Genetic analysis of six adult patients with Dilated cardiomyopathy and analysis of structnral variants
10.3760/cma.j.cn511374-20241001-00518
- VernacularTitle:扩张型心肌病成年患者6例的遗传学分析与变异结构解析
- Author:
Xuesen LIU
1
;
Yaoyu SONG
;
Jing ZHANG
;
Huafeng QIU
;
Jingjing SANG
;
Juan ZHANG
Author Information
1. 驻马店市中心医院心内科，黄淮学院附属医院，驻马店 463000
- Publication Type:Journal Article
- Keywords:
Cardiomyopathy, dilated;
Adult;
Genetic variation;
Genetic testing;
Protein structure, tertiary;
Whole exome sequencing;
Structural analysis
- From:
Chinese Journal of Medical Genetics
2025;42(4):433-440
- CountryChina
- Language:Chinese
-
Abstract:
Objectives:To investigate the genetic etiology of six adult patients with Dilated cardiomyopathy (DCM), and analyze the structure of the identified variants, for providing reference for the diagnosis of DCM.Methods:Six adult patients with DCM (patients 1-6) admitted to the Department of Cardiology of Zhumadian Central Hospital from January 2023 to December 2023 were recruited. Clinical data of the patients were retrospectively collected. And 3 mL of peripheral blood was collected from each patients. Pathogenic variants patients were detected by whole exome sequencing (WES), and candidate variants were verified by Sanger sequencing. The possible functional significance of the identified missense variants was evaluated using software including SIFT, PolyPhen-2 and Mutation Taster. Specific regions of the MYBPC protein encoded by the MYBPC3 gene from different species were aligned using Mutation Taster. The wild-type and mutant MYBPC proteins were constructed using homologous modeling software MODELLER v10.4 and three-dimensional structures were visualized using PyMOL software. The molecular interaction between MYBPC-C5 domain and myosin with or without the mutation was further analyzed using ZDOCK module in Discovery Studio 2019 software. Pathogenicity ratings for the detected variant sites were performed in accordance with the Standards and Guidelines for the Interpretation of Sequence variants by the American College of Medical Genetics and Genomics (ACMG) (hereafter referred to as the ACMG Guidelines). This study was reviewed and approved by the Ethics Committee of Zhumadian Central Hospital (Approval No. 2022092007). Results:The six DCM patients had typical symptoms of heart failure, and echocardiography showed whole-heart dilation and decreased ventricular wall motion. Left ventricular end-diastolic dimension (LVEDD) was 57-74 mm, left ventricular ejection fraction (LVEF) was 35%-43%, and left ventricular fractional shortening (LVFS) was 17%-28%. Variation in DCM related genes, the c. 98473A>T(p.Lys32825*) variation of the TTN gene and the c.1976T>C(p.Ile659Thr) variation of the MYBPC3 gene, were identified in two patients with DCM. Multiple software predicted that both mutations were deleterious. MYBPC3-Ile659Thr mutation affected the highly conserved residue within the C5 domain of MYBPC. Three-dimensional structural analysis of homologous modeling revealed the alterations in amino acid properties and interactions with surrounding amino acids caused by the MYBPC3-Ile659Thr mutation. Further molecular docking analysis showed that the Ile659Thr mutation altered both the hydrogen bond and salt-bridge interactions between the MYBPC-C5 domain and the ligand myosin. Conclusions:Two mutations associated with DCM were identified in this study. The abnormal conformation of the mutant protein further affected its interaction with the ligand myosin, resulting in the phenotype of DCM.
