The relationship between PEX7 and peroxisome biogenesis disorder (type 9B and type 1 Rhizomelic chondrodysplasia punctata included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of January, 2020. PEX7 encodes a receptor for some of the peroxisomal matrix proteins and is involved in the PTS2 import pathway. Peroxisomal biogenesis disorders are caused by defects in various stages of peroxisomal protein import and/or peroxisome biogenesis, involving at least 14 PEX genes. PEX7 belongs to complementation group 11, and mutations in the gene result in peroxisomes devoid of PTS2 import (Braverman et al, 2012, Gene Reviews).
PEX7 was first reported in relation to autosomal recessive Peroxisome biogenesis disorder in 1997. (Braverman et al, PMID: 9090381; Motley et al, PMID: 9090382; Purdue et al, PMID: 9090383). At least 38 nonsense, splice site, frameshift, deletion/duplication and missense variants have been reported in humans in the ClinVar database. 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 6 publications (PMID: 9090381, 12325024, 26587300, 28742517, 10083738, 25800479). More evidence is available in the literature, but the maximum score (12 points) for genetic evidence is reached. The recurring founder variant, Leu292Ter is most frequently reported and accounts for 51% of disease alleles.
The mechanism for disease is expected to be biallelic loss of function.
Summary of experimental data (5 points): This gene-disease association is supported by in vitro functional assays and animal models. PEX7 interacts with PEX5, which is involved in the PTS1 import pathway but also acts as a coreceptor for the PEX7-cargo protein complex in the PTS2 pathway (PMID: 26450166, 25538232). Mouse models of PEX7 recapitulate the human disease (PMIDs: 12915479, 20060764) and wild-type PEX7 restores peroxisome import in patient-derived PEX7-deficient cells (PMIDs: 9090381).
In summary, PEX7 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 February 14, 2020 (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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