Association of variants in MYH7, MYBPC3 and TNNT2 with sudden cardiac death-related risk factors in Brazilian patients with hypertrophic cardiomyopathy
| Autor: | Gisele Medeiros Bastos, Mario Hiroyuki Hirata, Glaucio Monteiro Ferreira, Cristina Moreno Fajardo, Lara Reinel de Castro, Angel Carracedo, Maria Brion, Amanda G. M. R. Sousa, Raul Hernandes Bortolin, Rosario Dominguez Crespo Hirata, José Carlos Pachón-Mateos, Victor Fernandes de Oliveira, Marcelo Ferraz Sampaio, Thiago Dominguez Crespo Hirata, Augusto Akira Mori, Dalmo Antonio Ribeiro Moreira, Edileide de Barros Correia |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Heterozygote FATORES DE RISCO TNNT2 Left ventricular hypertrophy Ventricular tachycardia Pathology and Forensic Medicine Sudden cardiac death 03 medical and health sciences 0302 clinical medicine Troponin T Risk Factors Internal medicine Genetics Heart Septum Medicine Humans cardiovascular diseases 030216 legal & forensic medicine Family history Genetic Association Studies Myosin Heavy Chains business.industry Hypertrophic cardiomyopathy Sequence Analysis DNA Cardiomyopathy Hypertrophic Middle Aged medicine.disease 030104 developmental biology Death Sudden Cardiac Echocardiography Mutation Cardiology Medical genetics MYH7 Female business Carrier Proteins Cardiac Myosins Brazil |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| Popis: | Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy (LVH) and is one of the major causes of sudden cardiac death (SCD). An exon-targeted gene sequencing strategy was used to investigate the association of functional variants in sarcomeric genes (MYBPC3, MYH7 and TNNT2) with severe LVH and other SCD-related risk factors in Brazilian HCM patients. Clinical data of 55 HCM patients attending a Cardiology Hospital (Sao Paulo city, Brazil) were recorded. Severe LVH, aborted SCD, family history of SCD, syncope, non-sustained ventricular tachycardia and abnormal blood pressure in response to exercise were evaluated as SCD risk factors. Blood samples were obtained for genomic DNA extraction and the exons and untranslated regions of the MYH7, MYBPC3 and TNNT2 were sequenced using Nextera® and MiSEq® reagents. Variants were identified and annotated using in silico tools, and further classified as pathogenic or benign according to the American College of Medical Genetics and Genomics guidelines. Variants with functional effects were identified in MYBPC3 (n = 9), MYH7 (n = 6) and TNNT2 (n = 4). The benign variants MYBPC3 p.Val158Met and TNNT2 p.Lys263Arg were associated with severe LVH (p 0.05), and the MYH7 p.Val320Met (pathogenic) was associated with family history of SCD (p = 0.037). Increased risk for severe LVH was found in carriers of MYBPC3 Met158 (c.472 A allele, OR = 13.5, 95% CI = 1.80-101.12, p = 0.011) or combined variants (MYBPC3, MYH7 and TNNT2: OR = 12.39, 95% CI = 2.14-60.39, p = 0.004). Carriers of TNNT2 p.Lys263Arg and combined variants had higher values of septum thickness than non-carriers (p 0.05). Molecular modeling analysis showed that MYBPC3 158Met reduces the interaction of cardiac myosin-binding protein C (cMyBP-C) RASK domain (amino acids Arg215-Ala216-Ser217-Lys218) with tropomyosin. In conclusion, the variants MYBPC3 p.Val158Met, TNNT2 p.Lys263Arg and MYH7 p.Val320Met individually or combined contribute to the risk of sudden cardiac death and other outcomes of hypertrophic cardiomyopathy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|