Hirschsprung disease, susceptibility to, 3

Summary

Hirschsprung disease, susceptibility to, 3 (MONDO:0013383) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 87

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Hirschsprung disease, susceptibility to, 3
Mondo ID	MONDO:0013383
MeSH	C538121
OMIM	613711
UMLS	C3150974
MedGen	462324
Is cancer (heuristic)	no

Also known as: GDNF Hirschsprung disease · Hirschsprung disease caused by mutation in GDNF · Hirschsprung disease modifier · Hirschsprung disease type 3 · Hirschsprung disease, susceptibility to, 3 · Hirschsprung disease, susceptibility to, type 3 · HSCR3

Data availability: 87 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › Hirschsprung disease, susceptibility to › Hirschsprung disease, susceptibility to, 3

Related subtypes (8): Hirschsprung disease, susceptibility to, 1, Hirschsprung disease, susceptibility to, 2, Hirschsprung disease, susceptibility to, 5, Hirschsprung disease, susceptibility to, 6, Hirschsprung disease, susceptibility to, 7, Hirschsprung disease, susceptibility to, 8, Hirschsprung disease, susceptibility to, 9, Hirschsprung disease, susceptibility to, 4

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

87 retrieved; paginated sample, class counts are floors:

48 uncertain significance, 20 benign, 13 likely benign, 3 benign/likely benign, 2 conflicting classifications of pathogenicity, 1 risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
8760	NM_000514.4(GDNF):c.460A>T (p.Thr154Ser)	GDNF	risk factor	no assertion criteria provided
667238	NM_000514.4(GDNF):c.*5G>A	GDNF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
906138	NM_000514.4(GDNF):c.292G>T (p.Ala98Ser)	GDNF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285762	NM_000514.4(GDNF):c.61C>T (p.Pro21Ser)	GDNF	Uncertain significance	criteria provided, multiple submitters, no conflicts
353473	NM_000514.4(GDNF):c.*2828T>A	GDNF	Uncertain significance	criteria provided, multiple submitters, no conflicts
353475	NM_000514.4(GDNF):c.*2651C>G	GDNF	Uncertain significance	criteria provided, single submitter
353477	NM_000514.4(GDNF):c.*2556T>A	GDNF	Uncertain significance	criteria provided, single submitter
353482	NM_000514.4(GDNF):c.*2059C>T	GDNF	Uncertain significance	criteria provided, single submitter
353484	NM_000514.4(GDNF):c.*1927C>T	GDNF	Uncertain significance	criteria provided, single submitter
353486	NM_000514.4(GDNF):c.*1788G>A	GDNF	Uncertain significance	criteria provided, single submitter
353488	NM_000514.4(GDNF):c.*1713C>T	GDNF	Uncertain significance	criteria provided, single submitter
353490	NM_000514.4(GDNF):c.*1657C>A	GDNF	Uncertain significance	criteria provided, single submitter
353492	NM_000514.4(GDNF):c.*1627C>T	GDNF	Uncertain significance	criteria provided, single submitter
353493	NM_000514.4(GDNF):c.*1612C>A	GDNF	Uncertain significance	criteria provided, single submitter
353496	NM_000514.4(GDNF):c.*1587G>T	GDNF	Uncertain significance	criteria provided, single submitter
353498	NM_000514.4(GDNF):c.*1534G>A	GDNF	Uncertain significance	criteria provided, single submitter
353501	NM_000514.4(GDNF):c.*1331G>C	GDNF	Uncertain significance	criteria provided, single submitter
353504	NM_000514.4(GDNF):c.*1244A>G	GDNF	Uncertain significance	criteria provided, single submitter
353508	NM_000514.4(GDNF):c.*958A>C	GDNF	Uncertain significance	criteria provided, single submitter
353509	NM_000514.4(GDNF):c.*912A>G	GDNF	Uncertain significance	criteria provided, single submitter
353510	NM_000514.4(GDNF):c.*907G>A	GDNF	Uncertain significance	criteria provided, single submitter
353511	NM_000514.4(GDNF):c.*807G>A	GDNF	Uncertain significance	criteria provided, single submitter
353512	NM_000514.4(GDNF):c.*717T>G	GDNF	Uncertain significance	criteria provided, single submitter
353513	NM_000514.4(GDNF):c.*532A>G	GDNF	Uncertain significance	criteria provided, single submitter
353516	NM_000514.4(GDNF):c.*346C>T	GDNF	Uncertain significance	criteria provided, single submitter
8761	NM_000514.4(GDNF):c.633C>G (p.Ile211Met)	GDNF	Uncertain significance	criteria provided, single submitter
903707	NM_000514.4(GDNF):c.*795C>T	GDNF	Uncertain significance	criteria provided, single submitter
903708	NM_000514.4(GDNF):c.*617A>G	GDNF	Uncertain significance	criteria provided, single submitter
904777	NM_000514.4(GDNF):c.*1699G>C	GDNF	Uncertain significance	criteria provided, single submitter
905489	NM_000514.4(GDNF):c.*2646C>G	GDNF	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · 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
GDNF	Limited	Autosomal dominant	Hirschsprung disease, susceptibility to, 3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GDNF	Orphanet:388	Hirschsprung disease
GDNF	Orphanet:661	Congenital central hypoventilation syndrome

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
GDNF	HGNC:4232	ENSG00000168621	P39905	Glial cell line-derived neurotrophic factor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GDNF	Glial cell line-derived neurotrophic factor	Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake.

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)
GDNF	Other/Unknown	no		TGF-b_C, GDNF, Cystine-knot_cytokine

Expression context

Cohort genes with no expression data: 0.

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
deltoid	1
hindlimb stylopod muscle	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GDNF	149	tissue_specific	yes	hindlimb stylopod muscle, tibialis anterior, deltoid

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GDNF	2,631

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GDNF	P39905	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Formation of the ureteric bud	1	496.5×	0.005	GDNF
RET signaling	1	259.6×	0.005	GDNF
NCAM1 interactions	1	248.3×	0.005	GDNF
RAF/MAP kinase cascade	1	61.1×	0.016	GDNF

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
postsynaptic membrane organization	1	4213.0×	0.002	GDNF
postganglionic parasympathetic fiber development	1	4213.0×	0.002	GDNF
regulation of morphogenesis of a branching structure	1	4213.0×	0.002	GDNF
regulation of semaphorin-plexin signaling pathway	1	4213.0×	0.002	GDNF
positive regulation of ureteric bud formation	1	2808.7×	0.002	GDNF
positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis	1	2808.7×	0.002	GDNF
regulation of dopamine uptake involved in synaptic transmission	1	2407.4×	0.002	GDNF
ureteric bud formation	1	2407.4×	0.002	GDNF
mesenchymal to epithelial transition involved in metanephros morphogenesis	1	2106.5×	0.002	GDNF
neural crest cell migration involved in autonomic nervous system development	1	1872.4×	0.002	GDNF
dorsal spinal cord development	1	1685.2×	0.002	GDNF
positive regulation of dopamine secretion	1	1685.2×	0.002	GDNF
peristalsis	1	1532.0×	0.002	GDNF
organ induction	1	1203.7×	0.002	GDNF
glial cell-derived neurotrophic factor receptor signaling pathway	1	1203.7×	0.002	GDNF
enteric nervous system development	1	991.3×	0.002	GDNF
commissural neuron axon guidance	1	991.3×	0.002	GDNF
sympathetic nervous system development	1	936.2×	0.002	GDNF
positive regulation of branching involved in ureteric bud morphogenesis	1	802.5×	0.002	GDNF
regulation of stem cell differentiation	1	766.0×	0.002	GDNF
peripheral nervous system development	1	581.1×	0.003	GDNF
metanephros development	1	510.7×	0.003	GDNF
embryonic organ development	1	481.5×	0.003	GDNF
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	411.0×	0.004	GDNF
branching involved in ureteric bud morphogenesis	1	366.4×	0.004	GDNF
mRNA stabilization	1	366.4×	0.004	GDNF
neural crest cell migration	1	337.0×	0.004	GDNF
adult locomotory behavior	1	300.9×	0.004	GDNF
positive regulation of cell differentiation	1	267.5×	0.005	GDNF
neuron projection development	1	122.1×	0.010	GDNF

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
GDNF	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	GDNF

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)
GDNF	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.