A Comprehensive Genotype-phenotype Correlation Demonstrated By Sarcomere Gene Testing In Patients With Hypertrophic Cardiomyopathy

BACKGROUND: Hypertrophic cardiomyopathy(HCM)is the leading cause of sudden death in young adults and has been a major concern of forensic staff.The explicit identification of HCM risk factors is helpful to provide new ideas and methods for the identification and analysis of death causes.With the emergence of gene testing,the genetic causes of hypertrophic cardiomyopathy HCM have been identified more and more.However,owing to the lack of univocal genotype-phenotype correlations,the use of gene testing results in guiding clinical management of patients with HCM is limited.OBJECTIVES: The aim of this study was to investigate genotype and phenotype correlations and to identify HCM risk factors for death in a comprehensive and systematic large HCM cohortMETHODS:A total of 1529 unrelated patients with HCM were enrolled.Diagnostic criteria for HCM: two-dimensional echocardiography and cardiac magnetic resonance imaging showed that the maximum left ventricular thickness was ?15mm,and if there was a family history of HCM,the maximum left ventricular thickness was ?13mm,without causing severe ventricular hypertrophy of other heart or systemic diseases.All patients were genotyped by whole exome or panel sequencing,and 8 genes encoding sarcomere proteins were analyzed.After a follow-up of 3.28±2.43 years,adverse prognostic events such as cardiovascular death were obtained,and the correlation between each group of patients and various events was evaluated.A database of clinical data was established,mainly including the history,physical signs and imaging examination of HCM patients,and correlation analysis between genotype and phenotype was conducted.RESULTS: We identified 419 pathogenic/likely pathogenic variants in 720(47.1%)patients,including 84(5.5%)carriers of multiple mutations.Patients with multiple variants presented worse clinical manifestation at baseline,and were associated with an increased risk of cardiovascular death both in lifetime(adjusted HR 3.291,95% CI 1.914-8.035,P<0.001,vs.none-mutation carriers;adjusted HR 3.254,95% CI 1.611-6.574,P=0.001,vs.single mutation carriers)and during the follow-up(adjusted HR 2.908,95% CI 1.533-5.517,P=0.001,vs.none-mutation carriers;adjusted HR 3.445,95% CI 1.838-6.496,P<0.001,vs.single mutation carriers).However,MYH7,thick-filament or truncating mutations were not associated with increased risk of malignant prognosis,compared with MYBPC3,thinfilament or non-truncating mutations,respectively.CONCLUSIONS: Through the comprehensive analysis in one of the largest genotyped HCM cohort,our study demonstrated that the presence of multiple sarcomere mutations,but not others,is a risk factor of malignant outcomes.This can not only assist clinicians to achieve accurate diagnosis of HCM,but also provide certain identification value for the clear cause of death of HCM patients.