Clinical And Genetic Studies In A Family Of Hypertrophic Cardiomyopathy With High-risk Sudden Cardiac Death

Background and purpose:Hypertrophic cardiomyopathy(HCM)is an autosomal dominant inherited disease caused by mutations in the gene encoding sarcomeric proteins,and its clinical features are left ventricular asymmetric hypertrophy and diastolic dysfunction.HCM has a wide range of clinical manifestations,ranging from asymptomatic to mild clinical symptoms,heart failure,and even sudden cardiac death(SCD).Generally speaking,most of HCM patients have a old/late-age onset,a mild clinical course,and a low incidence of SCD(0.5-1% per year).However,we found and reported hereof a HCM family,whose family members had the clinical phenotypes of high penetrance,severe cardiac hypertrophy,and high incidence of SCD.It is of great clinical significance to understand the relationship between the pathogenic mutation and clinical phenotype of this HCM family.Methods:Nine individuals(three people died and six people survived)were enrolled for this study from a HCM family treated at Xinqiao Hospital affiliated to the Army Military Medical University in December 2018.All the participants received and accepted the Informed Consent with fully aware of the purposes and risks of this study.Then,we conducted a clinical survey of members in this HCM family,which included general clinical symptoms and signs,routine electrocardiography(ECG),dynamic ECG,echocardiography and 3.0T cardiac magnetic resonance(CMR),with a regular follow-up of 1 year.Meanwhile,Venous blood was collected from the living members of this HCM family,the proband of this family and her parents,her niece received whole-exome sequencing(WES),and Sanger sequencing was used to verify the pathogenic mutation of the family members.Reverse transcription sequencing was used to detect abnormal mRNA transcripts,and homologous modeling was used to predict the possible structural damage of the mutation.Results:The family survey showed that the proband's elder brother,nephew,and her elder sister died of sudden death respectively at the age of 24(in 1999),18(in 2014),and 40(in 2018)for unknown reasons.Three of the five living pathogenic-gene carriers showed severe myocardial hypertrophy(IVS?23.4mm),and the most severe among them was a 23-year-old woman who had onset at the age of 13 and had a history of recurrent syncope for 10 years.Echocardiography showed that she had ventricular septal hypertrophy with bi-ventricle outflow tracts obstructed.The other two pathogenic-gene carriers were still young(16,4 years old respectively),without special clinical manifestations and abnormalities.Genetic sequencing showed that five of the six living family members carried a heterozygous mutation of the cleavage site in the MYBPC3 gene(c.2737+1(IVS26)G>T),which had not been previously reported.Reverse transcription sequencing of m RNA confirmed that exon 26 was skipped during transcription which caused truncation of cardiac myosin-binding protein C(c MyBP-C).And homologous modeling predicted that the partial ?-barrel structure of the mutant protein would be seriously damaged,which would lead to the collapse of C7 domain in cMy BP-C.Conclusions:1.This study reported a HCM family with high risk sudden death and identified a new mutation c.2737+1(IVS26)G>T in the MYBPC3 gene.2.The c.2737+1(IVS26)G>T mutation caused exon 26's skipping during transcription which resulted in structural collapse and functional disruption of the C7 domain,in turn preventing the cMy BP-C molecule from being correctly inserted and anchored into the sarcomere A-band.3.The usage of exon skipping strategies in MYBPC3-targeting therapy might be limited.