PUBLICATION

Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases

Authors
Hayashi, K., Teramoto, R., Nomura, A., Asano, Y., Beerens, M., Kurata, Y., Kobayashi, I., Fujino, N., Furusho, H., Sakata, K., Onoue, K., Chiang, D.Y., Kiviniemi, T.O., Buys, E., Sips, P., Burch, M.L., Zhao, Y., Kelly, A.E., Namura, M., Kita, Y., Tsuchiya, T., Kaku, B., Oe, K., Takeda, Y., Konno, T., Inoue, M., Fujita, T., Kato, T., Funada, A., Tada, H., Hodatsu, A., Nakanishi, C., Sakamoto, Y., Tsuda, T., Nagata, Y., Tanaka, Y., Okada, H., Usuda, K., Cui, S., Saito, Y., MacRae, C.A., Takashima, S., Yamagishi, M., Kawashiri, M.A., Takamura, M.
ID
ZDB-PUB-200125-8
Date
2020
Source
Cardiovascular research   116(13): 2116-2130 (Journal)
Registered Authors
Buys, Eva Plovie, Kobayashi, Isao, MacRae, Calum A.
Keywords
none
MeSH Terms
  • Action Potentials/genetics
  • Adult
  • Age of Onset
  • Aged
  • Animals
  • Cardiac Conduction System Disease/epidemiology
  • Cardiac Conduction System Disease/genetics*
  • Cardiac Conduction System Disease/metabolism
  • Cardiac Conduction System Disease/physiopathology
  • Case-Control Studies
  • Computer Simulation
  • ERG1 Potassium Channel/genetics
  • Exome Sequencing*
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Heart Rate/genetics*
  • Humans
  • Japan/epidemiology
  • Lamin Type A/genetics
  • Male
  • Membrane Proteins/genetics
  • Middle Aged
  • Models, Cardiovascular
  • Myocytes, Cardiac/metabolism
  • NAV1.5 Voltage-Gated Sodium Channel/genetics
  • NAV1.8 Voltage-Gated Sodium Channel/genetics
  • Nuclear Proteins/genetics
  • Phenotype
  • Predictive Value of Tests
  • Risk Assessment
  • Risk Factors
  • Young Adult
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
31977013 Full text @ Cardiovasc. Res.
Citation
Hayashi, K., Teramoto, R., Nomura, A., Asano, Y., Beerens, M., Kurata, Y., Kobayashi, I., Fujino, N., Furusho, H., Sakata, K., Onoue, K., Chiang, D.Y., Kiviniemi, T.O., Buys, E., Sips, P., Burch, M.L., Zhao, Y., Kelly, A.E., Namura, M., Kita, Y., Tsuchiya, T., Kaku, B., Oe, K., Takeda, Y., Konno, T., Inoue, M., Fujita, T., Kato, T., Funada, A., Tada, H., Hodatsu, A., Nakanishi, C., Sakamoto, Y., Tsuda, T., Nagata, Y., Tanaka, Y., Okada, H., Usuda, K., Cui, S., Saito, Y., MacRae, C.A., Takashima, S., Yamagishi, M., Kawashiri, M.A., Takamura, M. (2020) Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases. Cardiovascular research. 116(13):2116-2130.
Abstract
Aims The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them.
Methods and results We performed WES of 23 probands diagnosed with early-onset (<65 years) CCSD and analyzed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency < 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as "pathogenic" by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that 2 variants in KCNH2 and SCN5A, 4 variants in SCN10A, and 1 variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from "Uncertain significance" to "Likely pathogenic" in 6 probands.
Conclusions Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD.
Translational perspective Whole-exome sequencing (WES) may be helpful in determining the causes of cardiac conduction system disease (CCSD), however, the identification of pathogenic variants remains a challenge. We performed WES of 23 probands diagnosed with early-onset CCSD, and identified 12 pathogenic or likely pathogenic variants in 11 of these probands (48%) according to the 2015 ACMG standards and guidelines. In this context, functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants, and SCN10A may be one of the major development factors in CCSD.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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