Growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant

Summary

Growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant (MONDO:0100219) is a disease caused by STAT5B (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: STAT5B (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant
Mondo ID	MONDO:0100219
OMIM	618985
DOID	DOID:0080837
UMLS	C5436546
MedGen	1723138
GARD	0018312
Is cancer (heuristic)	no

Also known as: GHISID2 · GROWTH HORMONE INSENSITIVITY SYNDROME WITH IMMUNE DYSREGULATION 2, AUTOSOMAL DOMINANT · growth hormone insensitivity with immune dysregulation 2, autosomal dominant

Data availability: 21 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › growth hormone insensitivity syndrome with immune dysregulation › growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant

Related subtypes (2): growth hormone insensitivity with immune dysregulation 1, autosomal recessive, STAT5 haploinsufficiency

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

21 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 2 benign/likely benign, 2 pathogenic, 2 conflicting classifications of pathogenicity, 1 benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
492931	NM_012448.4(STAT5B):c.1421A>G (p.Gln474Arg)	STAT5B	Pathogenic	no assertion criteria provided
522611	NM_012448.4(STAT5B):c.530A>C (p.Gln177Pro)	STAT5B	Pathogenic	no assertion criteria provided
2446384	NM_012448.4(STAT5B):c.1896G>T (p.Lys632Asn)	STAT5B	Likely pathogenic	criteria provided, single submitter
534583	NM_012448.4(STAT5B):c.551-5T>C	STAT5B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
828010	NM_012448.4(STAT5B):c.550+7C>T	STAT5B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1037184	NM_012448.4(STAT5B):c.2359T>C (p.Ser787Pro)	STAT5B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1039656	NM_012448.4(STAT5B):c.638C>G (p.Ala213Gly)	STAT5B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1710252	NM_012448.4(STAT5B):c.1570G>T (p.Gly524Cys)	STAT5B	Uncertain significance	no assertion criteria provided
2444309	NM_012448.4(STAT5B):c.1012C>T (p.Pro338Ser)	STAT5B	Uncertain significance	criteria provided, single submitter
2501759	NM_012448.4(STAT5B):c.863A>T (p.Gln288Leu)	STAT5B	Uncertain significance	criteria provided, single submitter
2575224	NM_012448.4(STAT5B):c.2171C>T (p.Thr724Met)	STAT5B	Uncertain significance	criteria provided, multiple submitters, no conflicts
2585113	NM_012448.4(STAT5B):c.805G>A (p.Glu269Lys)	STAT5B	Uncertain significance	criteria provided, multiple submitters, no conflicts
2744045	NM_012448.4(STAT5B):c.2203T>C (p.Cys735Arg)	STAT5B	Uncertain significance	criteria provided, multiple submitters, no conflicts
517661	NM_012448.4(STAT5B):c.1433C>T (p.Ala478Val)	STAT5B	Uncertain significance	criteria provided, single submitter
572813	NM_012448.4(STAT5B):c.2161G>A (p.Gly721Ser)	STAT5B	Uncertain significance	criteria provided, multiple submitters, no conflicts
578442	NM_012448.4(STAT5B):c.773G>A (p.Arg258Gln)	STAT5B	Uncertain significance	criteria provided, multiple submitters, no conflicts
955195	NM_012448.4(STAT5B):c.1666T>A (p.Ser556Thr)	STAT5B	Uncertain significance	criteria provided, multiple submitters, no conflicts
992531	NM_012448.4(STAT5B):c.2353G>A (p.Ala785Thr)	STAT5B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1328004	NM_012448.4(STAT5B):c.375+17G>A	STAT5B	Benign	criteria provided, multiple submitters, no conflicts
194861	NM_012448.4(STAT5B):c.2237+15T>C	STAT5B	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
199128	NM_012448.4(STAT5B):c.993G>A (p.Thr331=)	STAT5B	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
STAT5B	Definitive	Semidominant	growth hormone insensitivity syndrome with immune dysregulation	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STAT5B	Orphanet:220465	Laron syndrome with immunodeficiency
STAT5B	Orphanet:520	Acute promyelocytic leukemia

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
STAT5B	HGNC:11367	ENSG00000173757	P51692	Signal transducer and activator of transcription 5B	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STAT5B	Signal transducer and activator of transcription 5B	Carries out a dual function: signal transduction and activation of transcription.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STAT5B	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf

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
blood	1
body of uterus	1
left uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STAT5B	295	ubiquitous	marker	blood, body of uterus, left uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STAT5B	3,986

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STAT5B	P51692	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 38. 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
Erythropoietin activates STAT5	1	1631.4×	0.004	STAT5B
STAT5 Activation	1	1631.4×	0.004	STAT5B
Interleukin-9 signaling	1	1268.9×	0.004	STAT5B
FGFR1 mutant receptor activation	1	1142.0×	0.004	STAT5B
Interleukin-21 signaling	1	1142.0×	0.004	STAT5B
Signaling by KIT in disease	1	1142.0×	0.004	STAT5B
FLT3 signaling in disease	1	1142.0×	0.004	STAT5B
STAT5 activation downstream of FLT3 ITD mutants	1	1142.0×	0.004	STAT5B
Signaling by Leptin	1	1038.2×	0.004	STAT5B
Signaling by Erythropoietin	1	1038.2×	0.004	STAT5B
Interleukin-2 signaling	1	951.7×	0.004	STAT5B
Prolactin receptor signaling	1	761.3×	0.004	STAT5B
Interleukin-15 signaling	1	761.3×	0.004	STAT5B
Signaling by FLT3 ITD and TKD mutants	1	761.3×	0.004	STAT5B
Signaling by cytosolic FGFR1 fusion mutants	1	634.4×	0.004	STAT5B
Interleukin-2 family signaling	1	634.4×	0.004	STAT5B
Signaling by CSF3 (G-CSF)	1	571.0×	0.004	STAT5B
Signaling by FLT3 fusion proteins	1	571.0×	0.004	STAT5B
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	519.1×	0.004	STAT5B
Growth hormone receptor signaling	1	475.8×	0.004	STAT5B
Inactivation of CSF3 (G-CSF) signaling	1	439.2×	0.004	STAT5B
Signaling by FGFR in disease	1	423.0×	0.004	STAT5B
Interleukin-20 family signaling	1	423.0×	0.004	STAT5B
Downstream signal transduction	1	380.7×	0.004	STAT5B
FLT3 Signaling	1	346.1×	0.004	STAT5B
Interleukin-7 signaling	1	317.2×	0.004	STAT5B
Interleukin-3, Interleukin-5 and GM-CSF signaling	1	317.2×	0.004	STAT5B
Signaling by FGFR1 in disease	1	292.8×	0.005	STAT5B
Signaling by PDGF	1	253.8×	0.005	STAT5B
Signaling by SCF-KIT	1	248.3×	0.005	STAT5B

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
response to interleukin-15	1	8426.0×	0.002	STAT5B
development of animal secondary female sexual characteristics	1	5617.3×	0.002	STAT5B
development of animal secondary male sexual characteristics	1	5617.3×	0.002	STAT5B
response to interleukin-2	1	5617.3×	0.002	STAT5B
mast cell migration	1	5617.3×	0.002	STAT5B
response to interleukin-4	1	4213.0×	0.002	STAT5B
natural killer cell proliferation	1	3370.4×	0.002	STAT5B
taurine metabolic process	1	2808.7×	0.002	STAT5B
erythropoietin-mediated signaling pathway	1	2808.7×	0.002	STAT5B
regulation of steroid metabolic process	1	2407.4×	0.002	STAT5B
myeloid cell apoptotic process	1	2106.5×	0.002	STAT5B
gamma-delta T cell differentiation	1	2106.5×	0.002	STAT5B
Peyer’s patch development	1	2106.5×	0.002	STAT5B
luteinization	1	1872.4×	0.002	STAT5B
regulation of epithelial cell differentiation	1	1872.4×	0.002	STAT5B
negative regulation of myeloid cell apoptotic process	1	1872.4×	0.002	STAT5B
positive regulation of gamma-delta T cell differentiation	1	1872.4×	0.002	STAT5B
activated T cell proliferation	1	1872.4×	0.002	STAT5B
positive regulation of natural killer cell differentiation	1	1685.2×	0.002	STAT5B
progesterone metabolic process	1	1685.2×	0.002	STAT5B
negative regulation of erythrocyte differentiation	1	1532.0×	0.002	STAT5B
growth hormone receptor signaling pathway via JAK-STAT	1	1532.0×	0.002	STAT5B
positive regulation of natural killer cell proliferation	1	1404.3×	0.002	STAT5B
positive regulation of B cell differentiation	1	1123.5×	0.002	STAT5B
natural killer cell differentiation	1	887.0×	0.002	STAT5B
positive regulation of activated T cell proliferation	1	674.1×	0.003	STAT5B
regulation of multicellular organism growth	1	648.1×	0.003	STAT5B
positive regulation of natural killer cell mediated cytotoxicity	1	561.7×	0.003	STAT5B
lipid storage	1	543.6×	0.003	STAT5B
positive regulation of erythrocyte differentiation	1	510.7×	0.003	STAT5B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STAT5B	1	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SURAMIN HEXASODIUM	3	STAT5B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
STAT5B	55	Binding:55

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)
SURAMIN HEXASODIUM	3	STAT5B

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	1	STAT5B
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.