Aarskog-Scott syndrome, X-linked

Summary

Aarskog-Scott syndrome, X-linked (MONDO:0010589) is a disease caused by FGD1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: FGD1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 91

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Aarskog-Scott syndrome, X-linked
Mondo ID	MONDO:0010589
MeSH	C535331
OMIM	305400
DOID	DOID:6683
NCIT	C129720
SNOMED CT	14921002
UMLS	C0175701
MedGen	61234
GARD	0024738
MedDRA	10067148
Is cancer (heuristic)	no

Also known as: Aarskog disease · Aarskog Scott syndrome · Aarskog syndrome · Aarskog syndrome, X-linked · Aarskog-like syndrome · Aarskog-Scott syndrome · Aarskog-Scott syndrome, X-linked · Aarskog-Scott syndrome, X-linked recessive · AAS · facio-digito-genital dysplasia · faciodigitogenital syndrome · faciodigitogenital syndrome, recessive · faciogenital dysplasia · FGD · FGDY · mental retardation, X-linked syndromic 16, X-linked recessive · mental retardation, X-linked, syndromic 16 · mental retardation, X-linked, syndromic 16, included · MRXS16, included · Scott Aarskog syndrome

Data availability: 91 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › Aarskog-Scott syndrome, X-linked

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, X-linked acrogigantism due to Xq26 microduplication, 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, 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

91 retrieved; paginated sample, class counts are floors:

31 uncertain significance, 21 pathogenic, 19 likely pathogenic, 9 conflicting classifications of pathogenicity, 5 pathogenic/likely pathogenic, 2 likely benign, 2 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
10824	NM_004463.3(FGD1):c.1392dup (p.Lys465fs)	FGD1	Pathogenic	no assertion criteria provided
10825	NM_004463.3(FGD1):c.1829G>A (p.Arg610Gln)	FGD1	Pathogenic	criteria provided, multiple submitters, no conflicts
10826	NM_004463.3(FGD1):c.1565G>A (p.Arg522His)	FGD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10827	NG_008054.1:g.(35701_?)_(?_50820)del	FGD1	Pathogenic	no assertion criteria provided
10831	NM_004463.3(FGD1):c.2192del (p.Lys731fs)	FGD1	Pathogenic	no assertion criteria provided
10832	NM_004463.3(FGD1):c.1328G>T (p.Arg443Leu)	FGD1	Pathogenic	no assertion criteria provided
10833	NM_004463.3(FGD1):c.944dup (p.Ala316fs)	FGD1	Pathogenic	criteria provided, single submitter
10834	NM_004463.3(FGD1):c.1396A>G (p.Met466Val)	FGD1	Pathogenic	no assertion criteria provided
29974	NM_004463.3(FGD1):c.1966C>T (p.Arg656Ter)	FGD1	Pathogenic	criteria provided, multiple submitters, no conflicts
3075723	NM_004463.3(FGD1):c.2016-36A>T	FGD1	Pathogenic	criteria provided, single submitter
3254768	NM_004463.3(FGD1):c.1564dup (p.Arg522fs)	FGD1	Pathogenic	criteria provided, single submitter
3255138	NM_004463.3(FGD1):c.1341G>A (p.Trp447Ter)	FGD1	Pathogenic	criteria provided, single submitter
374329	NM_004463.3(FGD1):c.527del (p.Pro176fs)	FGD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4531337	NM_004463.3(FGD1):c.1068del (p.Val357fs)	FGD1	Pathogenic	criteria provided, single submitter
496830	NM_004463.3(FGD1):c.577C>T (p.Arg193Ter)	FGD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
547364	NM_004463.3(FGD1):c.277dup (p.Tyr93fs)	FGD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
547370	NM_004463.3(FGD1):c.2728C>T (p.Arg910Ter)	FGD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694679	NM_004463.3(FGD1):c.1143_1145del (p.Leu382del)	FGD1	Pathogenic	criteria provided, single submitter
694686	NM_004463.3(FGD1):c.1590T>A (p.Tyr530Ter)	FGD1	Pathogenic	criteria provided, single submitter
804011	NM_004463.3(FGD1):c.1843-1G>A	FGD1	Pathogenic	criteria provided, single submitter
804012	NM_004463.3(FGD1):c.1452G>A (p.Trp484Ter)	FGD1	Pathogenic	criteria provided, single submitter
869445	NM_004463.3(FGD1):c.679del (p.Ser227fs)	FGD1	Pathogenic	criteria provided, single submitter
931968	NM_004463.3(FGD1):c.1695+1G>A	FGD1	Pathogenic	criteria provided, single submitter
981474	NM_004463.3(FGD1):c.1422del (p.Phe474fs)	FGD1	Pathogenic	no assertion criteria provided
981475	NM_004463.3(FGD1):c.367del (p.Ser122_Leu123insTer)	FGD1	Pathogenic	no assertion criteria provided
982779	NM_004463.3(FGD1):c.545del (p.Pro182fs)	FGD1	Pathogenic	criteria provided, single submitter
1031428	NM_004463.3(FGD1):c.2017A>G (p.Thr673Ala)	FGD1	Likely pathogenic	criteria provided, single submitter
1679314	NM_004463.3(FGD1):c.1336G>T (p.Glu446Ter)	FGD1	Likely pathogenic	criteria provided, single submitter
1705427	NM_004463.3(FGD1):c.2656A>T (p.Arg886Ter)	FGD1	Likely pathogenic	criteria provided, single submitter
1709736	NM_004463.3(FGD1):c.2514G>A (p.Trp838Ter)	FGD1	Likely pathogenic	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
FGD1	Definitive	X-linked	Aarskog-Scott syndrome, X-linked	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGD1	Orphanet:915	Aarskog-Scott syndrome

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
FGD1	HGNC:3663	ENSG00000102302	P98174	FYVE, RhoGEF and PH domain-containing protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGD1	FYVE, RhoGEF and PH domain-containing protein 1	Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP.

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)
FGD1	Transcription factor	no		DH_dom, Znf_FYVE, PH_domain

Expression context

Cohort genes with no expression data: 0.

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
cortical plate	1
ganglionic eminence	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGD1	179	ubiquitous	yes	cortical plate, stromal cell of endometrium, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGD1	932

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FGD1	P98174	66.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
NRAGE signals death through JNK	1	184.2×	0.011	FGD1
G alpha (12/13) signalling events	1	137.6×	0.011	FGD1
CDC42 GTPase cycle	1	72.3×	0.014	FGD1

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
filopodium assembly	1	648.1×	0.008	FGD1
regulation of GTPase activity	1	510.7×	0.008	FGD1
animal organ morphogenesis	1	191.5×	0.011	FGD1
regulation of small GTPase mediated signal transduction	1	144.0×	0.011	FGD1
cytoskeleton organization	1	132.7×	0.011	FGD1
regulation of cell shape	1	123.0×	0.011	FGD1
actin cytoskeleton organization	1	79.1×	0.014	FGD1
signal transduction	1	16.1×	0.062	FGD1

Therapeutics

Drug target analysis

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

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
FGD1	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
FGD1	1	Binding:1

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	FGD1

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)
FGD1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.