PIGW

protein-coding

phosphatidylinositol glycan anchor biosynthesis class W, the group of Phosphatidylinositol glycan anchor biosynthesis

Gene summary

The protein encoded by this gene is an inositol acyltransferase that acylates the inositol ring of phosphatidylinositol. This occurs in the endoplasmic reticulum and is a step in the biosynthesis of glycosylphosphatidylinositol (GPI), which anchors many cell surface proteins to the membrane. Defects in this gene are a cause of the age-dependent epileptic encephalopathy West syndrome as well as a syndrome exhibiting hyperphosphatasia and cognitive disability (HPMRS5). [provided by RefSeq, Jul 2017]

MANE transcript

NM_001346754.2

Inheritance

ClinVar variants

P:10U:207B:114

Top phenotype

Glycosylphosphatidylinositol biosynthesis defect 11

Max pathogenic AF

—

Genomic locus

chr17:36,534,987-36,539,310

External References & Databases

Ensembl (ENSG00000277161)

Transcript & Mutation Effects

hg38 • Region Span ~4.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypercoagulability syndrome due to glycosylphosphatidylinositol deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012465

Submitter: Orphanet

congenital disorder of glycosylationLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0015286

Submitter: ClinGen

*PIGW* was first reported in relation to autosomal recessive congenital disorder of glycosylation (also known as glycosylphosphatidylinositol (GPI) biosynthesis defect 11) in 2014 (Chiyonobu T et al., PMID:24367057). This rare congenital glycosylation disorder is characterized by hypotonia, severe developmental delay, intellectual disability, seizures, increased serum alkaline phosphatase, and dysmorphic facial features. Defects in this gene have been identified as a cause of age-dependent epileptic spasms (West syndrome) as well as a syndrome exhibiting hyperphosphatasia and cognitive disability (HPMRS5) [provided by RefSeq, Jul 2017]. It is caused by mutations in the *PIGW* gene, which functions in the third step of GPI biosynthesis by acylating the inositol ring of phosphatidylinositol and encodes a 504–amino acid inositol acyltransferase (Murakami et al., 2003, PubMed:14517336). Eight variants (missense) that have been reported in 6 probands in 6 publications (Chiyonobu T et al., 2014, PMID:24367057; Hogrebe M et al., 2016, PMID:27626616; Meier N et al., 2019, PMID:30679815; Fu L et al., 2019, PMID:30813920; Peron A et al., 2020, PMID:32198969; and Foskett GK et al., 2018, PMID: ), are included in this curation. This gene-disease relationship is also supported by a rescue in cell culture model that mimics a specific inherited GPI deficiency and assesses the effectiveness of various synthetic compounds in reestablishing normal GPI biosynthesis. (Guerrero PA et al., 2021, PMID:34618440). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Disorder of Glycosylation GCEP on the meeting date February 6, 2025 (SOP Version 11).

hyperphosphatasia with intellectual disability syndrome 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014457

Submitter: Labcorp Genetics (formerly Invitae)

hyperphosphatasia with intellectual disability syndrome 5LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014457

Submitter: G2P

hyperphosphatasia with intellectual disability syndrome 5MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014457

Submitter: Ambry Genetics

hyperphosphatasia-intellectual disability syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016596

Submitter: Orphanet

hyperphosphatasia with intellectual disability syndrome 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014457

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Glycosylphosphatidylinositol biosynthesis defect 11AR

Manifestation: Craniofacial; Gastrointestinal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 24367057

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIGW variants in ClinVar

10 Conditions Cataloged

Hyperphosphatasia with intellectual disability syndrome 5Total: 286

Inborn genetic diseasesTotal: 73

not providedTotal: 35

not specifiedTotal: 15

PIGW-related disorderTotal: 4

Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiencyTotal: 1

Abnormal skeletal morphologyTotal: 1

Cleft palateTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001346754.2. 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				101 clinvar	2 clinvar	103
missense	5 clinvar		178 clinvar	10 clinvar	1 clinvar	194
nonsense		2 clinvar	9 clinvar			11
start loss		1 clinvar				1
frameshift		2 clinvar	20 clinvar			22
splice donor/acceptor (+/-2bp)						0
Total	5	5	207	111	3	331

Highest pathogenic variant AF is 0.00019452818

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001346754.2	RefSeq	NP_001333683.1	1	MANE Select
ENST00000614443.2	Ensembl	ENSP00000482202.1	1	MANE Select
NM_001346755.2	RefSeq	NP_001333684.1	1	Standard
NM_178517.5	RefSeq	NP_848612.2	1	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 metabolic process
GPI anchor biosynthetic process
preassembly of GPI anchor in ER membrane
protein localization to plasma membrane

Molecular Function

O-acyltransferase activity
glucosaminyl-phosphotidylinositol O-acyltransferase activity

Cellular Component

endoplasmic reticulum membrane
integral component of membrane

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for the transport of GPI-anchored proteins to the plasma membrane (PubMed:24367057). Probable acetyltransferase, which acetylates the inositol ring of phosphatidylinositol during biosynthesis of GPI-anchor. Acetylation during GPI-anchor biosynthesis is not essential for the subsequent mannosylation and is usually removed soon after the attachment of GPIs to proteins (By similarity). {ECO:0000250|UniProtKB:Q7TSN4, ECO:0000269|PubMed:24367057}.;
Disease: DISEASE: Glycosylphosphatidylinositol biosynthesis defect 11 (GPIBD11) [MIM:616025]: An autosomal recessive neurologic disorder characterized by developmental delay, mental retardation, tonic seizures associated with hypsarrhythmia, dysmorphic facial features, and elevated serum alkaline phosphatase. {ECO:0000269|PubMed:24367057}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0819

Intolerance Scores

LoFtool: 0.297
RVIS EVS: -0.03
RVIS percentile EVS: 51.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.442

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium