Isolated growth hormone deficiency, type 4

Summary

Isolated growth hormone deficiency, type 4 (MONDO:0032567) is a disease caused by GHRHR (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GHRHR (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 25

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated growth hormone deficiency, type 4
Mondo ID	MONDO:0032567
OMIM	618157
Orphanet	684247
UMLS	C4722273
MedGen	1648300
GARD	0025703
Is cancer (heuristic)	no

Also known as: growth hormone deficiency, isolated, type IV · IGHD4

Data availability: 25 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › combined pituitary hormone deficiencies, genetic form › isolated congenital growth hormone deficiency › isolated growth hormone deficiency, type 4

Related subtypes (6): isolated growth hormone deficiency type II, isolated growth hormone deficiency type IA, short stature due to growth hormone qualitative anomaly, isolated growth hormone deficiency type III, isolated growth hormone deficiency type IB, isolated growth hormone deficiency, type 5

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

25 retrieved; paginated sample, class counts are floors:

10 likely pathogenic, 9 pathogenic, 4 pathogenic/likely pathogenic, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012248	NM_000823.4(GHRHR):c.481C>T (p.Arg161Trp)	GHRHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1064692	NM_000823.4(GHRHR):c.967C>T (p.Gln323Ter)	GHRHR	Pathogenic	no assertion criteria provided
1322999	NM_000823.4(GHRHR):c.1069C>T (p.Arg357Cys)	GHRHR	Pathogenic	criteria provided, multiple submitters, no conflicts
15989	NM_000823.4(GHRHR):c.214G>T (p.Glu72Ter)	GHRHR	Pathogenic	criteria provided, multiple submitters, no conflicts
15990	NM_000823.4(GHRHR):c.57+1G>A	GHRHR	Pathogenic	criteria provided, multiple submitters, no conflicts
15991	NM_000823.4(GHRHR):c.431T>A (p.Leu144His)	GHRHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15992	NM_000823.4(GHRHR):c.725T>G (p.Phe242Cys)	GHRHR	Pathogenic	no assertion criteria provided
15993	NM_000823.4(GHRHR):c.665C>A (p.Ala222Glu)	GHRHR	Pathogenic	no assertion criteria provided
15994	NM_000823.4(GHRHR):c.985A>G (p.Lys329Glu)	GHRHR	Pathogenic	no assertion criteria provided
15995	NC_000007.14:g.30963945A>C	GHRHR	Pathogenic	no assertion criteria provided
161436	NM_000823.4(GHRHR):c.281G>A (p.Arg94Gln)	GHRHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191335	NM_000823.4(GHRHR):c.458C>A (p.Ala153Asp)	GHRHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
998031	NM_000823.4(GHRHR):c.731G>A (p.Trp244Ter)	GHRHR	Pathogenic	criteria provided, single submitter
998042	NM_000823.4(GHRHR):c.[1102C>T;481C>T]		Likely pathogenic	no assertion criteria provided
1693449	NM_000823.4(GHRHR):c.527C>T (p.Ala176Val)	GHRHR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2440458	NM_000823.4(GHRHR):c.260C>A (p.Ser87Ter)	GHRHR	Likely pathogenic	criteria provided, single submitter
3339202	NM_000823.4(GHRHR):c.847T>C (p.Trp283Arg)	GHRHR	Likely pathogenic	criteria provided, single submitter
3391278	NM_000823.4(GHRHR):c.465-1G>A	GHRHR	Likely pathogenic	criteria provided, single submitter
3594527	NM_000823.4(GHRHR):c.558_559insA (p.Phe187fs)	GHRHR	Likely pathogenic	criteria provided, single submitter
3594528	NM_000823.4(GHRHR):c.812+2_812+3del	GHRHR	Likely pathogenic	criteria provided, single submitter
3594529	NM_000823.4(GHRHR):c.1120_1123del (p.Ile374fs)	GHRHR	Likely pathogenic	criteria provided, single submitter
3897784	NM_000823.4(GHRHR):c.367G>T (p.Glu123Ter)	GHRHR	Likely pathogenic	criteria provided, single submitter
910806	NM_000823.4(GHRHR):c.507C>G (p.Phe169Leu)	GHRHR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2432120	NM_000823.4(GHRHR):c.1213C>T (p.Arg405Cys)	GHRHR	Uncertain significance	criteria provided, multiple submitters, no conflicts
4278425	NM_000823.4(GHRHR):c.214G>A (p.Glu72Lys)	GHRHR	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
GHRHR	Definitive	Autosomal recessive	isolated growth hormone deficiency type IB	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GHRHR	Orphanet:684247	Isolated growth hormone deficiency type IV

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
GHRHR	HGNC:4266	ENSG00000106128	Q02643	Growth hormone-releasing hormone receptor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GHRHR	Growth hormone-releasing hormone receptor	Receptor for GRF, coupled to G proteins which activate adenylyl cyclase.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
GPCR	1	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GHRHR	GPCR	yes		GPCR_2_secretin-like, GPCR_2_extracellular_dom, GPCR_2_GHRH_rcpt

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
adenohypophysis	1
oocyte	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GHRHR	154	broad	marker	pituitary gland, adenohypophysis, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GHRHR	1,047

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GHRHR	Q02643	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Glucagon-type ligand receptors	1	346.1×	0.006	GHRHR
G alpha (s) signalling events	1	73.2×	0.014	GHRHR

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
regulation of intracellular steroid hormone receptor signaling pathway	1	16852.0×	7e-04	GHRHR
somatotropin secreting cell development	1	16852.0×	7e-04	GHRHR
positive regulation of circadian sleep/wake cycle, non-REM sleep	1	4213.0×	0.002	GHRHR
growth hormone secretion	1	2808.7×	0.002	GHRHR
regulation of protein metabolic process	1	2106.5×	0.002	GHRHR
positive regulation of growth hormone secretion	1	1872.4×	0.002	GHRHR
cAMP/PKA signal transduction	1	1404.3×	0.002	GHRHR
positive regulation of insulin-like growth factor receptor signaling pathway	1	1203.7×	0.002	GHRHR
hormone metabolic process	1	887.0×	0.003	GHRHR
positive regulation of multicellular organism growth	1	495.6×	0.004	GHRHR
cell maturation	1	443.5×	0.004	GHRHR
determination of adult lifespan	1	432.1×	0.004	GHRHR
lactation	1	421.3×	0.004	GHRHR
response to estrogen	1	343.9×	0.005	GHRHR
response to glucocorticoid	1	324.1×	0.005	GHRHR
cellular response to glucose stimulus	1	267.5×	0.005	GHRHR
response to insulin	1	230.8×	0.006	GHRHR
cellular response to insulin stimulus	1	170.2×	0.007	GHRHR
establishment of localization in cell	1	160.5×	0.007	GHRHR
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	113.1×	0.010	GHRHR
cell surface receptor signaling pathway	1	64.1×	0.016	GHRHR
positive regulation of cell population proliferation	1	33.6×	0.030	GHRHR

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GHRHR	DOCETAXEL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GHRHR	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DOCETAXEL	4	GHRHR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GHRHR	3	Binding:3

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
DOCETAXEL	4	GHRHR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GHRHR
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.