Browse by author
Lookup NU author(s): Dr Ramya Narayanan
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Authors.Purpose Primary mitochondrial diseases (PMD) arise from variants in the mitochondrial or nuclear genomes. Phenotype-based recognition of specific PMD genotypes remains difficult, prolonging the diagnostic odyssey. We expanded the MitoPhen database to characterize phenotypic variation across PMD more systematically. Methods Individual-level data on mitochondrial DNA disorders, nuclear-encoded mitochondrial diseases, and single large-scale mitochondrial DNA deletions were manually curated with Human Phenotype Ontology (HPO) terms to produce MitoPhen v2 . Principal-component analysis summarized system-level abnormalities; HPO-level enrichment and mean phenotype-similarity scores were then used to distinguish common PMD genotypes. Results MitoPhen v2 adds 3940 individuals to the original release, now encompassing 1597 publications, 10,626 individuals, and 117 genotypes. Among 7586 affected cases, 72,861 HPO terms were recorded. Principal-component analysis revealed 6 phenotype dimensions capturing most system-level variance. At the HPO level, we observed genotype-specific enrichments and identified 111 gene-phenotype links absent from the current HPO database. Using MT-TL1 , single large-scale mitochondrial DNA deletions, and POLG as exemplars, phenotype-similarity scores reliably separated individuals with these genotypes from those without. Conclusion MitoPhen v2 enabled systematic, genotype-aware analysis of heterogeneous PMD phenotypes and highlighted the diagnostic value of structured, individual-level data. Phenotype-similarity metrics from such data sets can refine variant interpretation in large rare-disease cohorts and provide a transferable framework for other phenotypically complex genetic disorders.
Author(s): Ratnaike T, Ramanan S, Elkhateeb N, Narayanan R, Yang J, Arany ES, Mirchandani M, Piper R, Schon K, Kule ME, Gilmartin C, Lochmuller A, Shaw E, Horvath R, Chinnery PF
Publication type: Article
Publication status: Published
Journal: Genetics in Medicine
Year: 2026
Volume: 28
Issue: 1
Print publication date: 01/01/2026
Online publication date: 24/10/2025
Acceptance date: 09/10/2025
Date deposited: 08/12/2025
ISSN (print): 1098-3600
ISSN (electronic): 1530-0366
Publisher: Elsevier B.V.
URL: https://doi.org/10.1016/j.gim.2025.101620
DOI: 10.1016/j.gim.2025.101620
Data Access Statement: The MitoPhen database is freely accessible through the website https://www.mitophen.org/. We have separately attached the new data that was added to create MitoPhen v2, as a Supplemental table. We would be grateful for acknowledgement and citation of this work in research involving the dataset.
Altmetrics provided by Altmetric
