Blue et al. (2024) Dual Diagnosis of UQCRFS1-related Mitochondrial Complex III Deficiency and recessive GJA8-related Cataracts
We describe the relationship between consanguinity, multi-system disease, and multiple genetic diagnoses of rare disease for a single proband. This report highlights the implementation of both genome sequencing and proteomics to increase diagnostic yield and early diagnosis. We demonstrate that proteomics analyses offered greater resolution of respiratory chain dysfunction than typical spectrophotometric assays. We characterize the phenotypic spectrum of recessive mitochondrial complex III disorders including our proband. We underscore the need to consider alternative modes of inheritance when evaluating DNA sequence variants: although recessive variants explain just 5% of GJA8-related cataracts, we find a rare truncating homozygous GJA8 variant caused recessive cataracts in our proband with no manifesting signs in the heterozygous parents. Contributing consortia: Undiagnosed Diseases Network, University of Washington Center for Rare Disease Research