Clinical Atlas Of Known Causal Genes And Identification Of Genetic Risks For Dilated Cardiomyopathy

Background: Dilated cardiomyopathy is the main cause of heart failure and heart transplantation,and has a significant genetic predisposition.However,the clinical significance of genetic factors in sporadic dilated cardiomyopathy in Chinese Han population remains unclear.Methods: From July 2007 to December 2018,we enrolled a total of 1041 patients with sporadic dilated cardiomyopathy.In this study,deep phenotyping and whole exome sequencing were performed on all subjects,and long-term clinical follow-up was carried out.Results: We conducted a prospective study on 1041 patients with sporadic dilated cardiomyopathy(DCM).Through whole exome sequencing,we described the genetic spectrum of DCM in Chinese Han population and further analyzed the variants carriers’ Clinical features.According to the standards and guidelines of the American Academy of Medical Genetics and Genomics(ACMG),the carrying rate of pathogenic/likely pathogenic variants of 37 known DCM-related genes in DCM population is 18.3%(191/1041).We found that TTN is the most common pathogenic gene for DCM in Chinese Han population,with a truncated variant(t TTN)carrying rate of 11.5% and a deleterious missense variant(m TTN)carrying rate of 27.6%.Compared with the East Asian population in the gnom AD database,both t TTN and m TTN were significantly enriched in the DCM population.We further focused on the clinical characteristics of t TTN,left ventricular ejection fraction of DCM with t TTN(28.89 ± 8.79 vs.31.81 ± 9.97,P = 0.002)and the incidence of left bundle branch block(3.3% vs.11.3%,P = 0.011)were lower than those without t TTN.During the long-term follow-up(median follow-up time: 44 months),t TTN was not associated with the composite primary endpoint of cardiac death and heart transplantation(adjusted HR: 0.912;95% CI: 0.464-1.793;P = 0.790).At the same time,the effect of t TTN on the long-term clinical prognosis of DCM patients is independent of gender factors.Concomitant t TTN and pathogenic variants in other known causal genes(OCG)were present in only 8 DCM patients and did not affect the outcome.Conclusions: These results shed insight into the genetic spectrum and clinical manifestations of sporadic DCM in Chinese Han population and expand the existing repertoire of pathogenic or likely pathogenic variants involved in known DCM-associated genes.And,the phenotype of DCM caused by t TTN,the major cause of sporadic DCM,are not distinctly different from those caused by OCG for DCM.And,there was no sex-dependent effect.Background: Although more than 60 genes have been identified as related to dilated cardiomyopathy,its genetic risk is still not fully understood,especially sporadic dilated cardiomyopathy(nearly 80% of sporadic patients have no clear genetic factors).Methods: We included 363 patients with DCM and 414 ethnically matched healthy controls.Whole exome sequencing was performed on 777 subjects,and 183cardiomyopathy-related genes were selected for further analysis.Results: Out of 363 patients with DCM,91 patients(25.07% of all patients)were found to carry deleterious variants.These deleterious variants included 26loss-of-function variants and 66 pathogenic variants,and most of them are previously unreported.Furthermore,rare missense variants in 21 genes were identified to be statistically significant relevant with DCM in burden tests.Other than rare variants,12 common SNPs reached a statistically significant association with increased risk of DCM in allele-based genetic model association analysis.Of note,in the cumulative risk model,high-risk subjects had a 3.113-folds risk of developing DCM compared to low-risk subjects in a dominant model of inheritance(Recessive inheritance model,OR: 1.801),and then,we found the age at onset of high-risk subjects are younger than those in low-risk group(36.57 ± 9.39 vs.39.24 ± 8.06,P = 0.006).In the phenotype-genotype association analyses,the mean left ventricular ejection fraction of patients with the deleterious variants is lower than those without(27.73 ± 10.02%vs.30.61 ± 10.85%,P = 0.026)and the patients with more than one deleterious variant had a younger age at onset than those with single deleterious variant(30.67±11.97 vs.40.71±6.51,P<0.001).Conclusions: This study revealed the genetic risks of sporadic dilated cardiomyopathy in the Chinese Han population through common and rare variants,identified a number of unreported candidate genes and loci,and constructed a risk stratification model.These results may lead to new insights to the mechanisms and risk stratification for DCM.