Genetic basis of cardiomyopathy and the genotypes involved in prognosis and left ventricular reverse remodeling

Takashige Tobita,Eiki Takimoto,Seiji Takashima,Yasushi Sakata,Haruhiro Toko,Masaru Hatano,Nobuhisa Hagiwara,Minoru Ôno ,Yoshihiro Asano,Atsuhiko T Naito ,Atsushi Suzuki,Kenji Onoue,Hiroyuki Morita,Eisuke Amiya,Takanori Fujita,Yoshihiko Saito,Masamichi Ito,Kanna Fujita,Tsuyoshi Shiga,Mutsuo Harada,Yasushi Imai,Hiroyuki Aburatani,Masahiro Satoh,Yoshiyuki Furutani,Toshio Nakanishi,Toshiyuki Ko,Seitaro Nomura,Issei Komuro

doi:10.1038/s41598-018-20114-9

Abstract

Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically heterogeneous. Cardiac function is improved after treatment in some cardiomyopathy patients, but little is known about genetic predictors of long-term outcomes and myocardial recovery following medical treatment. To elucidate the genetic basis of cardiomyopathy in Japan and the genotypes involved in prognosis and left ventricular reverse remodeling (LVRR), we performed targeted sequencing on 120 DCM (70 sporadic and 50 familial) and 52 HCM (15 sporadic and 37 familial) patients and integrated their genotypes with clinical phenotypes. Among the 120 DCM patients, 20 (16.7%) had TTN truncating variants and 13 (10.8%) had LMNA variants. TTN truncating variants were the major cause of sporadic DCM (21.4% of sporadic cases) as with Caucasians, whereas LMNA variants, which include a novel recurrent LMNA E115M variant, were the most frequent in familial DCM (24.0% of familial cases) unlike Caucasians. Of the 52 HCM patients, MYH7 and MYBPC3 variants were the most common (12 (23.1%) had MYH7 variants and 11 (21.2%) had MYBPC3 variants) as with Caucasians. DCM patients harboring TTN truncating variants had better prognosis than those with LMNA variants. Most patients with TTN truncating variants achieved LVRR, unlike most patients with LMNA variants.

Highlights

Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically heterogeneous
We explore the genetic basis and novel genotype–phenotype associations in Japanese patients with cardiomyopathies and elucidate the genotypes involved in clinical prognosis and left ventricular reverse remodeling (LVRR)
Through integration of targeted sequencing and genotype-phenotype correlation analysis, we unveiled the genetic basis of cardiomyopathy and the genotypes involved in LVRR

Summary

Introduction

Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically heterogeneous. To elucidate the genetic basis of cardiomyopathy in Japan and the genotypes involved in prognosis and left ventricular reverse remodeling (LVRR), we performed targeted sequencing on 120 DCM (70 sporadic and 50 familial) and 52 HCM (15 sporadic and 37 familial) patients and integrated their genotypes with clinical phenotypes. Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are genetic disorders that cause heart failure and life-threatening arrhythmia, eventually requiring heart transplantation or cardiac device implantation[1]. These cardiomyopathies have prevalence rates of approximately 0.004% and 0.2%, respectively, with familial cases accounting for 20–50% of all cases[2,3,4].

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Conclusion