The relationship between NDUFS8 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 6, 2023. The NDUFS8 gene encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit S8. Defects of this protein lead to complex I deficiency.
NDUFS8 was first reported in relation to primary mitochondrial disease in 1998 (PMID: 9837812). While various names have been given to the constellation of features seen in those with NDUFS8-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFS8 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, NDUFS8 was previously curated by this GCEP on November 20, 2019 (SOP Version 7) as having a moderate association with autosomal recessive Leigh syndrome spectrum (LSS). The scope of this current curation encompassed cases of primary mitochondrial disease, which includes cases with LSS.
Evidence supporting the relationship between NDUFS8 and autosomal recessive primary mitochondrial disease includes case-level data and experimental data. This curation includes 10 variants identified in 10 unrelated probands from eight publications (PMIDs: 9837812, 15159508, 20818383, 22499348, 23430795, 19336460, 20819849, 36101822). All reported variants were missense. Affected individuals present with complex I deficiency and variable other features with a typically progressive disease course. Age of onset is typically in infancy or childhood. Clinical features may include LSS, lactic acidosis, developmental delay and regression, dystonia, seizures, hypertrophic cardiomyopathy, respiratory insufficiency, episodic apnea, progressive external ophthalmoplegia, and poor feeding.
The mechanism of disease is 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 model systems (PMIDs: 33340416, 29285794, 19672299).
In summary, there is definitive evidence to support the relationship between NDUFS8 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 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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