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

Journal of Human Genetics volume 65, pages 1083–1091 (2020)Cite this article

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Abstract

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.

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Acknowledgements

This study was supported in part by MEXT KAKENHI Grant Number 15H04818 (to MH), 17K15999 (to MF) and 18K07875 (to SO), from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and a grant from the Ministry of Health, Labor and Welfare of Japan for Clinical Research on Intractable Disease (H27-032 and H29-055 to MH and SO). This research was partially supported by AMED under Grant Number JP17ek0109202 (to SO, MH), JP17ek0109219 (to MH, TM).

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Authors and Affiliations

  1. Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Suita, Japan

    Seiko Ohno

  2. Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan

    Seiko Ohno & Minoru Horie

  3. Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan

    Seiko Ohno, Megumi Fukuyama & Minoru Horie

  4. Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Junichi Ozawa

  5. Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Takeru Makiyama

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  1. Seiko Ohno
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Correspondence to Seiko Ohno.

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Ohno, S., Ozawa, J., Fukuyama, M. et al. An NGS-based genotyping in LQTS; minor genes are no longer minor. J Hum Genet 65, 1083–1091 (2020). https://doi.org/10.1038/s10038-020-0805-z

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