Screening Of Pathogenic Mutations In Familial Hypertrophic Cardiomyopathy By Whole-exome Sequencing

Objective:Whole-exome sequencing was used to screen for mutations in progenitors and family members of familial hypertrophic cardiomyopathy,to explore and analyze the correlation between mutations and clinical phenotypes,in order to establish an accurate medical model of HCM.Method:Four unrelated FHCM progenitors were enrolled in this study.Their medical history and imaging data(electrocardiogram and echocardiography)were collected and peripheral venous blood was collected for whole-exome sequencing.The probands with positive mutations were further followed up in their family,the traceability of the related family members would be verified by Sanger sequencing.Based on the latest research progress and clinical reports,the pathogenicity analysis was carried out and the correlation between mutation and clinical phenotype was analyzed individually.Result:① One proband carries double heterozygous mutations,which were MYL2-p.R58Q and MYH6-p.G257E.The mutation in MYL2 have been reported,which was defined as pathogenic mutation.The mutation in MYH6 were newly discovered with unknown significance.②TWO probands carry single heterozygous mutations.One of them carries TNN13-p.A157V,which was defined as pathogenic mutation.The other one carries MYH7-c.1502A>G(p.Y501C),a newly discovered pathogenic mutation.③One probands carries three kinds of heterozygous mutations involving two genes,all of them were newly discovered with unknown significance.Conclusion:HCM-related mutations were identified in all families.The mutations involved four sarcomere protein-related genes(MYL2、MYH6、MYH7、TNNI3)and two cellular structural protein-related genes(TTN、OBSCN).The MYH7-c.1502A>G(p.y501c)was firstly reported in FHCM.Although mutations in MYL2 and TNNI3 are infrequent in HCM,some mutations of them were usually reported to be associated with malignant phenotypes.TNNI3-p.A 157V is associated with high mutation penetrance、typical cardiac hypertrophy and fortuitous sudden death.In addition,we have comfirmed the strong co-segregation of MYL2-p.R58Q through a large three-generation FHCM family.The p.R58Q mutation carriers were characterized by rapid progression of early onset,significant cardiac hypertrophy,and especially high rate of sudden death.We found that mutation analysis under the background of big data is helpful for early diagnosis and prognosis assessment of HCM,and also provides a theoretical basis for clinical decision-making and individualized treatment.