title: Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy.
abstract: OBJECTIVE
  Although genetic testing has been recommended in patients with hypertrophic cardiomyopathy (HCM) in current clinical practice, its utility in prognostic prediction remains to be ascertained. We assessed the dosage effect of rare variants in sarcomere genes on the long-term outcomes of HCM.
  
  
  RESULTS
  A total of 529 unrelated HCM patients were prospectively recruited and followed for 4.7 ± 3.2 years. Eight sarcomere genes were screened with targeted resequencing and identified variants were validated through Sanger sequencing. After polymorphisms and likely neutral rare variants were excluded, the patients were segregated into three groups based on the dosage of rare variants: no rare variant, a single rare variant, and multiple rare variants. Multiple rare variants were identified in 7.2% (38/529) of the study patients. Patients with multiple rare variants were younger at diagnosis, and had greater maximum LV wall thicknesses and larger left atria. The risk for cardiovascular death in patients with multiple rare variants was higher than in those without rare variants (P =10⁻⁵) or in those with a single rare variant (P = 2 × 10⁻⁵). Multivariable analysis revealed that multiple rare variants were a risk factor for cardiovascular death [hazard ratio (HR) 3.74, 95% confidence interval (CI) 1.84-7.58, P = 0.0003], as well as sudden cardiac death (HR 3.57, 95% CI 1.23-10.35, P = 0.019) and heart failure-related death (HR 4.62, 95% CI 1.67-12.76, P = 0.003).
  
  
  CONCLUSIONS
  The presence of multiple rare variants in sarcomere genes is a risk factor for malignant outcomes in HCM, and may be appropriate to consider as a criterion in the risk stratification of HCM patients.
authors.affiliation: State Key Laboratory of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jizheng
authors.initials: J
authors.lastname: Wang
authors.forename: Yilu
authors.initials: Y
authors.lastname: Wang
authors.forename: Yubao
authors.initials: Y
authors.lastname: Zou
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Wang
authors.forename: Hu
authors.initials: H
authors.lastname: Ding
authors.forename: Jinqing
authors.initials: J
authors.lastname: Yuan
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Qing
authors.initials: Q
authors.lastname: Hou
authors.forename: Hu
authors.initials: H
authors.lastname: Wang
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.forename: Hongju
authors.initials: H
authors.lastname: Zhang
authors.forename: Yun
authors.initials: Y
authors.lastname: Ji
authors.forename: Xianliang
authors.initials: X
authors.lastname: Zhou
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Sharma
authors.forename: Daowen
authors.initials: D
authors.lastname: Wang
authors.forename: Ferhaan
authors.initials: F
authors.lastname: Ahmad
authors.forename: Rutai
authors.initials: R
authors.lastname: Hui
authors.forename: Lei
authors.initials: L
authors.lastname: Song
mesh_terms: D000328:Adult; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002681:China / Q000453:epidemiology; D004247:DNA / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D005820:Genetic Testing; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D012307:Risk Factors; D012518:Sarcomeres / Q000235:genetics* / Q000378:metabolism; D015996:Survival Rate / Q000639:trends; D013997:Time Factors
chemical_list: D004247:DNA
keywords: Hypertrophic cardiomyopathy; Multiple rare variants; Prognosis; Sarcomere gene