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. 2026 Sep 29;20:1968308. doi: 10.3389/fnins.2026.1968308

Figure 4.

Clinical spectrum and genotype–phenotype correlations of MT-CYB variants. Panel A shows phenotype distribution among 34 individuals, with mitochondrial myopathy accounting for 50%. Panel B shows age-at-onset distributions for initial manifestations. Panel C maps missense, nonsense, in-frame deletion, and frameshift variants across the cytochrome b protein and its transmembrane domains. Panel D compares age at onset between mitochondrial myopathy and non-myopathy groups. Panel E compares muscle-restricted and multi-tissue detectable variants between groups. Panel F shows hierarchical clustering based on genetic, functional, and clinical characteristics and multisystem involvement.

Clinical spectrum and genotype–phenotype correlation of MT-CYB variants. (A) Clinical phenotype distribution among 34 individuals carrying MT-CYB variants. (B) Age-at-onset distribution by initial symptoms. Age at onset is presented as median (25th–75th percentiles). The x-axis is displayed on a base-10 logarithmic scale. MELAS-spectrum manifestations include epilepsy, stroke-like episodes, and motor incoordination. When only categorical age-at-onset data were available, representative ages corresponding to the midpoint of each predefined age category were assigned for visualization (e.g., infant = 6 months, child = 9 years, and late childhood = 11 years). (C) Distribution of MT-CYB variants across the cytochrome b protein. Variant types are indicated by different symbols, and clinical phenotypes are indicated by different colors. Transmembrane domains (TM1–TM8) are shown below the protein schematic. (D) Comparison of age at onset between patients with mitochondrial myopathy (MM) and non-MM phenotypes. Age at onset is presented as individual values, with bars indicating the median and 25th–75th percentiles. Statistical comparison was performed using the Mann–Whitney U test. (E) Comparison of tissue distribution of MT-CYB variants between MM and non-MM phenotypes. Variants were classified as muscle-restricted variants or multi-tissue detectable variants according to the presence or absence of the variant in extra-muscular tissues. Statistical comparison was performed using Fisher’s exact test. (F) Hierarchical clustering of clinical, genetic, and functional characteristics of individuals with MT-CYB variants. Rows represent individual patients, and columns represent genetic and functional features, clinical phenotype, and number of involved systems. The right-side annotations indicate phenotype classification (MM vs. non-MM) and the number of involved systems. MM, mitochondrial myopathy; NSMD, non-syndromic mitochondrial disease; MCM, mitochondrial cardiomyopathy; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; LS, Leigh syndrome; LHON, Leber hereditary optic neuropathy; TM, transmembrane domain; CIII, complex III.