MitoPhen database: a human phenotype ontology-based approach to identify mitochondrial DNA diseases

Abstract

Diagnosing mitochondrial disorders remains challenging. This is partly because the clinical phenotypes of patients overlap with those of other sporadic and inherited disorders. Although the widespread availability of genetic testing has increased the rate of diagnosis, the combination of phenotypic and genetic heterogeneity still makes it difficult to reach a timely molecular diagnosis with confidence. An objective, systematic method for describing the phenotypic spectra for each variant provides a potential solution to this problem. We curated the clinical phenotypes of 6688 published individuals with 89 pathogenic mitochondrial DNA (mtDNA) mutations, collating 26 348 human phenotype ontology (HPO) terms to establish the MitoPhen database. This enabled a hypothesis-free definition of mtDNA clinical syndromes, an overview of heteroplasmy-phenotype relationships, the identification of under-recognized phenotypes, and provides a publicly available reference dataset for objective clinical comparison with new patients using the HPO. Studying 77 patients with independently confirmed positive mtDNA diagnoses and 1083 confirmed rare disease cases with a non-mitochondrial nuclear genetic diagnosis, we show that HPO-based phenotype similarity scores can distinguish these two classes of rare disease patients with a false discovery rate <10% at a sensitivity of 80%. Enriching the MitoPhen database with more patients will improve predictions for increasingly rare variants.

Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study

“…Alternatively, this could reflect the fact that genetic testing had not been offered previously to the doi: The relatively high frequency of partial diagnoses in this study (4%) may reflect our current knowledge of the phenotypic spectrum of ultra-rare genetic diseases, and some of the features we have not ascribed to the causal variants may actually be due to the underlying mutations. This is likely to be a particular problem for mitochondrial disorders because of their diverse phenotypes, some of which are only just being recognised, 36 but will become easier as our knowledge base increases.…”

“…We used an in-house pipeline to call mtDNA single nucleotide variants above an established detection threshold of 1% variant allele frequency (or percentage heteroplasmy level),35 after excluding likely errors 27. We compared these with a manually curated list of pathogenic mutations with functional evidence supporting pathogenicity 36. Our pipeline does not detect large scale mtDNA rearrangements, which usually require targeted mtDNA analysis in DNA extracted from skeletal muscle.…”

“…27 We compared these with a manually curated list of pathogenic mutations with functional evidence supporting pathogenicity. 36 Our pipeline does not detect large scale mtDNA rearrangements, which usually require targeted mtDNA analysis in DNA extracted from skeletal muscle.…”

Base editing in human cells with monomeric DddA-TALE fusion deaminases

“…Although it is possible to ignore the need for thymine at the 5′ termini or to use an engineered TALE N-terminal domain that recognizes all four bases 14 , it is unknown whether the resulting TALE proteins used in a DdCBE pair would be as efficient and specific as conventional TALE proteins recognizing thymine at the 5′ termini. As an example, we chose the MT-TC gene encoding tRNA-Cys: Various single-nucleotide substitutions in this gene are associated with myopathy or hearing loss 18 . We were able to design mDdCBEs but not dimeric DdCBEs to target a site in this gene, where there is no thymine within a stretch of 39 bp downstream of a potentially editable TC motif (Fig.…”

Human clinical mutations in mitochondrially encoded subunits of Complex I can be successfully modeled in E. coli

“…The mitochondrial haplotype can also influence the effect of a particular mutation, but generally, in unknown ways ( Klink et al, 2021 ). For all these reasons, the pathogenicity of an identified mitochondrial mutation can be difficult to ascertain ( Ratnaike et al, 2021 ; Wei et al, 2017 ; Wong et al, 2020 ).…”