The relationship between PEX11B and peroxisome biogenesis disorder (type 14B included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of January, 2020. PEX11B encodes an integral peroxisome membrane protein involved in peroxisome elongation and division. Peroxisomal biogenesis disorders are caused by defects in various stages of peroxisomal protein import and/or peroxisome biogenesis, involving at least 14 PEX genes. The PEX11 protein family comprises three isoforms, PEX11α, PEX11β and PEX11γ, encoded by PEX11A, PEX11B and PEX11G genes, respectively (Waterham and Ebberink 2012, PMID 22871920). While PEX11A and PEX11G have not been reported in relation to PBDs in humans, a few patients with mild PBD phenotype have been described with PEX11B mutations. A common feature observed in all affected individuals has been bilateral congenital cataracts.
PEX11B was first reported in relation to autosomal recessive Peroxisome biogenesis disorder in 2012. (Ebberink et al, 2012; PMID: 22581968). At least 5 nonsense or deletion variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Summary of Case Level Data (7 points): Variants in this gene have been reported in at least 5 probands in 3 publications (PMID: 22581968, 28129423, 31724321). The mechanism for disease is expected to be homozygous loss of function.
Summary of experimental data (4.5 points): This gene-disease association is supported by in vitro functional assays (PMIDs 22581968, 21669930, 24234511) and a mouse model (PMID: 12024045). PEX11B interacts with PEX19 (PMID: 12096124).
In summary, PEX11B 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 January 17, 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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