The relationship between NDUFS2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 18, 2024. NDUFS2 encodes NADH:ubiquinone oxidoreductase (complex I) iron-sulfur (Fe-S) protein 2, a core subunit of complex I. Defects of this protein lead to complex I deficiency.
NDUFS2 was first reported in relation to autosomal recessive primary mitochondrial disease in 2001 (PMID: 11220739). While various names have been given to the constellation of features seen in those with NDUFS2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFS2 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, NDUFS2 was previously curated by this GCEP on April 9, 2021 (SOP Version 7) as having a Definitive 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 this gene-disease relationship includes case-level data and experimental data. This curation included 12 variants (11 unique missense variants and a frameshift variant expected to result in protein truncation) in eight probands from fives publications (PMIDs: 11220739, 20819849, 22036843, 28031252, 31411514). Clinical features in affected individuals include Leigh syndrome spectrum, optic atrophy, lactic acidosis, cardiomyopathy, and hepatic involvement, and there is at least one reported case with clinical features consistent with Leber Hereditary Optic Neuropathy (PMIDs: 20819849, 22036843, 28031252, 31411514).
The mechanism of disease is loss of function. This gene-disease association is also supported by its known biochemical functional, functional alternation in HEK293 cells with NDUFS2 knockout, as well as model systems in C.elegans and mice (PMIDs: 27509854, 33744462, 18178500, 34732887, 31297047, 112788282).
In summary, there is definitive evidence to support the relationship between NDUFS2 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 January 18, 2024 (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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