The relationship between PEX16 and peroxisome biogenesis disorder (types 8A and 8B included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 19, 2019. PEX16 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 D and mutations in the gene result in cells devoid of peroxisomal remnants (Waterham and Ebberink 2012, PMID 22871920) or with a small number of enlarged peroxisomes (Ebberink et al, 2010, PMID 20647552).
PEX16 was first reported in relation to autosomal recessive Peroxisome biogenesis disorder in 1998. (Honsho et al, PMID: 9837814). At least 10 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 (12 points):
Variants in this gene have been reported in at least 11 probands in 9 publications (PMID: 20681997, 30078639, 26644994, 30094183, 20647552, 24091540, 11890679, 9837814, 21031596).
The mechanism for disease is expected to be homozygous loss of function.
Summary of experimental data (3.5 points): This gene-disease association is supported by in vitro functional assays and a fly model (PMIDs 12096124, 25002403, 21826223). PEX16 interacts with PEX19 and may have a role in the trafficking of PEX3.
In summary, PEX16 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 January 13, 2020.
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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