Wen Liu1, Zongkai Wei1, Yanfen Zhang1, Yan Liu1, Ruocen Bai1, Chunyan Ma1, Jun Yang2, Dandan Sun3. 1. Department of Cardiovascular Ultrasound, The First Affiliated Hospital of China Medical University, Shenyang 110001, China. 2. Department of Cardiovascular Ultrasound, The First Affiliated Hospital of China Medical University, Shenyang 110001, China. Electronic address: junyang63@sina.com. 3. Department of Cardiovascular Ultrasound, The First Affiliated Hospital of China Medical University, Shenyang 110001, China. Electronic address: dan_101912@163.com.
Abstract
BACKGROUND: Familial hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death, but exhibits hetrogeneous clinical features . A major research focus is to identify specific ultrasonic phenotypes, and causal gene mutations, as well as to elucidate the possible metabolic pathogenic effects in familial HCM through multi-omics study. METHODS: Nine members of two familial HCM pedigrees were enrolled in this study. Their clinical data were collected, and the data of multiparameter ultrasound, whole-exome sequencing, and untargeted metabolomics were analyzed. RESULTS: We identified three novel pathogenic sarcomere gene mutations, TNNT2-rs397516484, MYH6-rs372446459 and MYBPC3-rs786204339 in two familial HCM pedigrees. The proband of Family 1 and his father carried TNNT2-rs397516484 and MYH6-rs372446459 missense mutations, while the proband of Family 2 and her brother carried MYBPC3-rs786204339 frameshift mutation. They presented with heart failure and abnormal electrocardiogram, accompanied by diastolic and systolic dysfunction and impaired myocardial work. They also showed disturbances of carbohydrate metabolism, including the citrate cycle (TCA cycle), glycolysis/gluconeogenesis, fructose and mannose metabolism, pentose and glucuronate interconversions and amino sugar and nucleotide sugar metabolism. CONCLUSIONS: Novel TNNT2-rs397516484, MYH6-rs372446459, and MYBPC3-rs786204339 are pathogenic sarcomere gene mutations in familial HCM, leading to decreased cardiac function and metabolic disturbances of carbohydrate metabolism, which have important implications for biologically defined diagnoses and precision medicine.
BACKGROUND:Familial hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death, but exhibits hetrogeneous clinical features . A major research focus is to identify specific ultrasonic phenotypes, and causal gene mutations, as well as to elucidate the possible metabolic pathogenic effects in familial HCM through multi-omics study. METHODS: Nine members of two familial HCM pedigrees were enrolled in this study. Their clinical data were collected, and the data of multiparameter ultrasound, whole-exome sequencing, and untargeted metabolomics were analyzed. RESULTS: We identified three novel pathogenic sarcomere gene mutations, TNNT2-rs397516484, MYH6-rs372446459 and MYBPC3-rs786204339 in two familial HCM pedigrees. The proband of Family 1 and his father carried TNNT2-rs397516484 and MYH6-rs372446459 missense mutations, while the proband of Family 2 and her brother carried MYBPC3-rs786204339 frameshift mutation. They presented with heart failure and abnormal electrocardiogram, accompanied by diastolic and systolic dysfunction and impaired myocardial work. They also showed disturbances of carbohydrate metabolism, including the citrate cycle (TCA cycle), glycolysis/gluconeogenesis, fructose and mannose metabolism, pentose and glucuronate interconversions and amino sugar and nucleotide sugar metabolism. CONCLUSIONS: Novel TNNT2-rs397516484, MYH6-rs372446459, and MYBPC3-rs786204339 are pathogenic sarcomere gene mutations in familial HCM, leading to decreased cardiac function and metabolic disturbances of carbohydrate metabolism, which have important implications for biologically defined diagnoses and precision medicine.
Authors: Melissa Anfinson; Robert H Fitts; John W Lough; Jeanne M James; Pippa M Simpson; Stephanie S Handler; Michael E Mitchell; Aoy Tomita-Mitchell Journal: J Cardiovasc Dev Dis Date: 2022-05-03