Next-generation sequencing identifies pathogenic and modifier mutations in a consanguineous Chinese family with hypertrophic cardiomyopathy
| Autor: | Jun Xie, Biao Xu, Suhui Zhu, Yuhan Chen, Xinlin Zhang, Lian Wang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Genotyping Techniques Cardiomyopathy 030204 cardiovascular system & hematology Consanguinity 0302 clinical medicine Medicine Child mybpc3 Genetics genetic modifier Hypertrophic cardiomyopathy General Medicine Middle Aged Phenotype cacnb2 Echocardiography Mutation (genetic algorithm) ComputingMethodologies_DOCUMENTANDTEXTPROCESSING Female Sequence Analysis Research Article Adult China Adolescent Calcium Channels L-Type Observational Study 03 medical and health sciences Young Adult Channelopathy Asian People Cardiomyopathy Hypertrophic Familial Humans Genetic Predisposition to Disease Genotyping Genetic Association Studies Aged Myosin Heavy Chains business.industry medicine.disease hypertrophic cardiomyopathy 030104 developmental biology Mutation next-generation sequencing Age of onset business Carrier Proteins Cardiac Myosins |
| Zdroj: | Medicine |
| ISSN: | 1536-5964 0025-7974 |
| Popis: | Supplemental Digital Content is available in the text 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. |
| Databáze: | OpenAIRE |
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