Intellectual disability-severe speech delay-mild dysmorphism syndrome

Summary

Intellectual disability-severe speech delay-mild dysmorphism syndrome (MONDO:0013352) is a disease caused by FOXP1 (GenCC Definitive), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FOXP1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 183
• Phenotypes (HPO): 60
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		48	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

60 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0002474	Expressive language delay	Very frequent (80-99%)
HP:0009088	Speech articulation difficulties	Very frequent (80-99%)
HP:0011220	Prominent forehead	Very frequent (80-99%)
HP:0000119	Abnormality of the genitourinary system	Frequent (30-79%)
HP:0000194	Open mouth	Frequent (30-79%)
HP:0000303	Mandibular prognathia	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000403	Recurrent otitis media	Frequent (30-79%)
HP:0000455	Broad nasal tip	Frequent (30-79%)
HP:0000478	Abnormality of the eye	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000494	Downslanted palpebral fissures	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000539	Abnormality of refraction	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0000736	Short attention span	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0000954	Single transverse palmar crease	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001371	Flexion contracture	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001627	Abnormal heart morphology	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002236	Frontal upsweep of hair	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0002714	Downturned corners of mouth	Frequent (30-79%)
HP:0002788	Recurrent upper respiratory tract infections	Frequent (30-79%)
HP:0003196	Short nose	Frequent (30-79%)
HP:0005272	Prominent nasolabial fold	Frequent (30-79%)
HP:0007301	Oromotor apraxia	Frequent (30-79%)
HP:0008762	Repetitive compulsive behavior	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0011823	Chin with horizontal crease	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012471	Thick vermilion border	Frequent (30-79%)
HP:0410263	Brain imaging abnormality	Frequent (30-79%)
HP:0000077	Abnormality of the kidney	Occasional (5-29%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000278	Retrognathia	Occasional (5-29%)
HP:0000581	Blepharophimosis	Occasional (5-29%)
HP:0000598	Abnormality of the ear	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000819	Diabetes mellitus	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0001212	Prominent fingertip pads	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability-severe speech delay-mild dysmorphism syndrome
Mondo ID	MONDO:0013352
OMIM	613670
Orphanet	391372
DOID	DOID:0111331
UMLS	C4013764
MedGen	862201
GARD	0012501
Is cancer (heuristic)	no

Also known as: FOXP1 haploinsufficiency · FOXP1 related global developmental delay, intellectual disability and speech defects · FOXP1 syndrome · FOXP1-related neurodevelopmental disorder · intellectual disability with language impairment and with or without autistic features · intellectual disability-severe speech delay-mild dysmorphism syndrome · mental retardation with language impairment and with or without autistic features

Data availability: 183 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › autosomal dominant syndromic intellectual disability › intellectual disability-severe speech delay-mild dysmorphism syndrome

Related subtypes (33): Myhre syndrome, KBG syndrome, Rubinstein-Taybi syndrome due to CREBBP mutations, Mowat-Wilson syndrome, Schinzel-Giedion syndrome, intellectual disability-sparse hair-brachydactyly syndrome, Pierpont syndrome, Bohring-Opitz syndrome, hereditary cryohydrocytosis with reduced stomatin, Rubinstein-Taybi syndrome due to EP300 haploinsufficiency, DYRK1A-related intellectual disability syndrome, intellectual disability, autosomal dominant 13, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, CTCF-related neurodevelopmental disorder, Bosch-Boonstra-Schaaf optic atrophy syndrome, autism spectrum disorder due to AUTS2 deficiency, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, intellectual developmental disorder with dysmorphic facies and ptosis, intellectual disability, autosomal dominant 48, SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, SIN3A-related intellectual disability syndrome, Ververi-Brady syndrome 1, intellectual developmental disorder with dysmorphic facies and behavioral abnormalities, intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities, SATB2 associated disorder

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

183 retrieved; paginated sample, class counts are floors:

61 pathogenic, 54 uncertain significance, 39 likely pathogenic, 17 conflicting classifications of pathogenicity, 7 pathogenic/likely pathogenic, 2 not provided, 1 benign/likely benign, 1 likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1164044	NM_001349338.3(FOXP1):c.1553G>A (p.Ser518Asn)	FOXP1	Pathogenic	no assertion criteria provided
156540	NC_000003.12:g.70992485_71180270del	FOXP1	Pathogenic	no assertion criteria provided
1679344	NM_001349338.3(FOXP1):c.488del (p.His163fs)	FOXP1	Pathogenic	criteria provided, single submitter
1679348	NM_001349338.3(FOXP1):c.825del (p.Ser276fs)	FOXP1	Pathogenic	criteria provided, single submitter
1685827	NM_001349338.3(FOXP1):c.2018del (p.Asn673fs)	FOXP1	Pathogenic	criteria provided, single submitter
1685828	NM_001349338.3(FOXP1):c.975-2A>G	FOXP1	Pathogenic	criteria provided, single submitter
1698739	NM_001349338.3(FOXP1):c.738del (p.Asn247fs)	FOXP1	Pathogenic	criteria provided, single submitter
1699444	NM_001349338.3(FOXP1):c.1653_1669del (p.Asn552fs)	FOXP1	Pathogenic	criteria provided, single submitter
1701967	NM_001349338.3(FOXP1):c.494del (p.Gly165fs)	FOXP1	Pathogenic	criteria provided, single submitter
1802625	NM_001349338.3(FOXP1):c.1569_1570insA (p.Val524fs)	FOXP1	Pathogenic	criteria provided, single submitter
1803026	NM_001349338.3(FOXP1):c.573dup (p.Gln192fs)	FOXP1	Pathogenic	criteria provided, single submitter
1803027	NM_001349338.3(FOXP1):c.580C>T (p.Gln194Ter)	FOXP1	Pathogenic	criteria provided, single submitter
1805541	NM_001349338.3(FOXP1):c.1147-1_1161dup	FOXP1	Pathogenic	criteria provided, single submitter
1805564	NM_001349338.3(FOXP1):c.1241del (p.Leu414fs)	FOXP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1806120	NM_001349338.3(FOXP1):c.482_483dup (p.Gln162fs)	FOXP1	Pathogenic	criteria provided, single submitter
18428	NM_001349338.3(FOXP1):c.1573C>T (p.Arg525Ter)	FOXP1	Pathogenic	criteria provided, multiple submitters, no conflicts
194567	NM_001349338.3(FOXP1):c.1240dup (p.Leu414fs)	FOXP1	Pathogenic	criteria provided, multiple submitters, no conflicts
211038	NM_001349338.3(FOXP1):c.1507C>T (p.Arg503Ter)	FOXP1	Pathogenic	criteria provided, multiple submitters, no conflicts
211040	NM_001349338.3(FOXP1):c.1541G>A (p.Arg514His)	FOXP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217264	NM_001349338.3(FOXP1):c.1393A>G (p.Arg465Gly)	FOXP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217265	NM_001349338.3(FOXP1):c.1540C>T (p.Arg514Cys)	FOXP1	Pathogenic	criteria provided, multiple submitters, no conflicts
217266	NM_001349338.3(FOXP1):c.1317C>G (p.Tyr439Ter)	FOXP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2442365	NM_001349338.3(FOXP1):c.913_914del (p.His305fs)	FOXP1	Pathogenic	criteria provided, single submitter
2442375	NM_001349338.3(FOXP1):c.1321_1324dup (p.Lys442fs)	FOXP1	Pathogenic	criteria provided, single submitter
2443999	NM_001349338.3(FOXP1):c.1530+1G>T	FOXP1	Pathogenic	no assertion criteria provided
2577433	NM_001349338.3(FOXP1):c.930G>A (p.Trp310Ter)	FOXP1	Pathogenic	no assertion criteria provided
3370498	NM_001349338.3(FOXP1):c.1590del (p.Ala532fs)	FOXP1	Pathogenic	criteria provided, single submitter
3387770	NM_001349338.3(FOXP1):c.501delinsTGTTGTTTT (p.Gln167fs)	FOXP1	Pathogenic	criteria provided, single submitter
3764093	NM_001349338.3(FOXP1):c.604C>T (p.Gln202Ter)	FOXP1	Pathogenic	no assertion criteria provided
3764550	NM_001349338.3(FOXP1):c.1333_1335delinsAA (p.Val445fs)	FOXP1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
FOXP1	Definitive	Autosomal dominant	intellectual disability-severe speech delay-mild dysmorphism syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOXP1	Orphanet:391372	FOXP1 Syndrome
FOXP1	Orphanet:52417	MALT lymphoma
FOXP1	Orphanet:585877	B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality

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
FOXP1	HGNC:3823	ENSG00000114861	Q9H334	Forkhead box protein P1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FOXP1	Forkhead box protein P1	Transcriptional repressor.

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)
FOXP1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_2, FOXP-CC

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
cardia of stomach	1
oviduct epithelium	1
pancreatic ductal cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOXP1	256	ubiquitous	marker	pancreatic ductal cell, oviduct epithelium, cardia of stomach

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FOXP1	2,939

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FOXP1	Q9H334	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Transcriptional regulation of pluripotent stem cells	1	543.8×	0.002	FOXP1

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
regulation of macrophage colony-stimulating factor production	1	16852.0×	0.001	FOXP1
regulation of monocyte differentiation	1	8426.0×	0.001	FOXP1
regulation of defense response to bacterium	1	8426.0×	0.001	FOXP1
positive regulation of interleukin-21 production	1	5617.3×	0.001	FOXP1
regulation of chemokine (C-X-C motif) ligand 2 production	1	5617.3×	0.001	FOXP1
regulation of interleukin-12 production	1	4213.0×	0.001	FOXP1
positive regulation of hydrogen peroxide-mediated programmed cell death	1	4213.0×	0.001	FOXP1
regulation of endothelial tube morphogenesis	1	3370.4×	0.001	FOXP1
positive regulation of B cell receptor signaling pathway	1	2407.4×	0.001	FOXP1
regulation of interleukin-1 beta production	1	2106.5×	0.001	FOXP1
osteoclast development	1	2106.5×	0.001	FOXP1
monocyte activation	1	1872.4×	0.001	FOXP1
regulation of tumor necrosis factor production	1	1685.2×	0.001	FOXP1
endothelial cell activation	1	1685.2×	0.001	FOXP1
negative regulation of B cell apoptotic process	1	1532.0×	0.001	FOXP1
negative regulation of cell growth involved in cardiac muscle cell development	1	1404.3×	0.001	FOXP1
T follicular helper cell differentiation	1	1404.3×	0.001	FOXP1
striatum development	1	1123.5×	0.002	FOXP1
negative regulation of androgen receptor signaling pathway	1	936.2×	0.002	FOXP1
macrophage activation	1	702.2×	0.002	FOXP1
response to testosterone	1	468.1×	0.003	FOXP1
osteoclast differentiation	1	343.9×	0.004	FOXP1
positive regulation of smooth muscle cell proliferation	1	330.4×	0.004	FOXP1
positive regulation of endothelial cell migration	1	251.5×	0.005	FOXP1
regulation of inflammatory response	1	168.5×	0.008	FOXP1
cellular response to tumor necrosis factor	1	163.6×	0.008	FOXP1
response to lipopolysaccharide	1	124.8×	0.009	FOXP1
regulation of gene expression	1	83.4×	0.014	FOXP1
negative regulation of gene expression	1	69.1×	0.016	FOXP1
DNA damage response	1	53.5×	0.020	FOXP1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FOXP1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	FOXP1

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)
FOXP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03718923	Not specified	RECRUITING	FOXP1 Syndrome: The Seaver Autism Center for Research and Treatment is Characterizing FOXP1-related Neurodevelopmental Disorders Using Genetic, Medical, and Neuropsychological Measures.
NCT06211673	Not specified	COMPLETED	Psychiatric Phenotype Characterization of Individuals With FOXP1 Syndrome