The relationship between PEX13 and peroxisome biogenesis disorder (types 11A and 11B included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of August, 2019. PEX13 encodes a peroxisome membrane protein involved in PTS1 and PTS2 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. PEX13 belongs to complementation group H or group 13, and mutations in the gene result in cells devoid of peroxisomes (Waterham and Ebberink 2012, PMID 22871920).
PEX13 was first reported in relation to autosomal recessive Peroxisome biogenesis disorder in 1999. (Shimozawa et al, 1999; PMID: 10332040, Liu et al, 1999; PMID: 10441568). At least 9 nonsense, splice site, frameshift, deletion/duplication 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 (11 points):
Variants in this gene have been reported in at least 9 probands in 5 publications (PMIDs: 10332040, 21031596, 17041890, 10441568, 19449432).
The mechanism for disease is expected to be homozygous loss of function.
Summary of experimental data (5 points): This gene-disease association is supported by in vitro functional assays and animal models. PEX13 interacts with PEX19 and PEX14 (PMID: 12096124, 15798189). Mouse models of PEX13 recapitulate the human disease (PMIDs: 12897163, 29187321) and functional experiments show impaired PTS1 and PTS2 import in PEX13-deficient cells (PMIDs: 21669930, 8858165).
In summary, PEX13 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 Peroxisomal Disorders GCEP on October 4, 2019.
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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