Glycosylphosphatidylinositol biosynthesis defect 17

Summary

Glycosylphosphatidylinositol biosynthesis defect 17 (MONDO:0060724) is a disease caused by PIGH (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: PIGH (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	glycosylphosphatidylinositol biosynthesis defect 17
Mondo ID	MONDO:0060724
OMIM	618010
UMLS	C4747891
MedGen	1648437
GARD	0026006
Is cancer (heuristic)	no

Also known as: glycosylphosphatidylinositol biosynthesis defect 17 · GPIBD17

Data availability: 3 ClinVar variants · 5 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 17

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, glycosylphosphatidylinositol biosynthesis defect 18, 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, 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

3 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
545630	NM_004569.5(PIGH):c.1A>T (p.Met1Leu)	GPHN	Pathogenic	no assertion criteria provided
545631	NM_004569.5(PIGH):c.307T>C (p.Ser103Pro)	GPHN	Pathogenic	criteria provided, multiple submitters, no conflicts
1332855	NM_004569.5(PIGH):c.487C>T (p.Arg163Trp)	GPHN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
PIGH	Strong	Autosomal recessive	glycosylphosphatidylinositol biosynthesis defect 17	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GPHN	Orphanet:308400	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C
GPHN	Orphanet:3197	Hereditary hyperekplexia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIGH	HGNC:8964	ENSG00000100564	Q14442	Phosphatidylinositol N-acetylglucosaminyltransferase subunit H	gencc
GPHN	HGNC:15465	ENSG00000171723	Q9NQX3	Gephyrin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIGH	Phosphatidylinositol N-acetylglucosaminyltransferase subunit H	Part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI bi…
GPHN	Gephyrin	Microtubule-associated protein involved in membrane protein-cytoskeleton interactions.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIGH	Other/Unknown	no		PIGH-H_dom, PIG-H
GPHN	Other/Unknown	no		MoaB/Mog_dom, MoeA_linker/N, MoeA_C_domain_IV

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
left lobe of thyroid gland	1
right adrenal gland	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIGH	280	ubiquitous	marker	body of pancreas, left lobe of thyroid gland, right adrenal gland
GPHN	270	ubiquitous	marker	cerebellar cortex, cerebellar hemisphere, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GPHN	2,500
PIGH	673

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GPHN	Q9NQX3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PIGH	Q14442	87.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Molybdenum cofactor biosynthesis	1	815.7×	0.002	GPHN
Synthesis of glycosylphosphatidylinositol (GPI)	1	317.2×	0.003	PIGH

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycine receptor clustering	1	8426.0×	0.001	GPHN
establishment of synaptic specificity at neuromuscular junction	1	4213.0×	0.001	GPHN
gamma-aminobutyric acid receptor clustering	1	1685.2×	0.002	GPHN
Mo-molybdopterin cofactor biosynthetic process	1	1203.7×	0.002	GPHN
response to metal ion	1	766.0×	0.002	GPHN
neurotransmitter receptor localization to postsynaptic specialization membrane	1	401.2×	0.004	GPHN
GPI anchor biosynthetic process	1	247.8×	0.005	PIGH
establishment of protein localization	1	216.1×	0.005	GPHN
synapse assembly	1	115.4×	0.009	GPHN

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIGH	0	0
GPHN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	PIGH, GPHN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PIGH	0	—
GPHN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.