The relationship between GNPAT and glyceronephosphate O-acyltransferase deficiency (rhizomelic chondrodysplasia punctata type 2 [RCDP2] included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 16, 2019. GNPAT encodes glyceronephosphate O-acyltransferase (also known as dihydroxyacetone phosphate acyltransferase; DHAPAT, DAPAT), a peroxisomal enzyme involved in the synthesis of plasmalogens. Deficiency of plasmalogens is a feature of RCDP. Variants in GNPAT causing glyceronephosphate O-acyltransferase deficiency were first reported in 1998 (Ofman et al, PMID 9536089). Data from 13 patients with 12 unique variants (missense, nonsense, frameshift, splicing) from 4 publications were curated (Ofman et al, 1998, PMID 9536089; Ofman et al, 2001, PMID 11237722; Thai et al, 2001, PMID 11152660; Nimmo et al, 2010, PMID 20583171; Itzkovitz et al, 2012, PMID 21990100). Additional cases are available in the literature but the maximum score for genetic evidence (12 points) has been reached. The relationship between GNPAT and glyceronephosphate O-acyltransferase deficiency is supported by experimental evidence including the biochemical function of GNPAT which is consistent with the biochemical features of the disease (Hajra et al, 1995; PMID 8685243), that other genes with a role in plasmalogen synthesis (AGPS, and PEX7 which encodes the PTS2 receptor necessary for important of AGPS into the peroxisomes) are implicated in causing RCDP (Braverman et al, 1997, PMID 9090381; Itzkovitz et al, 2012, PMID 21990100), and a knock out mouse model which recapitulates the features of the condition (Rodemer et al, 2003, PMID 12874108; Teigler et al, 2009, PMID 19270340). In summary, GNPAT is definitively associated with glyceronephosphate O-acyltransferase deficiency. 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 February 7, 2020.
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