The relationship between NDUFA10 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 6, 2023. NDUFA10 encodes NADH:ubiquinone oxidoreductase (complex I) subunit A10, a non-catalytic complex I accessory protein required for complex I assembly and function within the mitochondria. Defects of this protein lead to complex I deficiency.
NDUFA10 was first reported in relation to primary mitochondrial disease in 2011 (PMID: 21150889), in a boy with a confirmed neuropathological diagnosis of Leigh syndrome. While various names could be given to the constellation of features seen in those with NDUFA10-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFA10 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, NDUFA10 was previously curated by this GCEP on June 10, 2019 (SOP V6) as having a Limited association with Leigh Syndrome Spectrum (LSS). The scope of this current curation encompassed cases of primary mitochondrial disease, which includes LSS.
Evidence supporting the gene-disease relationship between NDUFA10 and primary mitochondrial disease includes case-level data and experimental data. This curation includes nine variants (five missense, two deletions, one insertion, one frameshift) in seven probands from seven publications (PMIDs: 21150889; 22200994; 28247337; 26741492; 36270260; 35379322; 35094435). Affected individuals present with a broad phenotypic spectrum of disease which includes LSS. The age of onset ranges from birth to early childhood. Additional features seen include developmental delay, ataxia, spastic tetraparesis, seizures, hypertrophic cardiomyopathy, pulmonary hypertension, and feeding difficulty. Elevated blood and cerebrospinal fluid lactates are seen. Muscle biopsies showed a complex I deficiency. Loss of function is implicated as the mechanism of disease.
This gene-disease association is also supported by known biochemical function and functional alteration in patient fibroblasts and in a C. elegans model system (PMIDs: 27509854; 27626371, 21150889, 19672299).
In summary, there is moderate evidence to support the relationship between NDUFA10 and primary mitochondrial disease. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 6, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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