Patients with coronary heart disease, dilated cardiomyopathy and idiopathic ventricular tachycardia share overlapping patterns of pathogenic variation in cardiac risk genes

PeerJ

article

Christian Guelly¹  Zhannur Abilova²  Omirbek Nuralinov³  Katrin Panzitt¹  Ainur Akhmetova²  Saule Rakhimova²  Ulan Kozhamkulov²  Ulykbek Kairov⁴  Askhat Molkenov⁴  Ainur Ashenova⁴  Slave Trajanoski¹  Gulzhaina Abildinova (Rashbayeva)³  Galina Kaussova⁵  Christian Windpassinger⁶  Joseph H. Lee⁷  Zhaxybay Zhumadilov²  Makhabbat Bekbossynova³  Ainur Akilzhanova² 

[1] Center of Medical Research, Medical University of Graz;Laboratory of Genomic and Personalized Medicine, Center for Life Science, National Laboratory Astana, Nazarbayev University;National Research Cardiac Surgery Center;Laboratory of Bioinformatics and Systems Biology, Center for Life Sciences, National Laboratory Astana, Nazarbayev University;Kazakhstan medical university “KSPH”;Institute of Human Genetics, Medical University of Graz;Sergievsky Center Taub Institute, Columbia University Medical Center

关键词: Coronary heart disease;    Ventricular tachycardia;    Dilated cardiomyopathy;    Targeted sequencing;    Next generation sequencing;    96 cardiac genes panel;    Genetic variant;    HGMD;    ACMG;    Pathogenesis;   

DOI  :  10.7717/peerj.10711

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

BackgroundVentricular tachycardia (VT) is a major cause of sudden cardiac death (SCD). Clinical investigations can sometimes fail to identify the underlying cause of VT and the event is classified as idiopathic (iVT). VT contributes significantly to the morbidity and mortality in patients with coronary artery disease (CAD) and dilated cardiomyopathy (DCM). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility screening for disease-predisposing variants could improve VT diagnostics and prevent SCD in patients.MethodsNinety-two patients diagnosed with coronary heart disease (CHD), DCM, or iVT were included in our study. We evaluated genetic profiles and variants in known cardiac risk genes by targeted next generation sequencing (NGS) using a newly designed custom panel of 96 genes. We hypothesized that shared morphological and phenotypical features among these subgroups may have an overlapping molecular base. To our knowledge, this was the first study of the deep sequencing of 96 targeted cardiac genes in Kazakhstan. The clinical significance of the sequence variants was interpreted according to the guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015. The ClinVar and Varsome databases were used to determine the variant classifications.ResultsTargeted sequencing and stepwise filtering of the annotated variants identified a total of 307 unique variants in 74 genes, totally 456 variants in the overall study group. We found 168 mutations listed in the Human Genome Mutation Database (HGMD) and another 256 rare/unique variants with elevated pathogenic potential. There was a predominance of high- to intermediate pathogenicity variants in LAMA2, MYBPC3, MYH6, KCNQ1, GAA, and DSG2 in CHD VT patients. Similar frequencies were observed in DCM VT, and iVT patients, pointing to a common molecular disease association. TTN, GAA, LAMA2, and MYBPC3 contained the most variants in the three subgroups which confirm the impact of these genes in the complex pathogenesis of cardiomyopathies and VT. The classification of 307 variants according to ACMG guidelines showed that nine (2.9%) variants could be classified as pathogenic, nine (2.9%) were likely pathogenic, 98 (31.9%) were of uncertain significance, 73 (23.8%) were likely benign, and 118 (38.4%) were benign. CHD VT patients carry rare genetic variants with increased pathogenic potential at a comparable frequency to DCM VT and iVT patients in genes related to sarcomere function, nuclear function, ion flux, and metabolism.ConclusionsIn this study we showed that in patients with VT secondary to coronary artery disease, DCM, or idiopathic etiology multiple rare mutations and clinically significant sequence variants in classic cardiac risk genes associated with cardiac channelopathies and cardiomyopathies were found in a similar pattern and at a comparable frequency.

【 授权许可】

CC BY