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Keywords: Asians; cardiomyopathy, hypertrophic; genetic testing; hypertrophy EN Asians cardiomyopathy, hypertrophic genetic testing hypertrophy 2086 2089 4 11/25/20 20201124 NES 201124 Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder characterized by unexplained left ventricular hypertrophy.[1] Although considered as a dominant Mendelian disease mainly caused by rare pathogenic variants in sarcomere genes, the genetic underpinnings of nearly half of patients remain unsolved.[2] Increasing evidence implies that HCM has a more complex genetic architecture.[3] We identified an East Asian-specific common missense variant in I TNNI3 i (rs3729712) associated with HCM in an exome-wide case-control association study of Chinese origin and replicated the finding in 3 independent studies ( I P i =5.80×10 SP -22 sp ). The association was confirmed in each of the 3 replication studies, among which the Beijing replication samples and Xi'an-1 cases were genotyped by a panel sequencing of cardiomyopathy candidate genes, and the Xi'an-1 controls and Xi'an-2 samples by Sanger sequencing. Patients with HCM were classified into SARC+ (pathogenic or likely pathogenic variant identified in a sarcomere gene) and SARC- (no potentially pathogenic variant identified in a sarcomere gene) groups by the presence of any variant of pathogenic, likely pathogenic, or unknown significance in the 8 sarcomere genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, and ACTC1) in the discovery study (495 vs 491), Beijing replication study (226 vs 303), and Xi'an-1 study (342 vs 304). [Extracted from the article]

Background The FHOD3 (formin homology 2 domain-containing 3) gene has recently been identified as a causative gene of hypertrophic cardiomyopathy (HCM). However, the pathogenicity of FHOD3 variants remains to be evaluated. This study analyzed the spectrum of FHOD3 variants in a large HCM and control cohort, and explored its correlation with the disease. Methods and Results The genetic analysis of FHOD3 was performed using the whole exome sequencing data from 1000 patients with HCM and 761 controls without HCM. A total of 37 FHOD3 candidate variants were identified, including 25 missense variants and 2 truncating variants. In detail, there were 27 candidate variants detected in 33 (3.3%) patients with HCM, which was significantly higher than in the 12 controls (3.3% versus 1.6%; odds ratio, 2.13; P <0.05). On the basis of familial segregation, we identified one truncating variant (c.1286+2delT) as a causal variant in 4 patients. Furthermore, the FHOD3 candidate variant experienced significantly more risk of cardiovascular death and all-cause death (adjusted hazard ratio [HR], 3.71; 95%, 1.32-8.59; P =0.016; and adjusted HR, 3.02; 95% CI, 1.09-6.85; P= 0.035, respectively). Conclusions Our study suggests that FHOD3 is a causal gene for HCM, and that the presence of FHOD3 candidate variants is an independent risk for cardiovascular death and all-cause death in HCM.

Background: The lack of validated and effective sudden cardiac death (SCD) risk prediction methods is the biggest barrier to perform the lifesaving treatment with a prophylactic implantable cardioverter-defibrillator in Chinese patients with hypertrophic cardiomyopathy (HCM)., Objective: This study aimed to evaluate the efficacy of 3 existing SCD risk prediction methods recommended by the 2011 American College of Cardiology Foundation and American Heart Association (ACCF/AHA) guideline, the 2014 European Society of Cardiology (ESC) guideline, and the 2019 enhanced American College of Cardiology (ACC)/AHA strategy in Chinese patients with HCM., Methods: The present study consisted of 1369 consecutive adult patients with HCM without a history of SCD events. The primary end point was a composite of SCD and equivalent events, namely, resuscitation from cardiac arrest and appropriate implantable cardioverter-defibrillator shock therapy for ventricular tachycardia or fibrillation., Results: During follow-up of 3.2 ± 2.4 years, 39 patients reached SCD end points, of whom 26 (66.7%) were correctly predicted as those at a high risk of SCD by using methods recommended by the 2019 enhanced ACC/AHA strategy, 20 (51.3%) by the 2011 ACCF/AHA guideline, but only 5 (12.8%) by the 2014 ESC guideline. The 2019 enhanced ACC/AHA strategy showed a higher C-statistic (0.647) for SCD prediction than did the 2011 ACCF/AHA guideline (0.598) and 2014 ESC guideline (0.605) and resulted in the correct reclassification of SCD risk when compared with the 2011 ACCF/AHA guideline (net reclassification index 0.113; P = .074) and 2014 ESC guideline (net reclassification index 0.245; P = .038)., Conclusion: The 2019 enhanced ACC/AHA strategy showed better predictive performance for SCD risk stratification in Chinese patients with HCM, with a notably high sensitivity., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)