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

Abstract

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. 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. 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. 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.