PortalPublikationenImpact of functional studies on exome sequence variant inter...

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

Standard

Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases. / Hayashi, Kenshi; Teramoto, Ryota; Nomura, Akihiro; Asano, Yoshihiro; Beerens, Manu; Kurata, Yasutaka; Kobayashi, Isao; Fujino, Noboru; Furusho, Hiroshi; Sakata, Kenji; Onoue, Kenji; Chiang, David Y; Kiviniemi, Tuomas O; Buys, Eva; Sips, Patrick; Burch, Micah L; Zhao, Yanbin; Kelly, Amy E; Namura, Masanobu; Kita, Yoshihito; Tsuchiya, Taketsugu; Kaku, Bunji; Oe, Kotaro; Takeda, Yuko; Konno, Tetsuo; Inoue, Masaru; Fujita, Takashi; Kato, Takeshi; Funada, Akira; Tada, Hayato; Hodatsu, Akihiko; Nakanishi, Chiaki; Sakamoto, Yuichiro; Tsuda, Toyonobu; Nagata, Yoji; Tanaka, Yoshihiro; Okada, Hirofumi; Usuda, Keisuke; Cui, Shihe; Saito, Yoshihiko; MacRae, Calum A; Takashima, Seiji; Yamagishi, Masakazu; Kawashiri, Masa-Aki; Takamura, Masayuki.

in: CARDIOVASC RES, Jahrgang 116, Nr. 13, 01.11.2020, S. 2116-2130.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Hayashi, K, Teramoto, R, Nomura, A, Asano, Y, Beerens, M, Kurata, Y, Kobayashi, I, Fujino, N, Furusho, H, Sakata, K, Onoue, K, Chiang, DY, Kiviniemi, TO, Buys, E, Sips, P, Burch, ML, Zhao, Y, Kelly, AE, 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, CA, 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', CARDIOVASC RES, Jg. 116, Nr. 13, S. 2116-2130. https://doi.org/10.1093/cvr/cvaa010

APA

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., ... Takamura, M. (2020). Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases. CARDIOVASC RES, 116(13), 2116-2130. https://doi.org/10.1093/cvr/cvaa010

Vancouver

Hayashi K, Teramoto R, Nomura A, Asano Y, Beerens M, Kurata Y et al. Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases. CARDIOVASC RES. 2020 Nov 1;116(13):2116-2130. https://doi.org/10.1093/cvr/cvaa010

Bibtex

@article{ea62763dd7534aee8ef76756736e05f1,
title = "Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases",
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 analysed 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 two variants in KCNH2 and SCN5A, four variants in SCN10A, and one variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from 'Uncertain significance' to 'Likely pathogenic' in six probands.CONCLUSION: 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.",
keywords = "Action Potentials/genetics, Adult, Age of Onset, Aged, Animals, Cardiac Conduction System Disease/epidemiology, Case-Control Studies, Computer Simulation, ERG1 Potassium Channel/genetics, 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, Whole Exome Sequencing, Young Adult, Zebrafish/genetics, Zebrafish Proteins/genetics",
author = "Kenshi Hayashi and Ryota Teramoto and Akihiro Nomura and Yoshihiro Asano and Manu Beerens and Yasutaka Kurata and Isao Kobayashi and Noboru Fujino and Hiroshi Furusho and Kenji Sakata and Kenji Onoue and Chiang, {David Y} and Kiviniemi, {Tuomas O} and Eva Buys and Patrick Sips and Burch, {Micah L} and Yanbin Zhao and Kelly, {Amy E} and Masanobu Namura and Yoshihito Kita and Taketsugu Tsuchiya and Bunji Kaku and Kotaro Oe and Yuko Takeda and Tetsuo Konno and Masaru Inoue and Takashi Fujita and Takeshi Kato and Akira Funada and Hayato Tada and Akihiko Hodatsu and Chiaki Nakanishi and Yuichiro Sakamoto and Toyonobu Tsuda and Yoji Nagata and Yoshihiro Tanaka and Hirofumi Okada and Keisuke Usuda and Shihe Cui and Yoshihiko Saito and MacRae, {Calum A} and Seiji Takashima and Masakazu Yamagishi and Masa-Aki Kawashiri and Masayuki Takamura",
note = "Published on behalf of the European Society of Cardiology. All rights reserved. {\textcopyright} The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.",
year = "2020",
month = nov,
day = "1",
doi = "10.1093/cvr/cvaa010",
language = "English",
volume = "116",
pages = "2116--2130",
journal = "CARDIOVASC RES",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "13",

}

RIS

TY - JOUR

T1 - Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases

AU - Hayashi, Kenshi

AU - Teramoto, Ryota

AU - Nomura, Akihiro

AU - Asano, Yoshihiro

AU - Beerens, Manu

AU - Kurata, Yasutaka

AU - Kobayashi, Isao

AU - Fujino, Noboru

AU - Furusho, Hiroshi

AU - Sakata, Kenji

AU - Onoue, Kenji

AU - Chiang, David Y

AU - Kiviniemi, Tuomas O

AU - Buys, Eva

AU - Sips, Patrick

AU - Burch, Micah L

AU - Zhao, Yanbin

AU - Kelly, Amy E

AU - Namura, Masanobu

AU - Kita, Yoshihito

AU - Tsuchiya, Taketsugu

AU - Kaku, Bunji

AU - Oe, Kotaro

AU - Takeda, Yuko

AU - Konno, Tetsuo

AU - Inoue, Masaru

AU - Fujita, Takashi

AU - Kato, Takeshi

AU - Funada, Akira

AU - Tada, Hayato

AU - Hodatsu, Akihiko

AU - Nakanishi, Chiaki

AU - Sakamoto, Yuichiro

AU - Tsuda, Toyonobu

AU - Nagata, Yoji

AU - Tanaka, Yoshihiro

AU - Okada, Hirofumi

AU - Usuda, Keisuke

AU - Cui, Shihe

AU - Saito, Yoshihiko

AU - MacRae, Calum A

AU - Takashima, Seiji

AU - Yamagishi, Masakazu

AU - Kawashiri, Masa-Aki

AU - Takamura, Masayuki

N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.

PY - 2020/11/1

Y1 - 2020/11/1

N2 - 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 analysed 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 two variants in KCNH2 and SCN5A, four variants in SCN10A, and one variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from 'Uncertain significance' to 'Likely pathogenic' in six probands.CONCLUSION: 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.

AB - 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 analysed 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 two variants in KCNH2 and SCN5A, four variants in SCN10A, and one variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from 'Uncertain significance' to 'Likely pathogenic' in six probands.CONCLUSION: 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.

KW - Action Potentials/genetics

KW - Adult

KW - Age of Onset

KW - Aged

KW - Animals

KW - Cardiac Conduction System Disease/epidemiology

KW - Case-Control Studies

KW - Computer Simulation

KW - ERG1 Potassium Channel/genetics

KW - Female

KW - Gene Frequency

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Heart Rate/genetics

KW - Humans

KW - Japan/epidemiology

KW - Lamin Type A/genetics

KW - Male

KW - Membrane Proteins/genetics

KW - Middle Aged

KW - Models, Cardiovascular

KW - Myocytes, Cardiac/metabolism

KW - NAV1.5 Voltage-Gated Sodium Channel/genetics

KW - NAV1.8 Voltage-Gated Sodium Channel/genetics

KW - Nuclear Proteins/genetics

KW - Phenotype

KW - Predictive Value of Tests

KW - Risk Assessment

KW - Risk Factors

KW - Whole Exome Sequencing

KW - Young Adult

KW - Zebrafish/genetics

KW - Zebrafish Proteins/genetics

U2 - 10.1093/cvr/cvaa010

DO - 10.1093/cvr/cvaa010

M3 - SCORING: Journal article

C2 - 31977013

VL - 116

SP - 2116

EP - 2130

JO - CARDIOVASC RES

JF - CARDIOVASC RES

SN - 0008-6363

IS - 13

ER -