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PIGW
phosphatidylinositol glycan anchor biosynthesis class W
PIGW encodes an enzyme required for building the glycosylphosphatidylinositol anchor, a molecular tag that attaches proteins to cell membranes. The PIGW gene provides instructions for producing an enzyme involved in constructing glycosylphosphatidylinositol (GPI) anchors.
PIGW is located on the long (q) arm of chromosome 17, at band 17q12. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 17 in the library →Overview
PIGW is located on chromosome 17 and encodes phosphatidylinositol glycan anchor biosynthesis class W, an enzyme that participates in the assembly of glycosylphosphatidylinositol (GPI) anchors. GPI anchors are complex glycolipid structures that tether more than 150 different proteins to the cell surface, enabling crucial functions in cell signalling, immune recognition, and nervous system development.
Disruption of PIGW function affects the proper localisation of GPI-anchored proteins, which can impair cellular communication and membrane organisation. Biallelic pathogenic variants in this gene are associated with congenital disorders of glycosylation, a group of inherited metabolic conditions characterised by abnormal protein glycosylation. Affected individuals typically present with developmental delay, epilepsy, and distinctive facial features.
What the gene does
The PIGW protein functions as an acyltransferase within the endoplasmic reticulum, where it catalyses the addition of acyl chains to the inositol ring of phosphatidylinositol during the early steps of GPI anchor biosynthesis. This modification is essential for stabilising the developing anchor structure and ensuring efficient transfer of the mature GPI moiety to target proteins.
GPI anchor assembly requires the coordinated action of more than 25 enzymes working sequentially in the endoplasmic reticulum membrane. PIGW acts early in this pathway, contributing to the formation of the lipid backbone that will eventually link proteins to the cell surface. Without functional PIGW, cells produce incomplete or unstable GPI precursors, resulting in reduced surface expression of GPI-anchored proteins.
Many GPI-anchored proteins play critical roles in the developing and mature nervous system, including cell adhesion molecules, enzymes involved in neurotransmitter metabolism, and receptors that regulate neuronal migration. Deficiency of these proteins due to PIGW dysfunction particularly affects brain development and neuronal function.
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Chromosome location
PIGW is located on the long arm of chromosome 17 at position 17q12. This chromosomal region contains several genes involved in metabolic and developmental processes. The gene spans multiple exons encoding a 504-amino-acid protein. No large-scale structural variations affecting this locus have been commonly reported in the general population.
Protein structure
While detailed experimental structure determination has not been completed, the PIGW protein is predicted to contain multiple transmembrane segments that anchor it within the endoplasmic reticulum membrane, positioning the catalytic regions appropriately for substrate access during GPI anchor assembly. The 504-amino-acid sequence includes conserved motifs typical of acyltransferase enzymes, though the precise boundaries of functional domains remain under investigation.
Key variants
Pathogenic variants in PIGW follow an autosomal recessive inheritance pattern, meaning affected individuals typically carry variants on both gene copies inherited from carrier parents. In autosomal recessive inheritance, both parents are usually unaffected carriers who each have one typical copy and one variant copy of the gene. Each pregnancy between two carrier parents has a 25% (1 in 4) chance of being affected, a 50% (1 in 2) chance of being an unaffected carrier, and a 25% (1 in 4) chance of inheriting two typical copies.
Most reported pathogenic variants are missense changes that alter single amino acids within the protein sequence, disrupting enzyme activity or stability. Loss-of-function variants that completely abolish protein production have also been described. The severity of clinical features may vary depending on the residual enzymatic activity retained by specific variant combinations.
Sample of pathogenic variants
6 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.460A>G | p.Arg154Gly | Pathogenic | ★☆☆☆ | Hyperphosphatasia with intellectual disability syndrome 5 |
c.178G>A | p.Asp60Asn | Pathogenic | - | Hyperphosphatasia with intellectual disability syndrome 5 |
c.211A>C | p.Thr71Pro | Pathogenic | - | Hyperphosphatasia with intellectual disability syndrome 5 |
c.462A>T | p.Arg154Ser | Pathogenic | - | Hyperphosphatasia with intellectual disability syndrome 5 |
c.77T>C | p.Leu26Ser | Pathogenic | - | Hyperphosphatasia with intellectual disability syndrome 5 |
c.1321_1324del | p.Ile441fs | Likely pathogenic | ★☆☆☆ | Hyperphosphatasia with intellectual disability syndrome 5 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in PIGW cause a congenital disorder of glycosylation characterised by global developmental delay, early-onset epilepsy, intellectual disability, and dysmorphic facial features. Affected individuals often present in infancy with seizures, which may be challenging to control and often require specialist epilepsy management, though some individuals achieve better control with tailored treatment regimens. Additional features can include hypotonia, feeding difficulties, and varying degrees of cognitive impairment.
The condition is typically present from birth and is generally considered non-progressive at the genetic level, although ongoing medical input is usually required throughout life. Developmental progress and overall outcomes vary widely between individuals and depend on factors such as seizure control, the degree of developmental delay, and the presence of other medical needs.
The neurological manifestations reflect the critical role of GPI-anchored proteins in brain development and function. Some individuals may also have structural brain abnormalities visible on imaging studies. The condition is rare, and the full spectrum of clinical variability continues to be defined as additional cases are identified through genomic testing.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PIGW variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
PIGW appears on multiple NHS Genomic Medicine Service gene panels with green (diagnostic-grade) evidence ratings. The gene is included in the Congenital Disorders of Glycosylation panel, Early Onset or Syndromic Epilepsy panel (R59), Fetal Anomalies panel (R21), Intellectual Disability panel (R29), and Likely Inborn Error of Metabolism panel (R98). The gene appears on multiple panels because affected individuals may present with different combinations of features - such as seizures, developmental delay, or metabolic signs - and the panel chosen by the clinical team depends on the presenting symptoms rather than reflecting several different conditions. This panel membership reflects the established clinical validity of PIGW testing in individuals presenting with developmental delay, seizures, or suspected metabolic disorders. Genetic testing for PIGW variants may be considered through NHS pathways when clinical features align with GPI anchor biosynthesis defects.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
No specific lifestyle modifications are known to affect PIGW-related conditions. Management focuses on symptomatic treatment and supportive care, typically coordinated through specialist paediatric neurology, metabolic, and developmental services.
Supplement considerations
No specific supplements have been shown to modify PIGW function or alter the progression of PIGW-related conditions. Any nutritional support should be guided by the clinical team overseeing the individual's care.
Frequently asked questions
What does it mean to be a carrier of a PIGW variant?
Carriers have one pathogenic variant and one typical gene copy. Carriers generally do not show symptoms because the functioning copy produces sufficient enzyme activity. If both parents are carriers, each pregnancy has a 25% chance of inheriting variants from both parents, which would result in the associated condition.
How is PIGW-related glycosylation disorder diagnosed?
Diagnosis typically involves genetic testing to identify biallelic pathogenic variants in PIGW. Biochemical testing may reveal abnormal glycosylation patterns in blood samples, and specialised flow cytometry can detect reduced GPI-anchored protein expression on cell surfaces. Clinical evaluation and neuroimaging may provide additional supporting evidence.
Can PIGW variants be detected through prenatal testing?
If pathogenic PIGW variants have been identified in family members, prenatal testing through chorionic villus sampling or amniocentesis may be offered to determine whether a developing pregnancy has inherited the familial variants. Couples should discuss options with a genetic counsellor and their obstetric care team.