isolated growth hormone deficiency type III

Summary

isolated growth hormone deficiency type III (MONDO:0010615) is a disease caused by BTK (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: BTK (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 647

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated growth hormone deficiency type III
Mondo ID	MONDO:0010615
MeSH	C537149
OMIM	307200
Orphanet	231692
DOID	DOID:0060875
SNOMED CT	234533006
UMLS	C0472813
MedGen	141630
GARD	0003921
Is cancer (heuristic)	no

Also known as: congenital IGHD type III · congenital isolated GH deficiency type III · congenital isolated growth hormone deficiency type III · Fleisher syndrome · IGHD3 · isolated growth hormone deficiency type 3 · isolated growth hormone deficiency type III · isolated growth hormone deficiency, type III · isolated growth hormone deficiency, type IIi, with agammaglobulinemia, X-linked recessive · X-linked IGHD · X-linked isolated growth hormone deficiency

Data availability: 647 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

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 III

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 IB, isolated growth hormone deficiency, type 4, isolated growth hormone deficiency, type 5

Subtypes (1): short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia

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

600 retrieved; paginated sample, class counts are floors:

188 likely benign, 149 uncertain significance, 143 pathogenic, 40 likely pathogenic, 37 benign, 18 conflicting classifications of pathogenicity, 16 pathogenic/likely pathogenic, 9 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012315	NM_000061.3(BTK):c.1349+1G>A	BTK	Pathogenic	criteria provided, multiple submitters, no conflicts
1069599	NM_000061.3(BTK):c.62C>A (p.Ser21Ter)	BTK	Pathogenic	criteria provided, single submitter
1071572	NM_000061.3(BTK):c.1379T>A (p.Leu460Ter)	BTK	Pathogenic	criteria provided, single submitter
1071573	NM_000061.3(BTK):c.1102G>T (p.Gly368Ter)	BTK	Pathogenic	criteria provided, single submitter
1072527	NC_000023.10:g.(?100604853)(100609705_?)del	BTK	Pathogenic	criteria provided, single submitter
1072528	NC_000023.10:g.(?100608162)(100615763_?)del	BTK	Pathogenic	criteria provided, single submitter
1075549	NM_000061.3(BTK):c.520+1G>A	BTK	Pathogenic	criteria provided, single submitter
1075550	NM_000061.3(BTK):c.83G>T (p.Arg28Leu)	BTK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076964	NM_000061.3(BTK):c.241-1G>C	BTK	Pathogenic	criteria provided, single submitter
11342	NM_000061.3(BTK):c.1574G>A (p.Arg525Gln)	BTK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11344	NM_000061.3(BTK):c.37C>T (p.Arg13Ter)	BTK	Pathogenic	criteria provided, multiple submitters, no conflicts
11345	NM_000061.3(BTK):c.43C>T (p.Gln15Ter)	BTK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11347	NM_000061.3(BTK):c.1750+5G>A	BTK	Pathogenic	criteria provided, single submitter
11348	NM_000061.3(BTK):c.83G>A (p.Arg28His)	BTK	Pathogenic	criteria provided, multiple submitters, no conflicts
11349	NM_000061.3(BTK):c.2T>C (p.Met1Thr)	BTK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11352	NM_000061.3(BTK):c.228_231del (p.Glu76fs)	BTK	Pathogenic	criteria provided, single submitter
11354	NM_000061.3(BTK):c.310-1G>C	BTK	Pathogenic	criteria provided, single submitter
11357	NM_000061.3(BTK):c.389del (p.Asn130fs)	BTK	Pathogenic	criteria provided, single submitter
11358	NM_000061.3(BTK):c.557dup (p.Pro187fs)	BTK	Pathogenic	criteria provided, single submitter
11362	NM_000061.3(BTK):c.755G>A (p.Trp252Ter)	BTK	Pathogenic	criteria provided, multiple submitters, no conflicts
11363	NM_000061.3(BTK):c.763C>T (p.Arg255Ter)	BTK	Pathogenic	criteria provided, multiple submitters, no conflicts
11366	NM_000061.3(BTK):c.862C>T (p.Arg288Trp)	BTK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11371	NM_000061.3(BTK):c.1125T>G (p.Tyr375Ter)	BTK	Pathogenic	criteria provided, single submitter
11377	NM_000061.3(BTK):c.1558C>T (p.Arg520Ter)	BTK	Pathogenic	criteria provided, multiple submitters, no conflicts
11378	NM_000061.3(BTK):c.1559G>A (p.Arg520Gln)	BTK	Pathogenic	criteria provided, multiple submitters, no conflicts
11383	NM_000061.3(BTK):c.1684C>T (p.Arg562Trp)	BTK	Pathogenic	criteria provided, multiple submitters, no conflicts
11386	NM_000061.3(BTK):c.1773C>A (p.Tyr591Ter)	BTK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11394	NM_000061.3(BTK):c.1685G>C (p.Arg562Pro)	BTK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325383	NM_000061.3(BTK):c.215del (p.Asn72fs)	BTK	Pathogenic	criteria provided, multiple submitters, no conflicts
1356999	NM_000061.3(BTK):c.336C>A (p.Tyr112Ter)	BTK	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · 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

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
GLA	Orphanet:324	Fabry disease

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BTK	HGNC:1133	ENSG00000010671	Q06187	Tyrosine-protein kinase BTK	gencc,clinvar
ARL13A	HGNC:31709	ENSG00000174225	Q5H913	ADP-ribosylation factor-like protein 13A	clinvar
GLA	HGNC:4296	ENSG00000102393	P06280	Alpha-galactosidase A	clinvar

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.
GLA	Alpha-galactosidase A	Catalyzes the hydrolysis of glycosphingolipids and participates in their degradation in the lysosome.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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	9.2×	0.313
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

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
ARL13A	Other/Unknown	no		Small_GTPase_ARF/SAR, P-loop_NTPase, Ciliary_GTPase
GLA	Enzyme (other)	yes	3.2.1.22	Glyco_hydro_27/36_CS, Glyco_hydro_27, Glyco_hydro_b

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	2
mononuclear cell	2
leukocyte	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
pancreatic ductal cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BTK	206	broad	marker	monocyte, mononuclear cell, leukocyte
ARL13A	129	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, left testis
GLA	263	ubiquitous	marker	pancreatic ductal cell, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BTK	4,467
GLA	1,826
ARL13A	527

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BTK	Q06187	156
GLA	P06280	31

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARL13A	Q5H913	70.91

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 51. Enrichment computed across 3 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
G-protein beta:gamma signalling	1	951.7×	0.018	BTK
Diseases of Immune System	1	439.2×	0.018	BTK
Diseases associated with the TLR signaling cascade	1	439.2×	0.018	BTK
G beta:gamma signalling through BTK	1	317.2×	0.018	BTK
MyD88 deficiency (TLR2/4)	1	300.5×	0.018	BTK
IRAK4 deficiency (TLR2/4)	1	285.5×	0.018	BTK
DAP12 interactions	1	237.9×	0.018	BTK
DAP12 signaling	1	184.2×	0.018	BTK
FCERI mediated Ca+2 mobilization	1	178.4×	0.018	BTK
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	178.4×	0.018	BTK
Parasite infection	1	173.0×	0.018	BTK
Leishmania phagocytosis	1	173.0×	0.018	BTK
Signaling by the B Cell Receptor (BCR)	1	173.0×	0.018	BTK
Antigen processing-Cross presentation	1	158.6×	0.018	BTK
RHO GTPases Activate WASPs and WAVEs	1	158.6×	0.018	BTK
Glycosphingolipid metabolism	1	150.3×	0.018	GLA
Glycosphingolipid catabolism	1	146.4×	0.018	GLA
Fcgamma receptor (FCGR) dependent phagocytosis	1	139.3×	0.018	BTK
Fc epsilon receptor (FCERI) signaling	1	135.9×	0.018	BTK
Innate Immune System	2	25.5×	0.018	BTK, GLA
Immune System	2	13.0×	0.018	BTK, GLA
FCGR3A-mediated phagocytosis	1	93.6×	0.021	BTK
Regulation of actin dynamics for phagocytic cup formation	1	92.1×	0.021	BTK
Toll Like Receptor TLR6:TLR2 Cascade	1	87.8×	0.021	BTK
Toll Like Receptor 2 (TLR2) Cascade	1	86.5×	0.021	BTK
Toll Like Receptor TLR1:TLR2 Cascade	1	84.0×	0.021	BTK
Sphingolipid metabolism	1	84.0×	0.021	GLA
Leishmania infection	1	81.6×	0.021	BTK
Parasitic Infection Pathways	1	81.6×	0.021	BTK
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1	76.1×	0.022	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 3 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	5617.3×	0.002	BTK
monocyte proliferation	1	5617.3×	0.002	BTK
positive regulation of interleukin-17A production	1	5617.3×	0.002	BTK
positive regulation of type I hypersensitivity	1	2808.7×	0.002	BTK
B cell affinity maturation	1	2808.7×	0.002	BTK
regulation of B cell apoptotic process	1	2808.7×	0.002	BTK
negative regulation of nitric-oxide synthase activity	1	2808.7×	0.002	GLA
positive regulation of type III hypersensitivity	1	1872.4×	0.002	BTK
proteoglycan catabolic process	1	1872.4×	0.002	BTK
glycosylceramide catabolic process	1	1872.4×	0.002	GLA
positive regulation of synoviocyte proliferation	1	1872.4×	0.002	BTK
eosinophil homeostasis	1	1872.4×	0.002	BTK
cellular response to molecule of fungal origin	1	1404.3×	0.003	BTK
histamine secretion by mast cell	1	1123.5×	0.003	BTK
receptor localization to non-motile cilium	1	1123.5×	0.003	ARL13A
glycoside catabolic process	1	936.2×	0.003	GLA
positive regulation of cGAS/STING signaling pathway	1	702.2×	0.004	BTK
neutrophil homeostasis	1	510.7×	0.005	BTK
glycosphingolipid catabolic process	1	510.7×	0.005	GLA
cellular response to interleukin-7	1	432.1×	0.006	BTK
positive regulation of B cell differentiation	1	374.5×	0.006	BTK
negative regulation of nitric oxide biosynthetic process	1	330.4×	0.007	GLA
MyD88-dependent toll-like receptor signaling pathway	1	312.1×	0.007	BTK
negative regulation of B cell proliferation	1	312.1×	0.007	BTK
negative regulation of interleukin-10 production	1	244.2×	0.008	BTK
Fc-epsilon receptor signaling pathway	1	244.2×	0.008	BTK
oligosaccharide metabolic process	1	234.1×	0.008	GLA
positive regulation of NLRP3 inflammasome complex assembly	1	193.7×	0.009	BTK
mesoderm development	1	175.5×	0.010	BTK
positive regulation of immunoglobulin production	1	160.5×	0.010	BTK

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
GLA	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BTK	84	4
GLA	62	4
ARL13A	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
CLOTRIMAZOLE	4	GLA
METHYSERGIDE	4	GLA
MIGALASTAT	4	GLA
PINACIDIL ANHYDROUS	4	GLA
DOXAZOSIN MESYLATE	4	GLA
AMPICILLIN SODIUM	4	GLA
PHENOXYBENZAMINE HYDROCHLORIDE	4	GLA
METHYSERGIDE MALEATE	4	GLA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
BTK	1,836	Binding:1810, Functional:23, ADMET:3
GLA	114	Binding:104, Functional:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BTK	2.7.10.2	non-specific protein-tyrosine kinase
GLA	3.2.1.22	alpha-galactosidase

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
GLA	114

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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
CLOTRIMAZOLE	4	GLA
METHYSERGIDE	4	GLA
MIGALASTAT	4	GLA
PINACIDIL ANHYDROUS	4	GLA
DOXAZOSIN MESYLATE	4	GLA
AMPICILLIN SODIUM	4	GLA
PHENOXYBENZAMINE HYDROCHLORIDE	4	GLA
METHYSERGIDE MALEATE	4	GLA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	BTK, GLA
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	ARL13A

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)
ARL13A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.