A wide and specific spectrum of genetic variants and genotype-phenotype correlations revealed by next-generation sequencing in patients with left ventricular noncompaction

for LVNC Study Collaborators

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background--Left ventricular noncompaction (LVNC) has since been classified as a primary genetic cardiomyopathy, but the genetic basis is not fully evaluated. The aim of the present study was to identify the genetic spectrum using next-generation sequencing and to evaluate genotype-phenotype correlations in LVNC patients. Methods and Results--Using next-generation sequencing, we targeted and sequenced 73 genes related to cardiomyopathy in 102 unrelated LVNC patients. We identified 43 pathogenic variants in 16 genes in 39 patients (38%); 28 were novel variants. Sarcomere gene variants accounted for 63%, and variants in genes associated with channelopathies accounted for 12%. MYH7 and TAZ pathogenic variants were the most common, and rare variant collapsing analysis showed variants in these genes contributed to the risk of LVNC, although patients carrying MYH7 and TAZ pathogenic variants displayed different phenotypes. Patients with pathogenic variants had early age of onset and more severely decreased left ventricular ejection fractions. Survival analysis showed poorer prognosis in patients with pathogenic variants, especially those with multiple variants: All died before their first birthdays. Adverse events were noted in 17 patients, including 13 deaths, 3 heart transplants, and 1 implantable cardioverter-defibrillator insertion. Congestive heart failure at diagnosis and pathogenic variants were independent risk factors for these adverse events. Conclusions--Next-generation sequencing revealed a wide spectrum of genetic variations and a high incidence of pathogenic variants in LVNC patients. These pathogenic variants were independent risk factors for adverse events. Patients harboring pathogenic variants showed poor prognosis and should be followed closely.

Original languageEnglish
Article numbere006210
JournalJournal of the American Heart Association
Volume6
Issue number9
DOIs
Publication statusPublished - Sep 1 2017

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Genetic Association Studies
Genes
Cardiomyopathies
Channelopathies
Sarcomeres
Implantable Defibrillators
Survival Analysis
Age of Onset
Stroke Volume
Heart Failure
Transplants
Phenotype
Incidence

Keywords

  • Genetics
  • Noncompaction cardiomyopathy
  • Prognosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

@article{c59d59f9b2dc49198231f8c3ec543b6d,
title = "A wide and specific spectrum of genetic variants and genotype-phenotype correlations revealed by next-generation sequencing in patients with left ventricular noncompaction",
abstract = "Background--Left ventricular noncompaction (LVNC) has since been classified as a primary genetic cardiomyopathy, but the genetic basis is not fully evaluated. The aim of the present study was to identify the genetic spectrum using next-generation sequencing and to evaluate genotype-phenotype correlations in LVNC patients. Methods and Results--Using next-generation sequencing, we targeted and sequenced 73 genes related to cardiomyopathy in 102 unrelated LVNC patients. We identified 43 pathogenic variants in 16 genes in 39 patients (38{\%}); 28 were novel variants. Sarcomere gene variants accounted for 63{\%}, and variants in genes associated with channelopathies accounted for 12{\%}. MYH7 and TAZ pathogenic variants were the most common, and rare variant collapsing analysis showed variants in these genes contributed to the risk of LVNC, although patients carrying MYH7 and TAZ pathogenic variants displayed different phenotypes. Patients with pathogenic variants had early age of onset and more severely decreased left ventricular ejection fractions. Survival analysis showed poorer prognosis in patients with pathogenic variants, especially those with multiple variants: All died before their first birthdays. Adverse events were noted in 17 patients, including 13 deaths, 3 heart transplants, and 1 implantable cardioverter-defibrillator insertion. Congestive heart failure at diagnosis and pathogenic variants were independent risk factors for these adverse events. Conclusions--Next-generation sequencing revealed a wide spectrum of genetic variations and a high incidence of pathogenic variants in LVNC patients. These pathogenic variants were independent risk factors for adverse events. Patients harboring pathogenic variants showed poor prognosis and should be followed closely.",
keywords = "Genetics, Noncompaction cardiomyopathy, Prognosis",
author = "{for LVNC Study Collaborators} and Ce Wang and Yukiko Hata and Keiichi Hirono and Asami Takasaki and Ozawa, {Sayaka Watanabe} and Hideyuki Nakaoka and Kazuyoshi Saito and Nariaki Miyao and Mako Okabe and Keijiro Ibuki and Naoki Nishida and Hideki Origasa and Xianyi Yu and Bowles, {Neil E.} and Fukiko Ichida and Akiko Komori and Arata Sashinami and Atsuko Ishihara and Atsushi Kuwahara and Chisato Akita and Dai Miura and Daichi Fukumi and Etsuko Tsuda and Eizo Akagawa and Heima Sakaguchi and Hideaki Ueda and Hidenori Iwasaki and Hideshi Tomita and Hiroaki Kise and Hirohiko Shiraishi and Hirohumi Tomimatsu and Hirokazu Taniguchi and Hiroki Kajino and Hiroki Nagamine and Hiromi Katayama and Hiromichi Hamada and Hiroo Ooki and Hiroshi Mito and Hiroshi Miura and Hiroshi Ono and Hirotaka Ooki and Hiroyuki Yoshizawa and Hitoshi Horigome and Hitoshi Tonegawa and Joji Hayashi and Jun Matsushita and Jun Yanai and Jun Yoshimoto and Junichi Ohata and Teiji Akagi",
year = "2017",
month = "9",
day = "1",
doi = "10.1161/JAHA.117.006210",
language = "English",
volume = "6",
journal = "Journal of the American Heart Association",
issn = "2047-9980",
publisher = "Wiley-Blackwell",
number = "9",

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TY - JOUR

T1 - A wide and specific spectrum of genetic variants and genotype-phenotype correlations revealed by next-generation sequencing in patients with left ventricular noncompaction

AU - for LVNC Study Collaborators

AU - Wang, Ce

AU - Hata, Yukiko

AU - Hirono, Keiichi

AU - Takasaki, Asami

AU - Ozawa, Sayaka Watanabe

AU - Nakaoka, Hideyuki

AU - Saito, Kazuyoshi

AU - Miyao, Nariaki

AU - Okabe, Mako

AU - Ibuki, Keijiro

AU - Nishida, Naoki

AU - Origasa, Hideki

AU - Yu, Xianyi

AU - Bowles, Neil E.

AU - Ichida, Fukiko

AU - Komori, Akiko

AU - Sashinami, Arata

AU - Ishihara, Atsuko

AU - Kuwahara, Atsushi

AU - Akita, Chisato

AU - Miura, Dai

AU - Fukumi, Daichi

AU - Tsuda, Etsuko

AU - Akagawa, Eizo

AU - Sakaguchi, Heima

AU - Ueda, Hideaki

AU - Iwasaki, Hidenori

AU - Tomita, Hideshi

AU - Kise, Hiroaki

AU - Shiraishi, Hirohiko

AU - Tomimatsu, Hirohumi

AU - Taniguchi, Hirokazu

AU - Kajino, Hiroki

AU - Nagamine, Hiroki

AU - Katayama, Hiromi

AU - Hamada, Hiromichi

AU - Ooki, Hiroo

AU - Mito, Hiroshi

AU - Miura, Hiroshi

AU - Ono, Hiroshi

AU - Ooki, Hirotaka

AU - Yoshizawa, Hiroyuki

AU - Horigome, Hitoshi

AU - Tonegawa, Hitoshi

AU - Hayashi, Joji

AU - Matsushita, Jun

AU - Yanai, Jun

AU - Yoshimoto, Jun

AU - Ohata, Junichi

AU - Akagi, Teiji

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Background--Left ventricular noncompaction (LVNC) has since been classified as a primary genetic cardiomyopathy, but the genetic basis is not fully evaluated. The aim of the present study was to identify the genetic spectrum using next-generation sequencing and to evaluate genotype-phenotype correlations in LVNC patients. Methods and Results--Using next-generation sequencing, we targeted and sequenced 73 genes related to cardiomyopathy in 102 unrelated LVNC patients. We identified 43 pathogenic variants in 16 genes in 39 patients (38%); 28 were novel variants. Sarcomere gene variants accounted for 63%, and variants in genes associated with channelopathies accounted for 12%. MYH7 and TAZ pathogenic variants were the most common, and rare variant collapsing analysis showed variants in these genes contributed to the risk of LVNC, although patients carrying MYH7 and TAZ pathogenic variants displayed different phenotypes. Patients with pathogenic variants had early age of onset and more severely decreased left ventricular ejection fractions. Survival analysis showed poorer prognosis in patients with pathogenic variants, especially those with multiple variants: All died before their first birthdays. Adverse events were noted in 17 patients, including 13 deaths, 3 heart transplants, and 1 implantable cardioverter-defibrillator insertion. Congestive heart failure at diagnosis and pathogenic variants were independent risk factors for these adverse events. Conclusions--Next-generation sequencing revealed a wide spectrum of genetic variations and a high incidence of pathogenic variants in LVNC patients. These pathogenic variants were independent risk factors for adverse events. Patients harboring pathogenic variants showed poor prognosis and should be followed closely.

AB - Background--Left ventricular noncompaction (LVNC) has since been classified as a primary genetic cardiomyopathy, but the genetic basis is not fully evaluated. The aim of the present study was to identify the genetic spectrum using next-generation sequencing and to evaluate genotype-phenotype correlations in LVNC patients. Methods and Results--Using next-generation sequencing, we targeted and sequenced 73 genes related to cardiomyopathy in 102 unrelated LVNC patients. We identified 43 pathogenic variants in 16 genes in 39 patients (38%); 28 were novel variants. Sarcomere gene variants accounted for 63%, and variants in genes associated with channelopathies accounted for 12%. MYH7 and TAZ pathogenic variants were the most common, and rare variant collapsing analysis showed variants in these genes contributed to the risk of LVNC, although patients carrying MYH7 and TAZ pathogenic variants displayed different phenotypes. Patients with pathogenic variants had early age of onset and more severely decreased left ventricular ejection fractions. Survival analysis showed poorer prognosis in patients with pathogenic variants, especially those with multiple variants: All died before their first birthdays. Adverse events were noted in 17 patients, including 13 deaths, 3 heart transplants, and 1 implantable cardioverter-defibrillator insertion. Congestive heart failure at diagnosis and pathogenic variants were independent risk factors for these adverse events. Conclusions--Next-generation sequencing revealed a wide spectrum of genetic variations and a high incidence of pathogenic variants in LVNC patients. These pathogenic variants were independent risk factors for adverse events. Patients harboring pathogenic variants showed poor prognosis and should be followed closely.

KW - Genetics

KW - Noncompaction cardiomyopathy

KW - Prognosis

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U2 - 10.1161/JAHA.117.006210

DO - 10.1161/JAHA.117.006210

M3 - Article

VL - 6

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 9

M1 - e006210

ER -