Submission Details

The relationship between PEX14 and peroxisome biogenesis disorder, an autosomal recesiive disorder, was evaluated using the ClinGen Clinical Validity Framework as of August, 2019. PEX14 encodes a membrane-bound peroxisomal protein that interacts with PEX13 to form the peroxisomal docking site for the PTS1 receptor PEX5 (reviewed in Waterham and Ebberink, 2016; PMID: 22871920). 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 PEX14 being one of the least commonly affected genes in patients (Steinberg et al., 2003; PMID: 20301621). Variants in PEX14 were first reported in humans with peroxisomal biogenesis disorder in 2004 (Shimozawa et al., PMID: 15146459). There are four patients reported in the literature with four unique variants (nonsense, deletion, and missense) (Shimozawa et al., 2004; PMID: 15146459; Huybrechts et al., 2009; PMID: 21686775; Komatsuzaki et al., 2015; PMID: 26627464; Galvez-Ruiz et al., 2018; PMID: 30224891). The relationship between PEX14 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 (Albertini et al., 1997; PMID: 9094717; Shimozawa et al., 2004; PMID: 15146459) and a protein interaction with PEX5 and PEX13 (Albertini et al., 1997; PMID: 9094717), which have also been implicated in the disorder. In summary, PEX14 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 20, 2019.