Submission Details

PIGF was first reported in relation to onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome (OORS), an autosomal recessive disorder in 2021 (Salian et al, PMID: 33386993). In this report, the same biallelic missense variant was identified by exome sequencing in two unrelated probands from the same geographical region of India (Salian et al, 2021, PMID: 33386993). The mechanism of pathogenicity appears to be loss of function, although data is limited. This gene-disease relationship is also supported by experimental evidence, including the biochemical function of PIGF. PIGF appears to stabilize two different enzymes, PIGG and PIGO, which are responsible for the transfer of phoshoethanolamine to mannose residues during the synthesis of glycosylphosphatidylinositol (GPI), and essential process for the cell surface localization of GPI-anchored proteins (Inoue et al, 1993, PMID: 8463218; Hong et al, 2000, PMID: 10781593; Shishioh et al, 2005, PMID: 15632136; Kinoshita et al, 2024, PMID: 39129667). GPI-anchored proteins have been shown to be lacking on the cell surface of fibroblasts from patients with OORS, and variants in other genes involved in the GPI synthesis pathway have been identified in patients with overlapping clinical symptoms (Salian et al, 2021, PMID: 33386993). In summary, there is currently limited evidence supporting the relationship between PIGF and the autosomal recessive disorder known as OORS. This classification was approved by the ClinGen Congenital Disorders of Glycosylation Gene Curation Expert Panel on November 7, 2024 (SOP Version 11).