Identification of three novel pathogenic mutations in sarcomere genes associated with familial hypertrophic...

Area of Science:

• Cardiovascular Genetics
• Metabolomics
• Molecular Cardiology

Background:

• Familial hypertrophic cardiomyopathy (HCM) is a primary cause of sudden cardiac death, characterized by diverse clinical presentations.
• Identifying specific ultrasonic phenotypes, causal gene mutations, and metabolic pathways is crucial for understanding familial HCM.
• Multi-omics studies are essential for elucidating the complex pathogenic mechanisms in familial HCM.

Purpose of the Study:

• To identify novel pathogenic sarcomere gene mutations in familial HCM pedigrees.
• To investigate the associated ultrasonic phenotypes and metabolic disturbances.
• To explore the implications for diagnosis and precision medicine in HCM.

Main Methods:

• Analysis of clinical data from nine individuals across two familial HCM pedigrees.
• Multiparameter ultrasound assessment, whole-exome sequencing, and untargeted metabolomics.
• Integration of genetic and metabolic data to identify pathogenic mutations and metabolic alterations.

Main Results:

• Discovery of three novel pathogenic sarcomere gene mutations: TNNT2-rs397516484, MYH6-rs372446459, and MYBPC3-rs786204339.
• Affected individuals exhibited heart failure, electrocardiogram abnormalities, impaired diastolic and systolic function, and reduced myocardial work.
• Significant disturbances in carbohydrate metabolism, including the citrate cycle (TCA cycle) and glycolysis, were observed.

Conclusions:

• TNNT2-rs397516484, MYH6-rs372446459, and MYBPC3-rs786204339 are confirmed as pathogenic mutations in familial HCM.
• These mutations lead to diminished cardiac function and notable metabolic derangements in carbohydrate metabolism.
• Findings support biologically defined diagnoses and the development of precision medicine strategies for familial HCM.