IMPE Abstracts

The term “mitochondrial disease” (MD) encompasses well over 300 monogenic disorders. MD genes encode either components of the oxidative phosphorylation (OXPHOS) system or cause a secondary impact on OXPHOS. MD can be caused by pathogenic variants in any of the 37 mitochondrial DNA (mtDNA) genes, which explain up to 70% of adult-onset MD. In paediatric-onset MD, the modes of inheritance appear to be ~30% mtDNA, ~50% autosomal recessive with the remainder X-linked or autosomal dominant. de novo variants are common in mtDNA and autosomal dominant MDs. The majority of MD genes are thus nuclear genes, nearly all encoding proteins located in the mitochondria with roles in OXPHOS biogenesis or a wide range of functions including mitochondrial protein import, processing or quality control plus mitochondrial metabolite transport, lipid homeostasis, morphology or metabolism. In patients suspected of MD, a “genomics first” approach is largely replacing traditional enzyme and histochemical testing although functional testing in cell lines or muscle biopsies can still be required e.g., for children with variants of uncertain significance. For patients with suspected MD, reported genomic diagnostic yields are typically in the range of 30-60% but depend on both numerator and denominator issues. The former includes the genomic approach and availability of samples, budget and expertise for functional genomic follow-up. The latter includes entry criteria for the cohort, e.g., prospective vs retrospective, age, referral sources and degree of suspicion. MDs have a wide phenotypic spectrum with symptoms often overlapping with non-mitochondrial diseases. Most studies of MD cohorts thus find that10-30% of genomic diagnoses are in phenocopy genes (“mitochondrial mimics”). In exome-unsolved patients with high suspicion of MD, computational and multi-omics analyses (RNAseq and proteomics) can increase diagnostic yield by 20-40%. Cryptic diagnoses are enriched for complex structural rearrangements, de novo dominant variants, deep intronic variants and splice-site altering synonymous variants.