The relationship between ACOX1 and peroxisomal acyl-CoA oxidase deficiency, inherited in the autosomal recessive manner, was evaluated using the ClinGen clinical validity framework as of December 2019 and re-evaluated in October 2022. ACOX1 was first reported in relation to autosomal recessive peroxisomal acyl-CoA oxidase deficiency in 1994 (Fournier et al., PMID: 8040306). Numerous variants have been reported in humans per ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case-level and experimental data: 17.5 points. Variants (nonsense, missense, and frameshift) in this gene have been reported in at least 11 probands in 6 publications (PMID:18536048, PMID: 17458872, PMID: 8040306, PMID: 26965209, PMID: 11815777, PMID: 33234382). The mechanism for disease is expected to be loss of function. This gene-disease association is supported by expression studies, in vitro functional assays, and animal models. In summary, ACOX1 is definitively associated with autosomal recessive peroxisomal acyl-CoA oxidase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Lumping and Splitting Considerations: OMIM entities: Mitchell syndrome (MIM# 618960), Peroxisomal acyl-CoA oxidase deficiency (MIM# 264470). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanisms, inheritance patterns AND phenotypic presentation. Therefore, we have split curations for the disease entities, ACOX1 deficiency and ACOX1 dysregulation.
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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