short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia

Summary

short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia (MONDO:0018967) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia
Mondo ID	MONDO:0018967
Orphanet	632
GARD	0016538
Is cancer (heuristic)	no

Data availability: 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › congenital hematological disorder › congenital agammaglobulinemia › short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia

Related subtypes (1): agammaglobulinemia-microcephaly-craniosynostosis-severe dermatitis syndrome

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 4 · 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
BTK	Strong	X-linked	isolated growth hormone deficiency type III	7
ELF4	Strong	X-linked	autoinflammatory syndrome, familial, X-linked, Behcet-like 2	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BTK	Orphanet:47	X-linked agammaglobulinemia
BTK	Orphanet:632	Short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia
ELF4	Orphanet:632	Short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia
ELF4	Orphanet:676125	X-linked immune dysregulation with inflammatory bowel disease due to ELF4 deficiency

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
BTK	HGNC:1133	ENSG00000010671	Q06187	Tyrosine-protein kinase BTK	gencc
ELF4	HGNC:3319	ENSG00000102034	Q99607	ETS-related transcription factor Elf-4	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BTK	Tyrosine-protein kinase BTK	Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling.
ELF4	ETS-related transcription factor Elf-4	Transcriptional activator that binds to DNA sequences containing the consensus 5’-WGGA-3'.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BTK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
ELF4	Transcription factor	no		Ets_dom, TF_Elf_N, WH-like_DNA-bd_sf

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
leukocyte	1
monocyte	1
mononuclear cell	1
blood	1
endometrium epithelium	1
granulocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BTK	206	broad	marker	monocyte, mononuclear cell, leukocyte
ELF4	246	ubiquitous	marker	endometrium epithelium, granulocyte, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BTK	4,467
ELF4	1,164

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BTK	Q06187	156

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ELF4	Q99607	49.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 45. Enrichment computed across 2 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
G-protein beta:gamma signalling	1	1903.3×	0.009	BTK
Diseases of Immune System	1	878.5×	0.009	BTK
Diseases associated with the TLR signaling cascade	1	878.5×	0.009	BTK
G beta:gamma signalling through BTK	1	634.4×	0.009	BTK
MyD88 deficiency (TLR2/4)	1	601.0×	0.009	BTK
IRAK4 deficiency (TLR2/4)	1	571.0×	0.009	BTK
DAP12 interactions	1	475.8×	0.009	BTK
DAP12 signaling	1	368.4×	0.009	BTK
FCERI mediated Ca+2 mobilization	1	356.9×	0.009	BTK
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	356.9×	0.009	BTK
Parasite infection	1	346.1×	0.009	BTK
Leishmania phagocytosis	1	346.1×	0.009	BTK
Signaling by the B Cell Receptor (BCR)	1	346.1×	0.009	BTK
Antigen processing-Cross presentation	1	317.2×	0.009	BTK
RHO GTPases Activate WASPs and WAVEs	1	317.2×	0.009	BTK
Fcgamma receptor (FCGR) dependent phagocytosis	1	278.5×	0.010	BTK
Fc epsilon receptor (FCERI) signaling	1	271.9×	0.010	BTK
FCGR3A-mediated phagocytosis	1	187.2×	0.011	BTK
Regulation of actin dynamics for phagocytic cup formation	1	184.2×	0.011	BTK
Toll Like Receptor TLR6:TLR2 Cascade	1	175.7×	0.011	BTK
Toll Like Receptor 2 (TLR2) Cascade	1	173.0×	0.011	BTK
Toll Like Receptor TLR1:TLR2 Cascade	1	167.9×	0.011	BTK
Leishmania infection	1	163.1×	0.011	BTK
Parasitic Infection Pathways	1	163.1×	0.011	BTK
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1	152.3×	0.012	BTK
G alpha (12/13) signalling events	1	137.6×	0.012	BTK
Toll Like Receptor 4 (TLR4) Cascade	1	131.3×	0.012	BTK
ER-Phagosome pathway	1	129.8×	0.012	BTK
Toll-like Receptor Cascades	1	124.1×	0.013	BTK
Potential therapeutics for SARS	1	114.2×	0.013	BTK

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
regulation of B cell cytokine production	1	8426.0×	0.002	BTK
monocyte proliferation	1	8426.0×	0.002	BTK
positive regulation of interleukin-17A production	1	8426.0×	0.002	BTK
positive regulation of type I hypersensitivity	1	4213.0×	0.002	BTK
B cell affinity maturation	1	4213.0×	0.002	BTK
regulation of B cell apoptotic process	1	4213.0×	0.002	BTK
positive regulation of type III hypersensitivity	1	2808.7×	0.002	BTK
NK T cell proliferation	1	2808.7×	0.002	ELF4
proteoglycan catabolic process	1	2808.7×	0.002	BTK
positive regulation of synoviocyte proliferation	1	2808.7×	0.002	BTK
eosinophil homeostasis	1	2808.7×	0.002	BTK
cellular response to molecule of fungal origin	1	2106.5×	0.002	BTK
natural killer cell proliferation	1	1685.2×	0.002	ELF4
histamine secretion by mast cell	1	1685.2×	0.002	BTK
positive regulation of cGAS/STING signaling pathway	1	1053.2×	0.003	BTK
neutrophil homeostasis	1	766.0×	0.004	BTK
cellular response to interleukin-7	1	648.1×	0.005	BTK
positive regulation of B cell differentiation	1	561.7×	0.005	BTK
MyD88-dependent toll-like receptor signaling pathway	1	468.1×	0.005	BTK
negative regulation of B cell proliferation	1	468.1×	0.005	BTK
negative regulation of interleukin-10 production	1	366.4×	0.006	BTK
Fc-epsilon receptor signaling pathway	1	366.4×	0.006	BTK
positive regulation of NLRP3 inflammasome complex assembly	1	290.6×	0.008	BTK
mesoderm development	1	263.3×	0.008	BTK
negative regulation of interleukin-1 beta production	1	255.3×	0.008	ELF4
positive regulation of immunoglobulin production	1	240.7×	0.008	BTK
B cell activation	1	227.7×	0.008	BTK
cell maturation	1	221.7×	0.008	BTK
peptidyl-tyrosine phosphorylation	1	210.7×	0.008	BTK
cellular response to reactive oxygen species	1	205.5×	0.008	BTK

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
BTK	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BTK	84	4
ELF4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	BTK
FEDRATINIB	4	BTK
NERATINIB	4	BTK
IBRUTINIB	4	BTK
ENTRECTINIB	4	BTK
CERITINIB	4	BTK
VANDETANIB	4	BTK
BOSUTINIB	4	BTK
OSIMERTINIB	4	BTK
BRIGATINIB	4	BTK
FUTIBATINIB	4	BTK
ACALABRUTINIB	4	BTK
OLMUTINIB	4	BTK
ZANUBRUTINIB	4	BTK
TIRABRUTINIB	4	BTK
RITLECITINIB	4	BTK
PIRTOBRUTINIB	4	BTK
NINTEDANIB	4	BTK
SUNITINIB	4	BTK
DASATINIB	4	BTK
MITOXANTRONE	4	BTK
CRIZOTINIB	4	BTK
SARACATINIB	3	BTK
CANERTINIB	3	BTK
ENTOSPLETINIB	3	BTK
TESEVATINIB	3	BTK
POZIOTINIB	3	BTK
ROCILETINIB	3	BTK
PYROTINIB	3	BTK
RILZABRUTINIB	3	BTK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BTK	1,836	Binding:1810, Functional:23, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BTK	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
BTK	1,836

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

30 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)
PONATINIB	4	BTK
FEDRATINIB	4	BTK
NERATINIB	4	BTK
IBRUTINIB	4	BTK
ENTRECTINIB	4	BTK
CERITINIB	4	BTK
VANDETANIB	4	BTK
BOSUTINIB	4	BTK
OSIMERTINIB	4	BTK
BRIGATINIB	4	BTK
FUTIBATINIB	4	BTK
ACALABRUTINIB	4	BTK
OLMUTINIB	4	BTK
ZANUBRUTINIB	4	BTK
TIRABRUTINIB	4	BTK
RITLECITINIB	4	BTK
PIRTOBRUTINIB	4	BTK
NINTEDANIB	4	BTK
SUNITINIB	4	BTK
DASATINIB	4	BTK
MITOXANTRONE	4	BTK
CRIZOTINIB	4	BTK
SARACATINIB	3	BTK
CANERTINIB	3	BTK
ENTOSPLETINIB	3	BTK
TESEVATINIB	3	BTK
POZIOTINIB	3	BTK
ROCILETINIB	3	BTK
PYROTINIB	3	BTK
RILZABRUTINIB	3	BTK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BTK
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	ELF4

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)
ELF4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.