Clinical spectrum and genotype-phenotype correlations of MT-CYB-associated mitochondrial disease: from the m.15045G > A variant to the broader disease landscape.

AIM: To characterize the clinical and molecular features associated with the MT-CYB m.15045G > A variant and investigate the clinical spectrum and genotype-phenotype relationships of MT-CYB-associated mitochondrial disease.

METHODS

We performed comprehensive clinical, metabolic, histopathological, genetic, and mitochondrial functional analyses in a patient carrying the m.15045G > A variant. A systematic literature review of previously reported disease-associated MT-CYB variants was conducted, followed by genotype-phenotype comparisons and unsupervised hierarchical clustering integrating clinical, genetic, and functional characteristics.

RESULTS

The patient presented with exercise intolerance, borderline intellectual functioning, and elevated medium and long-chain acylcarnitines. Muscle biopsy showed mitochondrial myopathic changes, and respiratory chain analysis demonstrated isolated complex III (CIII) deficiency. The m.15045G > A variant showed tissue-specific heteroplasmy of 22.5, 70.5, and 95.5% in blood, urine, and muscle, respectively, providing further evidence for its pathogenicity. Among 34 patients with disease-associated MT-CYB variants, mitochondrial myopathy (MM) was the most common phenotype (50.0%). Patients with MM showed a later age at onset, and muscle-restricted variants were markedly enriched in the MM group (p < 0.001). In contrast, muscle heteroplasmy level, variant type, and isolated CIII deficiency were not significantly associated with phenotype. Hierarchical clustering showed 88.2% concordance with clinical phenotype classification.

CONCLUSION

Our findings provide further evidence for the pathogenicity of m.15045G > A and broaden its associated clinical and metabolic features. Tissue-specific distribution of MT-CYB variants showed an association with clinical phenotype, while other genetic and functional factors may collectively contribute to phenotypic variability.