Submission Details

The relationship between AGPS and alkylglycerone-phosphate synthase deficiency (rhizomelic chondrodysplasia punctata 3 [RCDP3] included), an autosomal recessive peroxisomal disorder, was evaluated using the ClinGen Clinical Validity Framework as of September 20, 2019 and updated by April 2022. AGPS encodes alkylglycerone-phosphate synthase (also known as alkyldihroxyacetonephosphate synthase, ADHAPS, alkyl-DHAP synthase), a peroxisomal enzyme catalyzing the second (last) step of plasmalogen synthesis.

Deficiency of plasmalogens is a feature of RCDP. Variants in AGPS causing AGPS deficiency were first reported in 1998 (de Vet et al, PMID 9553082). Data from 8 patients with 9 unique variants (all missense except for one frameshift and one nonsense resulting from deletions) from six publications were curated (de Vet et al, 1998, PMID 9553082; de Vet et al, 1999, PMID 10553003; Thai et al, 2001, PMID 11152660; Itzkovitz et al, 2012, PMID 21990100; Noguchi et al, 2014, PMID 24849933, Shawi et al, 2021, PMID: 35070570). A total of 7.5 points were awarded for genetic evidence (note that this includes 2 points for a case for which the causative variant is unknown, and therefore the case could not be included in the summary matrix, but which appeared to be homozygous for a 128bp deletion in AGPS cDNA; PMID 10553003).

The relationship between AGPS and AGPS deficiency is supported by experimental evidence including the biochemical function of AGPS which is consistent with the low levels of plasmalogens observed in individuals with AGPS deficiency (Brown et al, 1982, PMID 7096336; Nagan et al, 1997, PMID 9114014); the physical interaction of alkylglycerone-phosphate synthase with glyceronephosphate O-acyltransferase (encoded by GNPAT) which catalyzes the first step of plasmalogen synthesis (Biermann et al, 1999, PMID 102158610); the finding that the activity and level glyceronephosphate O-acyltransferase is dependent on the physical presence of alkylglycerone-phosphate synthase (de Vet et al, 1999, PMID 10553003; Itzkovitz et al, PMID 21990100); the knowledge that other genes with a role in plasmalogen synthesis (GNPAT, and PEX7 which encodes the PTS2 receptor necessary for important of AGPS into the peroxisomes) are implicated in causing RCDP (Hajra et al, 1995, PMID 8685243; Braverman et al, 1997, PMID 9090381; Braverman et al, 2012, PMID 20301447); the finding of reduced levels of AGPS cDNA and protein in patients with AGPS deficiency (Noguchi et al, 2014, PMID 24849933); and the features of a natural and two knock-out mouse models (Liegel et al, 2011, PMID 21353609; Liegel et al, 2014, PMID 25197626). More evidence may be available but the maximum points for experimental evidence (6 points) have been reached.

In summary, AGPS is definitively associated with autosomal recessive AGPS deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.