Autosomal Recessive Transmission of MYBPC3 Mutation Results in Malignant Phenotype of Hypertrophic Cardiomyopathy

Yilu Wang,Zhimin Wang,Ferhaan Ahmad,Chaowu Yan,Jizheng Wang,Yin Zhang,Hongju Zhang,Rutai Hui,Yubao Zou,Lei Song,Yi Chen,Xinxing Feng,Qi Yang,Xianliang Zhou,Andreas R Janecke

doi:10.1371/journal.pone.0067087

Abstract

BackgroundHypertrophic cardiomyopathy (HCM) due to mutations in genes encoding sarcomere proteins is most commonly inherited as an autosomal dominant trait. Since nearly 50% of HCM cases occur in the absence of a family history, a recessive inheritance pattern may be involved.MethodsA pedigree was identified with suspected autosomal recessive transmission of HCM. Twenty-six HCM-related genes were comprehensively screened for mutations in the proband with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and 376 healthy controls.ResultsA novel missense mutation (c.1469G>T, p.Gly490Val) in exon 17 of MYBPC3 was identified. Two siblings with HCM were homozygous for this mutation, whereas other family members were either heterozygous or wild type. Clinical evaluation showed that both homozygotes manifested a typical HCM presentation, but none of others, including 5 adult heterozygous mutation carriers up to 71 years of age, had any clinical evidence of HCM.ConclusionsOur data identified a MYBPC3 mutation in HCM, which appeared autosomal recessively inherited in this family. The absence of a family history of clinical HCM may be due to not only a de novo mutation, but also recessive mutations that failed to produce a clinical phenotype in heterozygous family members. Therefore, consideration of recessive mutations leading to HCM is essential for risk stratification and genetic counseling.

Highlights

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and one of the common cause of sudden cardiac death (SCD) [1]
Most cases of HCM are caused by mutations in the genes encoding sarcomere proteins in a Mendelian autosomal dominant pattern [1,2,3]
Genetic testing of these genes in HCM patients has been recommended in the latest guidelines, because of its significant value in diagnosis and early identification of individuals who are at risk, especially among family members [4,5]

Summary

Methods

Subjects and Clinical Evaluation The proband and his family were recruited at Beijing Fuwai. Three hundred and seventy six individuals with normal ECGs and echocardiograms were included as healthy controls. Written informed consents were provided by this family and the healthy controls. The variant was considered as disease-causing mutation if it was absent in the genetic database of 307 Chinese healthy controls, in which the 26 HCM-related genes were completely screened in the same manner as did in the proband. The identified mutation in the proband was assessed in all family members and the other 376 healthy controls with bi-directional Sanger sequencing after PCR amplification of corresponding exon. Previous reports of the mutations in public polymorphism databases were determined by searching dbSNP and 1000 Genomes at http://www.ncbi.nlm. Protein sequence homology of mutation-affected regions among species was determined with Clustal W2 [17]

Results

Conclusions

Introduction

Discussion