NDUFS6

Inheritance Pattern: AR

Disease ID:MONDO:0032615

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0032615

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0032615

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0009640

Submitter: Illumina

The NDUFS6 gene is located on chromosome 5 at 5p15.33 and encodes the NADH:ubiquinone oxidoreductase subunit S6 protein. This protein is an accessory subunit of the first enzyme complex in the mitochondrial electron transport chain (complex 1) and aids the transfer of electrons from NADH to the respiratory chain. NDUFS6 was first reported in relation to autosomal recessive mitochondrial complex I deficiency in 2004 (15372108: Kirby et al. 2004). Evidence supporting this gene-disease relationship includes case-level and experimental data. At least five unique variants have been reported in affected individuals in three publications including one recurrent missense variant found in a homozygous state in two individuals of Ashkenazi Jewish origin (thought to be a common founder variant in this population), one splice donor site variant found in a homozygous state in one individual, one intragenic deletion found in a homozygous state in one individual and two frameshift variants found in a compound heterozygous state in one individual (15372108: Kirby et al. 2004; 19259137: Spiegel et al. 2009; 27290639: Pronicka et al. 2016). The mechanism of disease in unknown.This gene-disease relationship is supported by gene-trap knockdown mouse models showing reduced expression of Ndufs6 in cardiac and renal tissues showed the role of complex I in organ function, and the demonstration of reduced complex I activity and defects in mitochondrial function in non-patient cells (22474353: Ke et al. 2012; 23320803: Forbes et al. 2013; 25902503: Kmita et al. 2015). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.