The relationship between NDUFB10 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 7, 2022. The NDUFB10 gene encodes NADH:ubiquinone oxidoreductase (complex I) subunit B10, which is essential for complex I activity and assembly. Defects of this protein lead to complex I deficiency.
The NDUFB10 gene was first reported in relation to autosomal recessive mitochondrial disease in 2017 (PMID: 28040730). While various names have been given to the constellation of features seen in those with NDUFB10-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFB10 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three variants identified in two cases in two publications (PMIDs: 28040730, 33169436). Features seen in these cases include severe infantile lactic acidosis, cardiomyopathy, intrauterine growth restriction, and poor growth after birth, liver involvement, and sensorineural hearing loss. Both affected infants died before 12 months of age. No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, functional alteration in patient cells, functional alteration in non-patient cells, and animal models (PMIDs: 19672299, 27626371, 28040730, 32025618, 27509854).
In summary, there is moderate evidence to support this gene-disease relationship. 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 February 7, 2022 (SOP Version 8).
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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