The relationship between NDUFS1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 6, 2023. The NDUFS1 gene encodes the mitochondrial NADH-ubiquinone oxidoreductase 75 kDa subunit, a core subunit of mitochondrial complex I. Defects of this protein lead to complex I deficiency.
NDUFS1 was first reported in relation to primary mitochondrial disease in 2001 (PMID: 11349233), in three probands with Leigh syndrome spectrum (LSS). While various names have been given to the constellation of features seen in those with NDUFS1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFS1 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, NDUFS1 was previously curated by this GCEP on June 10, 2019 (SOP Version 6) as having a definitive association with autosomal recessive LSS. The scope of this current curation encompassed cases of primary mitochondrial disease, which includes LSS.
Evidence supporting the relationship between NDUFS1 and autosomal recessive primary mitochondrial disease includes case-level data and experimental data. This curation includes 18 variants identified in 13 unrelated probands from six publications (PMIDs: 11349233, 24952175, 25615419, 21458341, 22200994, 20382551). Variant types included missense, stop-gained, frameshift, and an in-frame deletion. Affected individuals present with complex I deficiency and variable other features with a typically progressive disease course. Age of onset is typically in infancy. Clinical features may include developmental delay and regression, movement disorder, seizures, leukodystrophy, atrophy and cystic lesions in the brain, hypotonia, optic atrophy, failure to thrive, and elevated serum and cerebrospinal fluid lactate. The mechanism of disease involves loss of function.
This gene-disease association is also supported by a biochemical function in mitochondrial complex I shared by more than 10 other genes also associated with primary mitochondrial disease as well as evidence of disrupted mitochondrial function in patient cells that could be rescued by expression of the wildtype protein (PMIDs: 21458341, 20382551, 33340416).
In summary, there is definitive evidence to support the relationship between NDUFS1 and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 6, 2023 (SOP Version 10).
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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