The relationship between PEX3 and peroxisome biogenesis disorder (types 10A and 10B included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 19, 2019. PEX3 encodes a peroxisome membrane protein involved in early peroxisome membrane biosynthesis prior to matrix protein import. Peroxisomal biogenesis disorders are caused by defects in various stages of peroxisomal protein import and/or peroxisome biogenesis, involving at least 14 PEX genes. PEX3 belongs to complementation group G and mutations in the gene result in cells devoid of peroxisomal remnants (Waterham and Ebberink 2012, PMID 22871920). PEX3 was FIRST reported in relation to autosomal recessive Peroxisome biogenesis disorder in 2000. (Muntau et al, PMID: 10958759; Shimozawa et al, PMID: 10942428; Ghaedi et al, PMID: 10968777). At least 8 nonsense, splice site, frameshift and missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 8 probands in 8 publications (PMIDs 10958759, 27557811, 28673549, 23245813, 10968777, 10942428, 20033294, 21031596). Variants in this gene segregated with disease in 1 additional family member.
The mechanism for disease is expected to be homozygous loss of function.
Summary of experimental data (4.5 points): This gene-disease association is supported by in vitro functional assays and animal models (PMIDs 10958759, 21826223, 12096124).
In summary, PEX3 is definitively associated with autosomal recessive Peroxisome biogenesis disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Peroxisomal Disorders GCEP on Nov 1, 2019 (SOP Version 7).
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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