GPAA1

Inheritance Pattern: AR

Disease ID:MONDO:0060627

Submitter: ClinGen

The *GPAA1* gene is located on chromosome 8 at 8q24.3 and encodes the glycosylphosphatidylinositol anchor attachment 1, a ubiquitously expressed protein which is a component of the glycosylphosphatidylinositol (GPI) transamidase complex that mediates coupling of the synthesized GPI anchor to mature proteins on the cell surface. GPI anchor proteins are structurally a diverse group of membrane bound glycoproteins that play an important role in cellular processes such as embryogenesis, fertilization, and neurogenesis. The *GPAA1* gene was first reported in relation to autosomal recessive glycosylphosphatidylinositol biosynthesis defect 15 in 2017 (Nguyen et al., 2017; PMID 29100095) and is characterized by delayed psychomotor development, variable intellectual disability, hypotonia, early-onset seizures in most patients, and cerebellar atrophy resulting in gait ataxia and dysarthria. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. At least 17 unique variants have been reported in either a compound heterozygous or homozygous state in nine probands from three publications (Nyugen et al., 2017, PMID: 29100095; Castle et al., 2021 PMID: 34703884; and Fontana et al., 2023, PMID: 37510348). These included eleven missense variants, five frameshift variants, and one intronic variant predicted to affect splicing. Variants in this gene segregate with disease in five families. More genetic evidence has been reported in the literature but was not scorable according to the current guidelines. This gene-disease relationship is supported by relevant experimental evidence including biochemical function, protein interaction, and functional alteration in patient cells. A number of genes involved in the biosynthesis of the GPI anchor have been associated with GPI biosynthesis deficiencies, characterized by a clinical spectrum of disease which includes global developmental delay, intellectual disability, and seizures (PMID 29100095). Specifically, four components of the GPI transamidase complex; PIGT, PIGS, PIGK, and PIGU have been shown to interact with each other and have all been associated with autosomal recessive glycosylphosphatidylinositol biosynthesis deficiencies (Ohishi K et al., 2001 PMID 11483512; Bellai-Dussault et al., 2018 PMID 30054924; Hong Y et al., 2003 PMID 12802054). Patient cells demonstrate GPI-AP deficiency and altered expression of cell surface markers on the cell surface of skin fibroblasts (PMID 29100095). In summary, there is definitive evidence supporting the relationship between *GPAA1* and autosomal recessive glycosylphosphatidylinositol biosynthesis defect 15. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the Syndromic Disorders GCEP on 12/07/2022. It was reevaluated on 3/11/2026. As a result of this re-evaluation the classification increased from strong to definitive with the addition of genetic evidence (Fontana et al., 2023, PMID: 37510348), satisfying the number of genetic evidence publications and three-year time period required for a definitive classification.

Inheritance Pattern: AR

Disease ID:MONDO:0060627

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0060627

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0060627

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0060627

Submitter: G2P