Submission Details

PIGL is involved in the biosynthesis of glycosylphosphatidylinositol (GPI), which is required to anchor proteins to the cell membrane. Variants in PIGL have been reported in patients with autosomal recessive syndromic intellectual disability, including CHIME syndrome (colobomas, heart defects, ichthyosiform dermatosis, intellectual disability, and ear abnormalities) and Mabry syndrome (hyperphosphatasia intellectual disability syndrome). PIGL was first reported in relation to CHIME syndrome in 2012 (Ng et al., PMID: 22444671). Five unrelated probands with CHIME syndrome had compound heterozygous variants in PIGL; they all shared the same p.Leu167Pro missense variant and had different null variants in the second allele . Variants in this gene have been reported in at least 12 probands in 8 publications (PMIDs: 22444671, 25706356, 28327575, 28371479, 29444765, 29473937, 30023290, 35258128), including 11 missense (p.Leu167Pro recurrent 8 times), 3 frameshift, 3 nonsense, 2 splice-site, and 3 partial or whole gene deletions . Affected individuals had CHIME syndrome, Mabry syndrome, overlapping features of both syndromes, or intellectual disability with dysmorphic features and seizures. Of note, all individuals with CHIME syndrome reported thus far carried the recurrent p.Leu167Pro variant. This gene-disease relationship is also supported by protein interaction with MEIS2 (PMID: 26186194), biochemical function (PMID: 10085243) and functional alteration in patient cells (PMID: 22444671). In summary, there is definitive evidence supporting the relationship between PIGL and autosomal recessive syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 7, 2022 (SOP Version 9).