The relationship between NDUFV2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 4, 2023. The NDUFV2 gene encodes the NADH:ubiquinone oxidoreductase (complex I) flavoprotein 2, a core subunit of mitochondrial complex I. Defects of this protein lead to complex I deficiency.
NDUFV2 was first reported in relation to autosomal recessive primary mitochondrial disease in 2003 (PMID: 12754703), in a proband with hypertrophic cardiomyopathy, encephalopathy, feeding difficulty, and growth failure who died at three months of age. While various names could be given to the constellation of features seen in those with NDUFV2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFV2 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, NDUFV2 was previously curated by this GCEP on November 20, 2019 (SOP Version 7) 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 NDUFV2 and primary mitochondrial disease includes case-level data and experimental data. This curation includes nine unique variants in ten probands from nine publications (PMIDs: 12754703, 19167255, 26008862, 33811136, 34405929, 28429146, 30369941, 34276053, 30831263). Variant types included five missense, one frameshift, one stop-gain, one intragenic deletion and one recurrent splice region variant (NM_021074.5:c.120+5_120+8del). Affected individuals present with a broad phenotypic spectrum of generally severe disease which includes LSS. Clinical features include developmental regression, seizures, progressive spasticity, microcephaly, hypotonia, hypertrophic cardiomyopathy, optic atrophy, feeding difficulty, and failure to thrive. The age of onset ranges from birth to early infancy. Loss of function is implicated as the mechanism of disease.
This gene-disease association is also supported by known biochemical function and a C. elegans model system (PMIDs: 33340416. 19672299).
In summary, there is Definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 4, 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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