Next-generation sequencing identifies pathogenic and modifier mutations in a consanguineous Chinese family with hypertrophic cardiomyopathy

被引:5
作者
Zhang, Xinlin [1 ]
Xie, Jun [1 ]
Zhu, Suhui [1 ]
Chen, Yuhan [1 ]
Wang, Lian [1 ]
Xu, Biao [1 ]
机构
[1] Nanjing Univ, Sch Med, Affiliated Drum Tower Hosp, Dept Cardiol, 321 Zhongshan Rd, Nanjing 210008, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
cacnb2; genetic modifier; hypertrophic cardiomyopathy; mybpc3; next-generation sequencing; BINDING-PROTEIN-C; LEFT-VENTRICULAR HYPERTROPHY; GENE-MUTATIONS; TASK-FORCE; DISEASE; EXPRESSION; GUIDELINES; MYBPC3; HEART; POLYMORPHISMS;
D O I
10.1097/MD.0000000000007010
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Hypertrophic cardiomyopathy (HCM) is a highly heterogeneous disease displaying considerable interfamilial and intrafamilial phenotypic variation, including disease severity, age of onset, and disease progression. This poorly understood variance raises the possibility of genetic modifier effects, particularly in MYBPC3-associated HCM. In a large consanguineous Chinese HCM family, we identified 8 members harboring the MYBPC3 c.3624delC (p.Lys1209Serfs) disease-causing mutation, but with very disparate phenotypes. Genotyping ruled out the modifying effect of previously described variants in renin-angiotensin-aldosterone system. Afterwards, we screened for modifying variants in all known causing genes and closely related genes for cardiomyopathy and channelopathy by performing targeted next-generation sequencing. For first time, we showed that a c.1598C>T (p.Ser533Leu) mutation in voltage-dependent l-type calcium channel subunit beta-2 (CACNB2) was present in all severely affected HCM patients, but not in those moderately affected or genotype-positive phenotype-negative patients. This CACNB2 p.Ser533Leu mutation is extremely conserved in evolution, and was not found in 550 healthy controls. Our results suggest that CACNB2 is a possible candidate genetic modifier of MYBPC3-associated familial HCM, but more genetic evidence and functional experiments are needed to confirm.
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页数:7
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