The relationship between PEX6 and peroxisome biogenesis disorder (types 4A and 4B and Heimler syndrome included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of August, 2019. PEX6 encodes a cystolic AAA protein (ATPase associated with diverse cellular activities) and is required for stability of the cytoplasmic PTS1 receptor (Yahraus et al., 1996; PMID 8670792). Peroxisomal biogenesis disorders are caused by defects in various stages of peroxisomal protein import and/or peroxisome biogenesis. There are at least 14 PEX genes implicated in peroxisome biogenesis disorders, with PEX6 being the second most commonly affected gene in patients with a frequency of ~14.5% (Steinberg et al., 2003; PMID 20301621). Variants in PEX6 were first reported in humans with peroxisomal biogenesis disorder in 1996 (Yahraus et al., PMID 8670792). Data from 10 patients with 9 unique variants (missense, nonsense, frameshift, splicing) from 4 publications were curated (Krause et al., 2006, PMID 17041890; Levesque et al., 2012, PMID 22894767; Ratbi et al., 2015, PMID 26387595; Yahraus et al., 1996, PMID 8670792). Additional cases are available in the literature but the maximum score for genetic evidence (12 points) has been reached. The relationship between PEX6 and peroxisome biogenesis disorder is supported by experimental evidence including a biochemical function similar to other PEX genes implicated in peroxisome biogenesis disorders (Waterham et al., 2012, PMID 22871920), in vitro assays (Levesque et al., 2012, PMID 22894767), and a protein interaction with PEX1 (Matsumoto et al., 2003, PMID 12717447), which is encoded by a known peroxisome biogensies disorder gene. In summary, PEX6 is definitively associated with peroxisome biogenesis disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Peroxisomal Disorders Gene Curation Expert Panel on September 6, 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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