X-linked acrogigantism due to Xq26 microduplication

Summary

X-linked acrogigantism due to Xq26 microduplication (MONDO:0010491) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 9
• Phenotypes (HPO): 36

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		33	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0000098	Tall stature	Very frequent (80-99%)
HP:0000845	Elevated circulating growth hormone concentration	Very frequent (80-99%)
HP:0000870	Increased circulating prolactin concentration	Very frequent (80-99%)
HP:0012503	Abnormality of the pituitary gland	Very frequent (80-99%)
HP:0030269	Increased circulating insulin-like growth factor 1 concentration	Very frequent (80-99%)
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0001072	Thickened skin	Frequent (30-79%)
HP:0002591	Polyphagia	Frequent (30-79%)
HP:0002893	Pituitary adenoma	Frequent (30-79%)
HP:0004924	Abnormal oral glucose tolerance	Frequent (30-79%)
HP:0008283	Fasting hyperinsulinemia	Frequent (30-79%)
HP:0010535	Sleep apnea	Frequent (30-79%)
HP:0025163	Abnormality of optic chiasm morphology	Frequent (30-79%)
HP:0025267	Snoring	Frequent (30-79%)
HP:0031098	Decreased thyroid-stimulating hormone level	Frequent (30-79%)
HP:0031418	Increased body mass index	Frequent (30-79%)
HP:0000135	Hypogonadism	Occasional (5-29%)
HP:0000699	Diastema	Occasional (5-29%)
HP:0000823	Delayed puberty	Occasional (5-29%)
HP:0000873	Diabetes insipidus	Occasional (5-29%)
HP:0000924	Abnormality of the skeletal system	Occasional (5-29%)
HP:0000956	Acanthosis nigricans	Occasional (5-29%)
HP:0001123	Visual field defect	Occasional (5-29%)
HP:0001176	Large hands	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001626	Abnormality of the cardiovascular system	Occasional (5-29%)
HP:0001833	Long foot	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0003270	Abdominal distention	Occasional (5-29%)
HP:0011748	Adrenocorticotropic hormone deficiency	Occasional (5-29%)
HP:0012505	Enlarged pituitary gland	Occasional (5-29%)
HP:0040075	Hypopituitarism	Occasional (5-29%)
HP:0000707	Abnormality of the nervous system	Very rare (<1-4%)
HP:0001249	Intellectual disability	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked acrogigantism due to Xq26 microduplication
Mondo ID	MONDO:0010491
OMIM	300942
Orphanet	300373, 448372
SNOMED CT	768472004
UMLS	C3891556
MedGen	856021
GARD	0018433
Is cancer (heuristic)	no

Also known as: chromosome xq26.3 duplication syndrome, X-linked dominant · familial infantile gigantism due to dup(X)q(26) · familial infantile gigantism due to Xq26 microduplication · X-LAG (X-linked acrogigantism) due to dup(X)q(26)

Data availability: 9 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › X-linked acrogigantism due to Xq26 microduplication

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked lissencephaly with abnormal genitalia, X-linked severe congenital neutropenia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked erythropoietic protoporphyria, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

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

9 retrieved; paginated sample, class counts are floors:

4 likely pathogenic, 2 pathogenic, 2 uncertain significance, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
224866	GRCh37/hg19 Xq26.3(chrX:135602028-136259908)x2	ARHGEF6	Pathogenic	criteria provided, single submitter
243065	Single allele	ARHGEF6	Pathogenic	criteria provided, single submitter
374409	Single allele	ARHGEF6	Likely pathogenic	criteria provided, single submitter
374410	Single allele	ARHGEF6	Likely pathogenic	criteria provided, single submitter
374411	Single allele	ARHGEF6	Likely pathogenic	criteria provided, single submitter
374412	Single allele	ARHGEF6	Likely pathogenic	criteria provided, single submitter
2252347	NM_054021.2(GPR101):c.1493T>C (p.Ile498Thr)	GPR101	Uncertain significance	criteria provided, multiple submitters, no conflicts
3893147	NM_054021.2(GPR101):c.677T>C (p.Leu226Pro)	GPR101	Uncertain significance	criteria provided, single submitter
1810323	GRCh37/hg19 Xq26.3(chrX:136647475-136892054)x3	ZIC3	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZIC3	Orphanet:157769	Situs ambiguus
ZIC3	Orphanet:216718	Isolated congenitally uncorrected transposition of the great arteries
GPR101	Orphanet:963	Acromegaly
ARHGEF6	Orphanet:777	X-linked non-syndromic intellectual disability

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
ZIC3	HGNC:12874	ENSG00000156925	O60481	Zinc finger protein ZIC 3	clinvar
GPR101	HGNC:14963	ENSG00000165370	Q96P66	Probable G-protein coupled receptor 101	clinvar
ARHGEF6	HGNC:685	ENSG00000129675	Q15052	Rho guanine nucleotide exchange factor 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZIC3	Zinc finger protein ZIC 3	Acts as a transcriptional activator.
GPR101	Probable G-protein coupled receptor 101	Orphan receptor.
ARHGEF6	Rho guanine nucleotide exchange factor 6	Acts as a RAC1 guanine nucleotide exchange factor (GEF).

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.33

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	8.0×	0.246
Scaffold/PPI	1	5.8×	0.246
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZIC3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Znf_ZIC
GPR101	GPCR	yes		GPCR_Rhodpsn, GPCR_Rhodpsn_7TM
ARHGEF6	Scaffold/PPI	no		DH_dom, SH3_domain, CH_dom

Expression context

Cohort genes with no expression data: 0.

3 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
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
caudate nucleus	1
hypothalamus	1
nucleus accumbens	1
biceps brachii	1
medial globus pallidus	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZIC3	81	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
GPR101	23	tissue_specific	marker	nucleus accumbens, caudate nucleus, hypothalamus
ARHGEF6	289	ubiquitous	marker	biceps brachii, skeletal muscle tissue of biceps brachii, medial globus pallidus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARHGEF6	1,668
ZIC3	1,600
GPR101	837

Intra-cohort edges

A	B	Sources
ARHGEF6	GPR101	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GPR101	Q96P66	3
ZIC3	O60481	2
ARHGEF6	Q15052	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. 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×	0.013	ARHGEF6
Regulation of cytoskeletal remodeling and cell spreading by IPP complex components	1	713.8×	0.013	ARHGEF6
POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation	1	439.2×	0.013	ZIC3
Cell-extracellular matrix interactions	1	335.9×	0.013	ARHGEF6
G beta:gamma signalling through CDC42	1	285.5×	0.013	ARHGEF6
Transcriptional regulation of pluripotent stem cells	1	271.9×	0.013	ZIC3
RHOU GTPase cycle	1	139.3×	0.022	ARHGEF6
Cell death signalling via NRAGE, NRIF and NADE	1	109.8×	0.022	ARHGEF6
p75 NTR receptor-mediated signalling	1	93.6×	0.022	ARHGEF6
Cell junction organization	1	93.6×	0.022	ARHGEF6
NRAGE signals death through JNK	1	92.1×	0.022	ARHGEF6
Death Receptor Signaling	1	69.6×	0.023	ARHGEF6
Cell-Cell communication	1	68.8×	0.023	ARHGEF6
G alpha (12/13) signalling events	1	68.8×	0.023	ARHGEF6
CDC42 GTPase cycle	1	36.1×	0.040	ARHGEF6
RAC1 GTPase cycle	1	30.5×	0.043	ARHGEF6
RHO GTPase cycle	1	30.1×	0.043	ARHGEF6
GPCR downstream signalling	1	21.7×	0.056	ARHGEF6
Signaling by GPCR	1	20.0×	0.057	ARHGEF6
Signaling by Rho GTPases	1	17.1×	0.062	ARHGEF6
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.062	ARHGEF6
Signal Transduction	1	5.1×	0.187	ARHGEF6

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
central nervous system segmentation	1	5617.3×	0.004	ZIC3
neural plate development	1	2808.7×	0.004	ZIC3
determination of left/right asymmetry in nervous system	1	2808.7×	0.004	ZIC3
atrial cardiac muscle tissue development	1	1404.3×	0.004	ZIC3
determination of pancreatic left/right asymmetry	1	1123.5×	0.004	ZIC3
axial mesoderm development	1	1123.5×	0.004	ZIC3
germ-line stem cell population maintenance	1	936.2×	0.004	ZIC3
determination of digestive tract left/right asymmetry	1	936.2×	0.004	ZIC3
determination of liver left/right asymmetry	1	936.2×	0.004	ZIC3
paraxial mesoderm development	1	561.7×	0.006	ZIC3
outer ear morphogenesis	1	510.7×	0.006	ZIC3
primitive streak formation	1	468.1×	0.006	ZIC3
left/right axis specification	1	401.2×	0.006	ZIC3
adenylate cyclase-activating adrenergic receptor signaling pathway	1	401.2×	0.006	GPR101
limb morphogenesis	1	351.1×	0.007	ZIC3
cranial skeletal system development	1	312.1×	0.007	ZIC3
face development	1	267.5×	0.008	ZIC3
olfactory bulb development	1	255.3×	0.008	ZIC3
embryonic pattern specification	1	181.2×	0.010	ZIC3
lamellipodium assembly	1	147.8×	0.012	ARHGEF6
mRNA transcription by RNA polymerase II	1	110.1×	0.015	ZIC3
stem cell differentiation	1	100.3×	0.016	ZIC3
JNK cascade	1	90.6×	0.016	ARHGEF6
heart looping	1	89.2×	0.016	ZIC3
determination of left/right symmetry	1	85.1×	0.016	ZIC3
hippocampus development	1	77.0×	0.017	ZIC3
lung development	1	66.1×	0.020	ZIC3
smoothened signaling pathway	1	60.4×	0.021	ZIC3
skeletal system development	1	41.9×	0.029	ZIC3
central nervous system development	1	38.5×	0.030	ZIC3

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ZIC3	0	0
GPR101	0	0
ARHGEF6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ARHGEF6	6	Binding:6
GPR101	2	Binding:2

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

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	1	GPR101
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ZIC3, ARHGEF6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ZIC3	0	—
GPR101	2	—
ARHGEF6	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.