Glycosylphosphatidylinositol biosynthesis defect 18

Summary

Glycosylphosphatidylinositol biosynthesis defect 18 (MONDO:0029140) is a disease caused by PIGS (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PIGS (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 17

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	glycosylphosphatidylinositol biosynthesis defect 18
Mondo ID	MONDO:0029140
OMIM	618143
DOID	DOID:0070382
UMLS	C4748357
MedGen	1648478
GARD	0025503
Is cancer (heuristic)	no

Also known as: developmental and epileptic encephalopathy 95 · glycosylphosphatidylinositol biosynthesis defect 18 · GPIBD18

Data availability: 17 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › glycosylphosphatidylinositol biosynthesis defect 18

Related subtypes (28): cortisone reductase deficiency, familial hyperlipidemia, hypolipoproteinemia, steroid inherited metabolic disorder, corticosterone methyloxidase type 1 deficiency, lipoid proteinosis, 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency, vitamin D hydroxylation-deficient rickets, type 1B, mitochondrial trifunctional protein deficiency, pancreatic triacylglycerol lipase deficiency, glucocorticoid resistance, syndromic dyslipidemia, inborn disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation, disorder of plasmalogens biosynthesis, disorder of phospholipids, sphingolipids and fatty acids biosynthesis, inborn disorder of ketolysis, lysosomal lipid storage disorder, sterol metabolism disorder, disorder of sphingolipid biosynthesis, neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 55, inherited fatty acid metabolism disorder, glycosylphosphatidylinositol biosynthesis defect 16, glycosylphosphatidylinositol biosynthesis defect 15, glycosylphosphatidylinositol biosynthesis defect 17, CYP7B1-related disorder of oxysterol accumulation

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

17 retrieved; paginated sample, class counts are floors:

8 pathogenic, 5 uncertain significance, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1119953	NM_033198.4(PIGS):c.174G>C (p.Gln58His)	PIGS	Pathogenic	no assertion criteria provided
1119954	NM_033198.4(PIGS):c.1070G>A (p.Gly357Asp)	PIGS	Pathogenic	no assertion criteria provided
1119955	NM_033198.4(PIGS):c.986C>G (p.Pro329Arg)	PIGS	Pathogenic	no assertion criteria provided
1119956	NM_033198.4(PIGS):c.1141_1164dup (p.Asp381_Val388dup)	PIGS	Pathogenic	no assertion criteria provided
1119957	NM_033198.4(PIGS):c.734G>A (p.Trp245Ter)	PIGS	Pathogenic	criteria provided, single submitter
3769036	NM_033198.4(PIGS):c.662_663del (p.Leu221fs)	PIGS	Pathogenic	criteria provided, single submitter
585255	NM_033198.4(PIGS):c.1316_1352delinsGGTTGCT (p.Thr439_Lys451delinsArgLeuLeu)	PIGS	Pathogenic	no assertion criteria provided
585257	NM_033198.4(PIGS):c.468+1G>C	PIGS	Pathogenic	no assertion criteria provided
3338277	NM_033198.4(PIGS):c.1436T>A (p.Leu479Ter)	PIGS	Likely pathogenic	criteria provided, single submitter
585253	NM_033198.4(PIGS):c.108G>A (p.Trp36Ter)	PIGS	Likely pathogenic	criteria provided, single submitter
585254	NM_033198.4(PIGS):c.101T>C (p.Leu34Pro)	PIGS	Likely pathogenic	criteria provided, single submitter
585256	NM_033198.4(PIGS):c.923A>G (p.Glu308Gly)	PIGS	Likely pathogenic	criteria provided, single submitter
1028510	NM_033198.4(PIGS):c.1274G>A (p.Arg425Gln)	PIGS	Uncertain significance	criteria provided, single submitter
1028511	NM_033198.4(PIGS):c.526C>T (p.Arg176Trp)	PIGS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031035	NM_033198.4(PIGS):c.1204C>T (p.Pro402Ser)	PIGS	Uncertain significance	criteria provided, multiple submitters, no conflicts
3068026	NM_033198.4(PIGS):c.550C>T (p.Arg184Cys)	PIGS	Uncertain significance	criteria provided, single submitter
3338278	NM_033198.4(PIGS):c.37G>T (p.Val13Leu)	PIGS	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PIGS	Strong	Autosomal recessive	glycosylphosphatidylinositol biosynthesis defect 18	4

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIGS	HGNC:14937	ENSG00000087111	Q96S52	GPI-anchor transamidase component PIGS	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIGS	GPI-anchor transamidase component PIGS	Component of the glycosylphosphatidylinositol-anchor (GPI-anchor) transamidase (GPI-T) complex that catalyzes the formation of the linkage between a proprotein and a GPI-anchor and participates in GPI anchored protein biosynthesis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIGS	Other/Unknown	no		PtdIno-glycan_biosynth_class_S

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
islet of Langerhans	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIGS	141	ubiquitous	marker	stromal cell of endometrium, granulocyte, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIGS	1,025

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIGS	Q96S52	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Attachment of GPI anchor to uPAR	1	1268.9×	8e-04	PIGS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
GPI anchored protein biosynthesis	1	2808.7×	7e-04	PIGS
attachment of GPI anchor to protein	1	2106.5×	7e-04	PIGS
GPI anchor biosynthetic process	1	495.6×	0.002	PIGS

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIGS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PIGS	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PIGS

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PIGS	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.