PIGA
protein-codingphosphatidylinositol glycan anchor biosynthesis class A, the group of Phosphatidylinositol glycan anchor biosynthesis|Glycosylphosphatidylinositol-N-acetylglucosaminyltransferase complex|Glycosyl transferases group 1 domain containing
Gene summary
This gene encodes a protein required for synthesis of N-acetylglucosaminyl phosphatidylinositol (GlcNAc-PI), the first intermediate in the biosynthetic pathway of GPI anchor. The GPI anchor is a glycolipid found on many blood cells and which serves to anchor proteins to the cell surface. Paroxysmal nocturnal hemoglobinuria, an acquired hematologic disorder, has been shown to result from mutations in this gene. Alternate splice variants have been characterized. A related pseudogene is located on chromosome 12. [provided by RefSeq, Jun 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~16.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010466
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0017385
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0100038
Submitter: ClinGen
PIGA was first reported in relation to X-linked complex neurodevelopmental disorder in 2012 (Johnston et al., PMID: 22305531). Pathogenic variants in PIGA result in a glycosyphosphatidylinositol (GPI) anchor protein defect, leading to a congenital disorder of glycosylation (CDG). The most common clinical presentation is infantile-onset developmental and epileptic encephalopathy with seizures that are refractory to treatment, myoclonus, hypotonia, severe to profound intellectual disability, characteristic facial features, and brain abnormalities (PMID: 32452540, 25885527). Liver, renal, and/or cardiac involvement, elevated alkaline phosphatase, ichthyosis or other skin manifestations, and systemic iron overload have been described in some patients, and early death can occur. Some individuals have a less severe clinical presentation consisting of mild to severe intellectual disability, developmental delay, and treatment-responsive seizures in the absence of involvement of other organs (PMID: 32452540, 25885527). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability to support splitting the curation into different diseases. Therefore, the following disease entities have been lumped into one disease entity: multiple congenital anomalies-hypotonia-seizures syndrome 2 (OMIM: 300868, ORPHA:300496), malignant migrating focal seizures of infancy (ORPHA:293181), infantile epileptic spasms syndrome (ORPHA:3451), ferro-cerebro-cutaneous syndrome (ORPHA:397922), and neurodevelopmental disorder with epilepsy and hemochromatosis (OMIM: 301072). This curation does not address the association of somatic variants in PIGA with paroxysmal nocturnal hemoglobinuria (OMIM: 300818). The ClinGen Epilepsy GCEP opted to curate this gene for complex neurodevelopmental disorder (MONDO:0100038) rather than congenital disorder of glycosylation (MONDO:0015286) to convey the specific phenotype of reported patients rather than curating for a more generic term (referring to a large group of disorders that can often only be diagnosed after the specific genetic etiology is known and are associated with a broad, nonspecific phenotypic spectrum.) This curation includes more than 25 missense, nonsense, and frameshift variants reported in over 40 probands from 22 publications (PMIDs: 22305531, 24706016, 24259184, 24357517, 24259288, 25326635, 25885527, 25473036, 26545172, 26545172, 26993267, 27126216, 26923721, 29656098, 29414593, 29502866, 29974678, 28133863, 32452540, 32694024, 34875027, 36324500). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is partial loss of function of an enzyme that is part of a complex that catalyzes the first step of GPI-anchor protein biosynthesis, and truncating variants are hypomorphic (PMID: 32452540). The gene-disease relationship is also supported by animal models (PMIDs: 37961693). In summary, there is definitive evidence supporting the relationship between PIGA and X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date April 16, 2024 (SOP Version 10). This gene-disease pair was originally evaluated by the ClinGen Epilepsy GCEP on April 25, 2019. In 2024, the GCEP added several new papers and patients. As a result of this reevaluation, the classification changed from moderate to definitive.
Inheritance Pattern: XL
Disease ID:MONDO:0010466
Submitter: Illumina
Inheritance Pattern: XL
Disease ID:MONDO:0010466
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: Unknown
Disease ID:MONDO:0100244
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0018346
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010466
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010466
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Dermatologic; Gastrointestinal; Genitourinary; Hematologic; Neurologic
Intervention: Cardiovascular; Gastrointestinal; Hematologic
Rationale: Multiple congenital anomalies-hypotonia-seizures syndrome 2 can involve congenital cardiac anomalies, and awareness may allow early management; Neurodevelopmental disorder with epilepsy and hemochromatosis can involve early-onset iron overload, and awareness may allow more precise management
Comments: The condition can involve multiple congenital anomalies
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PIGA variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002641.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 14 | 72 | 3 | 89 | ||
| missense | 8 | 28 | 223 | 29 | 5 | 293 |
| nonsense | 3 | 1 | 8 | 12 | ||
| start loss | 1 | 1 | ||||
| frameshift | 10 | 7 | 1 | 18 | ||
| splice donor/acceptor (+/-2bp) | 2 | 3 | 9 | 14 | ||
| Total | 23 | 40 | 255 | 101 | 8 | 427 |
Highest pathogenic variant AF is 0.0000024781734
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002632.1 | 5 | MANE Select | |
| Ensembl | ENSP00000369820.3 | 5 | MANE Select | |
| RefSeq | NP_001427718.1 | 6 | Standard | |
| RefSeq | NP_001427719.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Glycosylphosphatidylinositol (GPI)-anchor biosynthesis - Homo sapiens (human)
- Synthesis of glycosylphosphatidylinositol (GPI)
- Post-translational modification: synthesis of GPI-anchored proteins
- Post-translational protein modification
- Metabolism of proteins
Biological Process
- GPI anchor biosynthetic process
- positive regulation of metabolic process
- preassembly of GPI anchor in ER membrane
- cellular response to leukemia inhibitory factor
Molecular Function
- protein binding
- UDP-glycosyltransferase activity
- phosphatidylinositol N-acetylglucosaminyltransferase activity
Cellular Component
- glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex
- endoplasmic reticulum membrane
- membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000333590
- Coding exons
- 5
- Length
- 16104
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.17 | 105 | 189 | 0.556 | 0.0000143 | 3169 |
| Missense (PolyPhen) | 14 | 74.454 | 0.18804 | 1266 | ||
| Synonymous | 1.61 | 51 | 67.8 | 0.752 | 0.00000508 | 988 |
| Loss of Function | 2.95 | 0 | 10.1 | 0.00 | 7.74e-7 | 205 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Necessary for the synthesis of N-acetylglucosaminyl- phosphatidylinositol, the very early intermediate in GPI-anchor biosynthesis.;
- Disease
- DISEASE: Paroxysmal nocturnal hemoglobinuria 1 (PNH1) [MIM:300818]: A disorder characterized by hemolytic anemia with hemoglobinuria, thromboses in large vessels, and a deficiency in hematopoiesis. Red blood cell breakdown with release of hemoglobin into the urine is manifested most prominently by dark-colored urine in the morning. {ECO:0000269|PubMed:10087994, ECO:0000269|PubMed:12037021, ECO:0000269|PubMed:8167330, ECO:0000269|PubMed:8306954, ECO:0000269|PubMed:8500164}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) [MIM:300868]: An X-linked recessive developmental disorder characterized by dysmorphic features, neonatal hypotonia, myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Most affected individuals die in infancy. {ECO:0000269|PubMed:22305531, ECO:0000269|PubMed:24259184, ECO:0000269|PubMed:24259288, ECO:0000269|PubMed:24706016, ECO:0000269|PubMed:26993267}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.226
Intolerance Scores
- RVIS EVS
- 0.24
- RVIS percentile EVS
- 68.98
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.676
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |