ACOX2 was first reported in relation to autosomal recessive congenital bile acid synthesis defect 6 in 2016 (Vilarinho et al., PMID: 27647924). ACOX2 encodes a branched-chain acyl-CoA oxidase that acts on C27 intermediate bile acid species in the peroxisome that generates C24 primary bile acids. The clinical presentation may be variable, but all reported probands to date have had elevated serum C27 bile acid intermediates, consistent with loss of ACOX2 enzyme activity. Three variants (missense, nonsense, frameshift) that have been reported in six probands in three publications (PMID: 27647924, 27884763, 35395098) are included in this publication. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098). Based on the available genetic and experimental evidence, the association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive. This assertion has been upheld over time, and no contradictory evidence has yet emerged. This gene-disease pair was originally evaluated by the ClinGen Inborn Errors of Metabolism GCEP on December 10, 2021. It was reevaluated on July 12, 2024 (SOP 10). As a result of this reevaluation, the classification was increased from Moderate to Definitive with the addition of new cases and experimental evidence, including a new mouse model.
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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