331: Bi-allelic NDUFA5 variants and complex I mitochondriopathy

Tan et al et al., The American Journal of Human Genetics - This report identifies bi-allelic NDUFA5 variants in four individuals from three families causing an isolated mitochondrial complex I deficiency with variable multisystem features. The study combines genomic, transcriptomic, proteomic, biochemical, structural modeling, and zebrafish functional data to support pathogenicity. Key terms: NDUFA5, complex I deficiency, mitochondriopathy, proteomics, zebrafish model. Study Highlights:Bi-allelic NDUFA5 variants were found in four individuals from three unrelated families presenting with a variable multisystem phenotype including congenital heart defects, hematological abnormalities, and Leigh-like neurological features. Multi-tissue RNA-seq and RT-PCR revealed aberrant splicing and NMD, while proteomics and BN-PAGE demonstrated reduced NDUFA5 protein, isolated complex I deficiency, and stalled assembly at a Q/P intermediate. CRISPR-Cas9 ndufa5 zebrafish crispants showed developmental delays, locomotor deficits, reduced survival, and epileptiform neural activity, corroborating functional impact. Conclusion:Combined clinical, molecular, and animal-model evidence supports that bi-allelic NDUFA5 variants cause a recessive mitochondriopathy with isolated complex I deficiency and variable multisystem involvement; NDUFA5 should be considered in molecular reanalysis of undiagnosed complex I disorders. Music:Enjoy the music based on this article at the end of the episode. Article title:Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency First author:Tan et al Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.03.003 Reference:Tan et al., 2026, The American Journal of Human Genetics 113, 1–14, May 7, 2026. https://doi.org/10.1016/j.ajhg.2026.03.003 License:CC BY (http://creativecommons.org/licenses/by/4.0/) Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/ndufa5-complex-i-mitochondriopathy QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-31. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript portions describing NDUFA5 variants, splicing consequences, proteomics/BN-PAGE findings, zebrafish model outcomes, and the diagnostic paradigm shift.- transcript topics: Complex I biology and mitochondrial energy metabolism; Gene discovery via GeneMatcher and patient cohorts; NDUFA5 variant classes and their consequences; RNA sequencing and exon skipping due to synonymous variant; Protein abundance and complex I assembly defects; Blue native PAGE and assembly intermediates QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- Bi-allelic NDUFA5 variants cause a mitochondrial complex I deficiency with multisystem disease- Two distinct variant classes observed: frameshift + missense in Family 1; start-loss + synonymous splice variant in Family 2; homozygous synonymous splice variant in Family 3- RNA-seq reveals aberrant splicing and nonsense-mediated decay for some alleles; exon 3 skipping yields a 39-amino-acid in-frame deletion- Proteomics shows ma...