The relationship between NDUFS6 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 31, 2022. The NDUFS6 gene encodes an accessory subunit of complex I of the mitochondrial respiratory chain.
The NDUFS6 gene was first reported in relation to autosomal recessive mitochondrial disease in 2004 (PMID: 15372108). While various names have been given to the constellation of features seen in those with NDUFS6-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFS6 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three unique homozygous loss of function variants, one homozygous missense variant present in two cases, and one compound heterozygous pair of a loss of function and a missense variant identified in six cases from four publications (PMIDs:15372108, 19259137, 22200994, 30948790). These individuals had profound hypotonia and lethargy shortly after birth, abnormal drifting eye movements, rotatory nystagmus, seizures, absent Moro and grasp reflexes, variable (diminished to brisk) tendon reflexes, lactic acidemia, and hypoventilation leading to infantile death. The Mitochondrial Disease Gene Curation Expert Panel reviewed scoring homozygous variants in cases with consanguinity and decided that no scoring alteration was needed in these three cases given (1) comprehensive analyses (exome sequencing) were performed, (2) homozygous variants are a common cause of mitochondrial disease, and (3) biochemical evidence in these cases supported a complex I defect. Segregation data are available but did not meet criteria to be considered for scoring per ClinGen Gene Curation SOP V8. This gene-disease association is also supported by the known biochemical function and animal models (PMIDs: 27509854, 22474353, 25902503, 19672299).
In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 31, 2022 (SOP Version 8).
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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