️ 25: Uncovering Mitochondrial DNA Diseases — The Solve-RD Experience with Genotype and Phenotype Integration

️ Episode 25: Uncovering Mitochondrial DNA Diseases — The Solve-RD Experience with Genotype and Phenotype Integration In this episode of Base por Base, we delve into a groundbreaking study by Ratnaike et al. (2025) published in The American Journal of Human Genetics, which presents a semi-automated workflow combining mtDNA variant filtering and MitoPhen-based HPO phenotype similarity scoring applied to exome and genome data from the Solve-RD cohort of undiagnosed rare disease cases . Study highlights:Our workflow applied MToolBox for mtDNA reconstruction and MITOMAP annotations with stringent quality filters (≥50% mtDNA assembly and ≥5× coverage) to prioritize 136 rare variants across 9,923 individuals from 9,483 families without prior suspicion of mitochondrial disease .Phenotype similarity scoring using the curated MitoPhen database achieved 100% sensitivity at a 0.3 threshold and distinguished confirmed mtDNA disease cases from nuclear genetic diagnoses with an AUC of 0.82 .A total of 21 confirmed and 16 likely causative mtDNA diagnoses were made, boosting the overall diagnostic yield by 0.4% and uncovering 37 new diagnoses .The pipeline efficiently handled off-target exome sequencing data, retaining 90% of datasets for analysis and enabling detection of pathogenic variants at heteroplasmy levels as low as 1% .Structured, phenotype-driven curation underscored the importance of comprehensive HPO annotation and highlighted the value of iterative genotype-phenotype evaluation in improving rare disease diagnostics . Conclusion:This study demonstrates a scalable approach to integrate mtDNA analysis into routine exome and genome reanalysis by leveraging automated bioinformatic filtering and phenotype similarity scoring, offering a powerful tool to improve diagnostic rates for mitochondrial disorders in heterogeneous cohorts . Reference:Ratnaike, T., Paramonov, I., Olimpio, C., et al. (2025). Mitochondrial DNA disease discovery through evaluation of genotype and phenotype data: The Solve-RD experience. The American Journal of Human Genetics, 112(1), 1–12. https://doi.org/10.1016/j.ajhg.2025.04.003 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International (CC BY 4.0) license – http://creativecommons.org/licenses/by/4.0/

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