Myhre syndrome

Summary

Myhre syndrome (MONDO:0007688) is a disease caused by SMAD4 (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SMAD4 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 225
• Phenotypes (HPO): 47
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

47 HPO clinical features (Orphanet curated; top 47 by frequency):

HPO ID	Term	Frequency
HP:0000160	Narrow mouth	Very frequent (80-99%)
HP:0000233	Thin vermilion border	Very frequent (80-99%)
HP:0000303	Mandibular prognathia	Very frequent (80-99%)
HP:0000327	Hypoplasia of the maxilla	Very frequent (80-99%)
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000772	Abnormal rib morphology	Very frequent (80-99%)
HP:0000926	Platyspondyly	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001328	Specific learning disability	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0003172	Abnormality of the pubic bone	Very frequent (80-99%)
HP:0003510	Severe short stature	Very frequent (80-99%)
HP:0003712	Skeletal muscle hypertrophy	Very frequent (80-99%)
HP:0004279	Short palm	Very frequent (80-99%)
HP:0004493	Craniofacial hyperostosis	Very frequent (80-99%)
HP:0008818	Large iliac wings	Very frequent (80-99%)
HP:0011800	Midface retrusion	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000159	Abnormal lip morphology	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000581	Blepharophimosis	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0000944	Abnormal metaphysis morphology	Frequent (30-79%)
HP:0001072	Thickened skin	Frequent (30-79%)
HP:0001671	Abnormal cardiac septum morphology	Frequent (30-79%)
HP:0003457	EMG abnormality	Frequent (30-79%)
HP:0005930	Abnormality of epiphysis morphology	Frequent (30-79%)
HP:0008499	High hypermetropia	Frequent (30-79%)
HP:0012745	Short palpebral fissure	Frequent (30-79%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000036	Abnormality of the penis	Occasional (5-29%)
HP:0000039	Epispadias	Occasional (5-29%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000135	Hypogonadism	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000176	Submucous cleft hard palate	Occasional (5-29%)
HP:0000193	Bifid uvula	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000826	Precocious puberty	Occasional (5-29%)
HP:0003241	External genital hypoplasia	Occasional (5-29%)
HP:0030690	Gingival cleft	Occasional (5-29%)
HP:0100333	Unilateral cleft lip	Occasional (5-29%)
HP:0100541	Femoral hernia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Myhre syndrome
Mondo ID	MONDO:0007688
MeSH	C537620
OMIM	139210
Orphanet	2588
NCIT	C123815
SNOMED CT	699316006
UMLS	C0796081
MedGen	167103
GARD	0002572
NORD	1481
Is cancer (heuristic)	no

Also known as: facial dysmorphism - intellectual deficit - short stature - hearing loss · facial dysmorphism-intellectual disability-short stature-hearing loss syndrome · Growth mental deficiency syndrome of Myhre · LAPS syndrome · Myhre syndrome · MYHRS

Data availability: 225 ClinVar variants · 4 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › Myhre syndrome

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

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

225 retrieved; paginated sample, class counts are floors:

124 uncertain significance, 40 conflicting classifications of pathogenicity, 24 benign, 23 benign/likely benign, 8 pathogenic, 3 likely pathogenic, 2 pathogenic/likely pathogenic, 1 benign; confers sensitivity

ClinVar	Variant (HGVS)	Gene	Classification	Review
3892514	NC_000015.10:g.48310852_48310879dup	DUT-AS1	Pathogenic	criteria provided, single submitter
142253	NM_005359.6(SMAD4):c.1245_1248del (p.Asp415Glufs)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
1734287	NM_005359.6(SMAD4):c.372_373dup (p.Ser125fs)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
24832	NM_005359.6(SMAD4):c.1082G>A (p.Arg361His)	SMAD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2626886	NM_005359.6(SMAD4):c.875del (p.Pro292fs)	SMAD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30149	NM_005359.6(SMAD4):c.1499T>C (p.Ile500Thr)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
30150	NM_005359.6(SMAD4):c.1498A>G (p.Ile500Val)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
30151	NM_005359.6(SMAD4):c.1500A>G (p.Ile500Met)	SMAD4	Pathogenic	criteria provided, single submitter
3341089	R496C	SMAD4	Pathogenic	no assertion criteria provided
548563	NM_005359.6(SMAD4):c.1308+2T>C	SMAD4	Pathogenic	criteria provided, single submitter
2572319	NM_005359.6(SMAD4):c.50_51del (p.Leu17fs)	SMAD4	Likely pathogenic	criteria provided, single submitter
3383020	NM_005359.6(SMAD4):c.1541del (p.Pro514fs)	SMAD4	Likely pathogenic	criteria provided, single submitter
3583369	NM_005359.6(SMAD4):c.1060_1066delinsT (p.Val354_Pro356delinsSer)	SMAD4	Likely pathogenic	criteria provided, single submitter
127950	NM_005359.6(SMAD4):c.424+5G>A	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136074	NM_005359.6(SMAD4):c.1653A>G (p.Leu551=)	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136077	NM_005359.6(SMAD4):c.671A>T (p.Gln224Leu)	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
139219	NM_005359.6(SMAD4):c.1140-10T>C	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
142165	NM_005359.6(SMAD4):c.1106A>G (p.Asn369Ser)	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
182869	NM_005359.6(SMAD4):c.677C>T (p.Ala226Val)	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
182870	NM_005359.6(SMAD4):c.917A>G (p.Asn306Ser)	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
183733	NM_005359.6(SMAD4):c.20C>T (p.Thr7Met)	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
183751	NM_005359.6(SMAD4):c.852A>G (p.Gln284=)	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
183887	NM_005359.6(SMAD4):c.21G>A (p.Thr7=)	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
185866	NM_005359.6(SMAD4):c.535A>G (p.Ile179Val)	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
188234	NM_005359.6(SMAD4):c.172A>G (p.Ile58Val)	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
231829	NM_005359.6(SMAD4):c.70A>G (p.Met24Val)	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
232751	NM_005359.6(SMAD4):c.736C>A (p.Pro246Thr)	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240146	NM_005359.6(SMAD4):c.1644A>G (p.Pro548=)	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240149	NM_005359.6(SMAD4):c.342T>C (p.Tyr114=)	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327107	NM_005359.6(SMAD4):c.-128+12A>G	SMAD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 5 · 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
SMAD4	Definitive	Autosomal dominant	Myhre syndrome	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMAD4	Orphanet:1333	Familial pancreatic carcinoma
SMAD4	Orphanet:2588	Myhre syndrome
SMAD4	Orphanet:329971	Generalized juvenile polyposis/juvenile polyposis coli
SMAD4	Orphanet:774	Hereditary hemorrhagic telangiectasia
SMAD4	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMAD4	HGNC:6770	ENSG00000141646	Q13485	SMAD family member 4	gencc,clinvar
DUT-AS1	HGNC:55420	ENSG00000259488		DUT antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMAD4	SMAD family member 4	In muscle physiology, plays a central role in the balance between atrophy and hypertrophy.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMAD4	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
DUT-AS1	Other/Unknown	no

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
calcaneal tendon	1
ganglionic eminence	1
ventricular zone	1
bone marrow cell	1
colonic epithelium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMAD4	288	ubiquitous	marker	ventricular zone, ganglionic eminence, calcaneal tendon
DUT-AS1	132		marker	sural nerve, colonic epithelium, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMAD4	7,320
DUT-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMAD4	Q13485	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. 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
Loss of Function of SMAD4 in Cancer	1	3806.7×	0.004	SMAD4
SMAD4 MH2 Domain Mutants in Cancer	1	3806.7×	0.004	SMAD4
SMAD2/3 MH2 Domain Mutants in Cancer	1	3806.7×	0.004	SMAD4
RUNX3 regulates BCL2L11 (BIM) transcription	1	2284.0×	0.004	SMAD4
Loss of Function of SMAD2/3 in Cancer	1	1903.3×	0.004	SMAD4
Signaling by TGF-beta Receptor Complex in Cancer	1	1903.3×	0.004	SMAD4
RUNX3 regulates CDKN1A transcription	1	1631.4×	0.004	SMAD4
Transcriptional regulation of brown and beige adipocyte differentiation	1	1142.0×	0.005	SMAD4
RUNX2 regulates bone development	1	815.7×	0.005	SMAD4
Signaling by Activin	1	761.3×	0.005	SMAD4
Formation of definitive endoderm	1	713.8×	0.005	SMAD4
FOXO-mediated transcription of cell cycle genes	1	671.8×	0.005	SMAD4
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	1	671.8×	0.005	SMAD4
Germ layer formation at gastrulation	1	671.8×	0.005	SMAD4
Transcriptional regulation of pluripotent stem cells	1	543.8×	0.006	SMAD4
Signaling by NODAL	1	496.5×	0.006	SMAD4
TGFBR3 expression	1	456.8×	0.006	SMAD4
Cardiogenesis	1	423.0×	0.006	SMAD4
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	380.7×	0.006	SMAD4
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	1	380.7×	0.006	SMAD4
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	368.4×	0.006	SMAD4
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	368.4×	0.006	SMAD4
Signaling by TGFBR3	1	368.4×	0.006	SMAD4
Signaling by BMP	1	356.9×	0.006	SMAD4
FOXO-mediated transcription	1	335.9×	0.006	SMAD4
TGF-beta receptor signaling activates SMADs	1	326.3×	0.006	SMAD4
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	308.6×	0.006	SMAD4
Transcriptional regulation by RUNX3	1	271.9×	0.006	SMAD4
Gastrulation	1	259.6×	0.006	SMAD4
Transcriptional regulation by RUNX2	1	253.8×	0.006	SMAD4

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
obsolete positive regulation of cell proliferation involved in heart valve morphogenesis	1	16852.0×	0.002	SMAD4
female gonad morphogenesis	1	16852.0×	0.002	SMAD4
negative regulation of cardiac myofibril assembly	1	16852.0×	0.002	SMAD4
nephrogenic mesenchyme morphogenesis	1	8426.0×	0.002	SMAD4
metanephric mesenchyme morphogenesis	1	5617.3×	0.002	SMAD4
atrioventricular valve formation	1	4213.0×	0.002	SMAD4
left ventricular cardiac muscle tissue morphogenesis	1	4213.0×	0.002	SMAD4
regulation of transforming growth factor beta2 production	1	4213.0×	0.002	SMAD4
formation of anatomical boundary	1	4213.0×	0.002	SMAD4
regulation of hair follicle development	1	4213.0×	0.002	SMAD4
positive regulation of luteinizing hormone secretion	1	3370.4×	0.002	SMAD4
positive regulation of follicle-stimulating hormone secretion	1	2808.7×	0.002	SMAD4
endocardial cell differentiation	1	2808.7×	0.002	SMAD4
brainstem development	1	2106.5×	0.002	SMAD4
sebaceous gland development	1	2106.5×	0.002	SMAD4
mesendoderm development	1	1872.4×	0.002	SMAD4
response to transforming growth factor beta	1	1872.4×	0.002	SMAD4
positive regulation of extracellular matrix assembly	1	1872.4×	0.002	SMAD4
endothelial cell activation	1	1685.2×	0.002	SMAD4
neural crest cell differentiation	1	1532.0×	0.002	SMAD4
somite rostral/caudal axis specification	1	1532.0×	0.002	SMAD4
atrioventricular canal development	1	1532.0×	0.002	SMAD4
epithelial to mesenchymal transition involved in endocardial cushion formation	1	1404.3×	0.002	SMAD4
positive regulation of cardiac muscle cell apoptotic process	1	1203.7×	0.003	SMAD4
secondary palate development	1	1203.7×	0.003	SMAD4
negative regulation of cardiac muscle hypertrophy	1	1123.5×	0.003	SMAD4
interleukin-6-mediated signaling pathway	1	1123.5×	0.003	SMAD4
cardiac conduction system development	1	1053.2×	0.003	SMAD4
cardiac muscle hypertrophy in response to stress	1	1053.2×	0.003	SMAD4
gastrulation with mouth forming second	1	936.2×	0.003	SMAD4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMAD4	0	0
DUT-AS1	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
SMAD4	6	Binding:6

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	2	SMAD4, DUT-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SMAD4	6	—
DUT-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford