805-z