COQ9

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *COQ9* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 29, 2024. The *COQ9* gene encodes coenzyme Q9, which is involved in mitochondrial ubiquinone (coenzyme Q10, CoQ10) biosynthesis. Coenzyme Q10 is critical for many processes in the cell, including in the mitochondrial respiratory chain transferring electrons from complexes I and II to complex III. The *COQ9* gene was first reported in relation to autosomal recessive CoQ10 deficiency in 2009 (PMID: 19375058). CoQ10 deficiency is a multisystem primary mitochondrial disease characterized by heterogeneous clinical manifestations that include encephalopathy, seizures, movement disorder, hypotonia, nephrotic syndrome, hypertrophic cardiomyopathy, muscle weakness, and exercise intolerance. Retinopathy and sensorineural hearing loss may also be present but are not invariable findings. Laboratory findings include reduced CoQ10 biosynthesis, reduced activity of mitochondrial complex I+II and I+III and II+III, and increased serum lactate and alanine. Neuroimaging may show findings consistent with Leigh syndrome spectrum (LSS) and/or mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). While various names have been given to the constellation of features seen in those with COQ9-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *COQ9* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *COQ9* was previously curated by this panel for its association with LSS on April 9, 2021 (SOP v7), with a final classification of limited. This current curation for the association with primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three unique variants: one splice variant, one stop-gained variant, and one frameshift variant, which were reported in four unrelated individuals in four publications (PMIDs: 19375058, 26081641, 29560582, 31821167). The mechanism of disease is loss of function. The maximum for genetic evidence has been reached. This gene-disease relationship is also supported by a biochemical function in CoQ10 biosynthesis/mitochondrial cofactor biosynthesis shared with at least 10 other genes associated with primary mitochondrial disease; evidence of mitochondrial dysfunction plus rescue in patient cells; and knock-in mouse models which recapitulate neuropathological, biochemical, and neurological findings similar to human patients (PMIDs: 19375058, 20495179, 26081641, 23255162, 25802402). The maximum for experimental evidence has also been reached. In summary, there is definitive evidence to support the relationship between *COQ9* and autosomal recessive 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 29, 2024, (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0013840

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013840

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between COQ9 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of September 21, 2020. The COQ9 gene encodes an enzyme critical for the synthesis of coenzyme Q10. Coenzyme Q10 is critical for many processes in the cell, including in the mitochondrial respiratory chain transferring electrons from complexes I and II to complex III. The COQ9 gene has been reported only once in relation to autosomal recessive Leigh syndrome spectrum, in 2018 (PMID: 29560582). There was another case reported with brain ultrasound findings reported by the authors to be consistent with Leigh syndrome spectrum; however this expert panel considered that there are too many confounding factors in ultrasonography to confirm the presence of brain lesions consistent with Leigh syndrome spectrum. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two variants identified in one case in one publication (PMID: 29560582). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, expression, functional alteration in patient cells, and animal models (PMIDs: 19375058, 25613900, 20495179, 25802402, 23255162). In summary, there is limited evidence to support this gene-disease relationship. Although the total score (8) falls in the moderate range, only one case with Leigh syndrome spectrum has been reported, therefore this gene-disease association can only reach a limited classification at this time. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 21, 2020 (SOP Version 7).