The relationship between NDUFS7 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 15, 2024. The NDUFS7 gene encodes encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit S7. Defects of this protein lead to complex I deficiency.
NDUFS7 was first reported in relation to autosomal recessive primary mitochondrial disease in 1999 (Triepels et al 2001; PMID: 10360771). While various names have been given to the constellation of features seen in those with NDUFS7-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFS7 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, NDUFS7 was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on August 21, 2019 (SOP V6), with a final classification of Moderate. This current curation for the association with primary mitochondrial disease includes the four cases included in the LSS curation.
Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three variants (two missense and one deep intronic variant resulting in generation of a cryptic exon and protein truncation) in six probands from five publications (PMIDs: 10360771, 17604671, 17275378, 22644603, 30369941). Clinical features in affected individuals include LSS, developmental delay, developmental regression, ataxia, seizures, hemiplegia, ophthalmoplegia, and lactic acidosis. Ragged red fibers were seen on muscle biopsy and complex I deficiency was noted in muscle and skin fibroblasts.
The mechanism of disease is loss of function This gene-disease association is also supported by the known biochemical function of NDUFS7 as a subunit of complex I, functional alternation in patient fibroblast cells, and several model systems (fruit fly, fungi, canine, embryonic lethal mouse model; PMIDs: 27509854, 30429455, 30972103, 12049648, 15956670, 27626380, 38316835).
In summary, there is definitive evidence to support the relationship between NDUFS7 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 April 15, 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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