The relationship between PXDN and anterior segment dysgenesis 7 (ASD7), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of June 15, 2023. PXDN encodes a heme-containing peroxidase that is secreted into the extracellular matrix (ECM). It catalyzes the formation of the sulfilimine bond between methionine and hydroxylysine in Collagen IV, which may be necessary to reinforce the mechanical strength of ECM and maintain tissue integrity (PMID: 31817535). ASD7 is also associated with partial or total corneal opacification, microcornea, microphthalmia, cataract in humans.
PXDN was first reported in relation to autosomal recessive ASD7 in 2011 (Khan et al, 2011, PMID: 21907015). At least 15 nonsense, frameshift, 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 9 probands in 4 publications (PMID: 32499604, 35595447, 32015378, 21907015). Variants in this gene segregated with disease in 8 additional family members. The mechanism for disease is biallelic loss of function.
Summary of experimental data (3 points): This gene-disease association is supported by animal models. PXDN is expressed in the corneal epithelial layer, lens epithelium in the adult mouse eye (PMID: 21907015). Two homozygous knock out mouse models of Pxdn recapitulate the human phenotype. An ENU-induced knock-out of Pxdn due to a nonsense variant in exon 17 leads to anterior segment dysgenesis in mice (PMID: 24895407). CRISPR-mediated knock-out of Pxdn in mice leads to severe defects in eye morphology including absence of lenses, eyelids and disorganized retinal structures (PMID: 31817535).
In summary, PXDN is definitively associated with autosomal recessive ASD7. 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 Glaucoma and Neuro-Ophthalmology GCEP on June 15th, 2023.
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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