Homoplasmic MT-TG m.9997T>C variant associated with hypertrophic cardiomyopathy: Pathogenicity and genotype–phenotype analysis

Abstract

Background

Mitochondrial cardiomyopathy (MCM), a common subtype of mitochondrial disorders accounting for 20-40% of cases, presents significant diagnostic and therapeutic challenges due to genetic heterogeneity and variable clinical phenotypes.

Methods

We conducted a comprehensive analysis of the clinical, histopathological, molecular, and genetic characteristics of a 23-year-old male with maternally inherited hypertrophic cardiomyopathy (HCM) associated with the homoplasmic m.9997 T > C variant.

Results

The patient exhibited early-onset exercise intolerance, arrhythmias, and cardiac dysfunction. Cardiac Magnetic Resonance Imaging confirmed asymmetric HCM with left ventricular enlargement. Genetic analysis identified a homoplasmic m.9997T > C variant across multiple tissues (blood, urine, mucosa, muscle). Muscle biopsy revealed typical mitochondrial abnormalities, and reduced expression of complex IV subunits.

Conclusion

Our findings support the pathogenic association of the homoplasmic m.9997T > C variant in HCM and highlight the clinical significance of homoplasmic mtDNA mutations in tissue-specific mitochondrial disorders, contributing to the broader understanding of homoplasmic mutations in mitochondrial disease.