Show Notes
Ratnaike et al et al., The American Journal of Human Genetics - A semi-automated mtDNA reanalysis pipeline using MToolBox and MitoPhen HPO-based phenotype similarity was applied to the Solve-RD cohort, identifying previously undiagnosed mtDNA variants and adding a 0.4% diagnostic uplift. Key terms: mitochondrial DNA, heteroplasmy, MitoPhen, Solve-RD, phenotype similarity.
Study Highlights:
The authors validated an mtDNA calling and prioritization workflow on 42 pre-solved exomes and then applied it to 10,157 ES/GS datasets from 9,923 individuals in Solve-RD. Automated filtering (heteroplasmy ≥1%, MITOMAP annotation, haplogroup exclusion) prioritized 136 mtDNA variants in 135 undiagnosed individuals. An HPO-based phenotype similarity score from MitoPhen (threshold >0.3) was tested and used to prioritize candidates, capturing 34 of 37 confirmed or likely causative diagnoses. The integrated genotype-phenotype pipeline yielded 37 new confirmed or likely mtDNA diagnoses, a 0.4% diagnostic uplift in this heterogeneous cohort.
Conclusion:
Incorporating structured mtDNA analysis and HPO-based phenotype similarity scoring into ES/GS reanalysis can reveal previously undiagnosed mitochondrial diagnoses and modestly increase diagnostic yield in large rare-disease cohorts.
QC:
This episode was checked against the original article PDF and publication metadata.
Scope: article metadata and core scientific claims from the narration, excluding analogies, intro/outro, and music.
Factual QC score: 10/10.
Metadata QC score: 10/10.
Supported core claims: 7.
Claims flagged for review: 0.
Metadata checks passed: 4.
Metadata issues found: 0.
QC result: Pass.
Music:
Enjoy the music based on this article at the end of the episode.
Article title:
Mitochondrial DNA disease discovery through evaluation of genotype and phenotype data: The Solve-RD experience
First author:
Ratnaike et al
Journal:
The American Journal of Human Genetics
DOI:
https://doi.org/10.1016/j.ajhg.2025.04.003
Reference:
Ratnaike et al., Mitochondrial DNA disease discovery through evaluation of genotype and phenotype data: The Solve-RD experience, The American Journal of Human Genetics 112, 1–12 (2025). https://doi.org/10.1016/j.ajhg.2025.04.003
License:
http://creativecommons.org/licenses/by/4.0/
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