PIGQ

protein-coding

phosphatidylinositol glycan anchor biosynthesis class Q, the group of Phosphatidylinositol glycan anchor biosynthesis|Glycosylphosphatidylinositol-N-acetylglucosaminyltransferase complex

Gene summary

This gene is involved in the first step in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This gene encodes a N-acetylglucosaminyl transferase component that is part of the complex that catalyzes transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]

MANE transcript

NM_004204.5

Inheritance

AD, AR

ClinVar variants

P:47U:326B:261

Top phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 4

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr16:566,995-584,109

External References & Databases

Ensembl (ENSG00000007541)

Transcript & Mutation Effects

hg38 • Region Span ~17.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

genetic developmental and epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: Orphanet

developmental and epileptic encephalopathy, 77STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032808

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 77STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032808

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 77MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032808

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 77DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032808

Submitter: ClinGen

*PIGQ* (formerly known as GPI1) was first reported in relation to “developmental and epileptic encephalopathy, 77” an autosomal recessive condition, in 2014 (Martin et al, PMID: 24463883). This is the only condition associated with *PIGQ* in OMIM. Twelve variants (5 frameshift variants, 4 of which are in the 3’ end of the gene and predicted to escape NMD; 2 canonical splice site variants; 2 missense variants; 2 inframe deletions, one of which was identified in 3 unrelated patients; and one nonsense variant) that have been reported in 9 probands in 4 publications (Martin et al, 2014, PMID: 24463883; Alazami et al, 2015, PMID: 25558065; Starr et al, 2019, PMID: 31148362; Johnstone et al, 2020, PMID: 32588908) are included in this curation. Additional reports are available in the literature (e.g. PMID: 34089469) but the maximum score for genetic evidence (12 points) has already been reached. The mechanism of pathogenicity appears to be loss of function based on lack of PIGQ protein on Western blot in cells from a patient (Martin et al, 2014, PMID: 24463883) and reduction of surface localization of GPI-anchored proteins as well as FLAER labeling in granulocytes and fibroblasts from affected individuals (Martin et al, 2014, PMID: 24463883; Johnstone et al, 2020, PMID: 32588908). This gene-disease relationship is also supported by the biochemical function of the gene product, which appears to stabilize the enzyme complex involved in the first step of GPI biosynthesis, GPI-N-acetylglucosaminyl-transferase (Watanabe et al, 1998, PMID: 9463366; Tiede et al, 1998, PMID: 9729469; Hong et al, 1999, PMID: 10373468), and interaction with the products of other genes, such as *PIGA*, which have been associated with a similar condition (Watanabe et al, 1998, PMID: 9463366). *PIGA* has been definitively associated with “complex neurological disorder” by the Epilepsy Gene Curation Expert Panel. (Score for experimental evidence = 2 points) In summary, there is definitive evidence supporting the relationship between *PIGQ* and the autosomal recessive disorder “developmental and epileptic encephalopathy, 77”. 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 Congenital Disorders of Glycosylation Gene Curation Expert Panel on February 19, 2025 (SOP version 11).

developmental and epileptic encephalopathy, 77STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032808

Submitter: G2P

Clinical Genomic Database (CGD)

Multiple congenital anomalies-hypotonia-seizures syndrome 4AR

Manifestation: Craniofacial; Musculoskeletal; 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: 24463883; 25558065; 31148362

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIGQ variants in ClinVar

10 Conditions Cataloged

EpilepsyTotal: 663

Inborn genetic diseasesTotal: 126

not providedTotal: 107

not specifiedTotal: 48

PIGQ-related disorderTotal: 37

Developmental and epileptic encephalopathy, 77Total: 36

Optic atrophyTotal: 1

Intractable seizureTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004204.5. 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			11 clinvar	220 clinvar	2 clinvar	233
missense		3 clinvar	296 clinvar	37 clinvar	2 clinvar	338
nonsense	15 clinvar	4 clinvar	3 clinvar			22
start loss			1 clinvar			1
frameshift	17 clinvar	2 clinvar	7 clinvar			26
splice donor/acceptor (+/-2bp)	2 clinvar	4 clinvar	8 clinvar			14
Total	34	13	326	257	4	634

Highest pathogenic variant AF is 0.00020710738

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004204.5	RefSeq	NP_004195.2	10	MANE Select
ENST00000321878.10	Ensembl	ENSP00000326674.6	10	MANE Select
NM_148920.4	RefSeq	NP_683721.1	9	Standard
ENST00000026218.10	Ensembl	ENSP00000026218.5	9	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

carbohydrate metabolic process
preassembly of GPI anchor in ER membrane

Molecular Function

phosphatidylinositol N-acetylglucosaminyltransferase activity

Cellular Component

glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex
endoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000026218
Coding exons: 9
Length: 17142
Individuals with no LoFs: 125639
Homozygous LoFs: 0
Heterozygous LoFs: 37
Defined: 125676
p: 0.000147

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0950	488	482	1.01	0.0000324	4773
Missense (PolyPhen)		130	126.08	1.0311		1285
Synonymous	-1.91	260	224	1.16	0.0000156	1701
Loss of Function	1.91	13	22.9	0.568	0.00000115	221

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00021	0.00018	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00027	rare
Finnish	0.000099	0.000092	rare
European (Non-Finnish)	0.00019	0.00018	rare
South Asian	0	0.0	absent
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Part of the complex catalyzing the transfer of N- acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol, the first step of GPI biosynthesis.;

Recessive Scores

pRec: 0.147

Intolerance Scores

LoFtool: 0.829
RVIS EVS: 0.08
RVIS percentile EVS: 59.21

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.394

Gene Damage Prediction

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