ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder

Summary

ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder (MONDO:0014379) is a disease caused by ADNP (GenCC Definitive), with 4 cohort genes and 2 clinical trials. Top therapeutic interventions include ketamine.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: ADNP (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 188
• Phenotypes (HPO): 80
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000020	Urinary incontinence	Very frequent (80-99%)
HP:0000729	Autistic behavior	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0012760	Reduced social responsiveness	Very frequent (80-99%)
HP:0000722	Compulsive behaviors	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0001167	Abnormality of finger	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002591	Polyphagia	Frequent (30-79%)
HP:0007018	Attention deficit hyperactivity disorder	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0011343	Moderate global developmental delay	Frequent (30-79%)
HP:0011344	Severe global developmental delay	Frequent (30-79%)
HP:0012443	Abnormality of brain morphology	Frequent (30-79%)
HP:0012450	Chronic constipation	Frequent (30-79%)
HP:0025160	Abnormal temper tantrums	Frequent (30-79%)
HP:0200136	Oral-pharyngeal dysphagia	Frequent (30-79%)
HP:0000010	Recurrent urinary tract infections	Occasional (5-29%)
HP:0000179	Thick lower lip vermilion	Occasional (5-29%)
HP:0000219	Thin upper lip vermilion	Occasional (5-29%)
HP:0000243	Trigonocephaly	Occasional (5-29%)
HP:0000319	Smooth philtrum	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000411	Protruding ear	Occasional (5-29%)
HP:0000483	Astigmatism	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000540	Hypermetropia	Occasional (5-29%)
HP:0000718	Aggressive behavior	Occasional (5-29%)
HP:0000954	Single transverse palmar crease	Occasional (5-29%)
HP:0001357	Plagiocephaly	Occasional (5-29%)
HP:0001488	Bilateral ptosis	Occasional (5-29%)
HP:0001597	Abnormality of the nail	Occasional (5-29%)
HP:0001780	Abnormality of toe	Occasional (5-29%)
HP:0001852	Sandal gap	Occasional (5-29%)
HP:0001956	Truncal obesity	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002360	Sleep abnormality	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0002788	Recurrent upper respiratory tract infections	Occasional (5-29%)
HP:0002835	Aspiration	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0005216	Impaired mastication	Occasional (5-29%)
HP:0006288	Advanced eruption of teeth	Occasional (5-29%)
HP:0006610	Wide intermamillary distance	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder
Mondo ID	MONDO:0014379
OMIM	615873
Orphanet	404448
DOID	DOID:0070058
SNOMED CT	766824003
UMLS	C4014538
MedGen	862975
GARD	0012931
NORD	1965
Is cancer (heuristic)	no

Also known as: ADNP Syndrome · ADNP syndrome · ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder · autosomal dominant intellectual disability 28 · Helsmoortel-Van der Aa syndrome · HVDAS · mental retardation, autosomal dominant 28

Data availability: 188 ClinVar variants · 5 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder

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, Myhre syndrome, 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, 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

188 retrieved; paginated sample, class counts are floors:

49 pathogenic, 44 uncertain significance, 33 likely pathogenic, 23 conflicting classifications of pathogenicity, 20 benign/likely benign, 6 pathogenic/likely pathogenic, 6 likely benign, 4 benign, 3 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1174075	NM_001282531.3(ADNP):c.898dup (p.Ser300fs)	ADNP	Pathogenic	no assertion criteria provided
1299548	NM_001282531.3(ADNP):c.655_656del (p.Glu218_Ser219insTer)	ADNP	Pathogenic	criteria provided, multiple submitters, no conflicts
1334645	NM_001282531.3(ADNP):c.2454C>G (p.Tyr818Ter)	ADNP	Pathogenic	criteria provided, multiple submitters, no conflicts
1338860	NM_001282531.3(ADNP):c.2387G>A (p.Trp796Ter)	ADNP	Pathogenic	criteria provided, single submitter
139631	NM_001282531.3(ADNP):c.2491_2494del (p.Leu831fs)	ADNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
139632	NM_001282531.3(ADNP):c.2496_2499del (p.Asn832fs)	ADNP	Pathogenic	criteria provided, multiple submitters, no conflicts
139633	NM_001282531.3(ADNP):c.1211C>A (p.Ser404Ter)	ADNP	Pathogenic	no assertion criteria provided
139634	NM_001282531.3(ADNP):c.2808del (p.Lys935_Tyr936insTer)	ADNP	Pathogenic	no assertion criteria provided
139635	NM_001282531.3(ADNP):c.2157C>G (p.Tyr719Ter)	ADNP	Pathogenic	criteria provided, multiple submitters, no conflicts
1527880	NM_001282531.3(ADNP):c.2167del (p.Glu723fs)	ADNP	Pathogenic	criteria provided, single submitter
1527885	NM_001282531.3(ADNP):c.2495_2499del (p.Asn832fs)	ADNP	Pathogenic	criteria provided, multiple submitters, no conflicts
1684264	NM_001282531.3(ADNP):c.95_96insT (p.Lys32fs)	ADNP	Pathogenic	criteria provided, single submitter
1685506	NM_001282531.3(ADNP):c.2424_2427del (p.Lys809fs)	ADNP	Pathogenic	criteria provided, single submitter
1698716	NM_001282531.3(ADNP):c.2155del (p.Tyr719fs)	ADNP	Pathogenic	criteria provided, single submitter
1709398	NM_001282531.3(ADNP):c.2292T>G (p.Tyr764Ter)	ADNP	Pathogenic	criteria provided, single submitter
1804918	NM_001282531.3(ADNP):c.2212dup (p.Ser738fs)	ADNP	Pathogenic	criteria provided, multiple submitters, no conflicts
1805170	NM_001282531.3(ADNP):c.2483dup (p.Met828fs)	ADNP	Pathogenic	criteria provided, single submitter
190278	NM_001282531.3(ADNP):c.2156dup (p.Tyr719Ter)	ADNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2442385	NM_001282531.3(ADNP):c.1191dup (p.Asn398Ter)	ADNP	Pathogenic	criteria provided, single submitter
279598	NM_001282531.3(ADNP):c.2188C>T (p.Arg730Ter)	ADNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280262	NM_001282531.3(ADNP):c.819del (p.Lys274fs)	ADNP	Pathogenic	criteria provided, single submitter
280557	NM_001282531.3(ADNP):c.190dup (p.Thr64fs)	ADNP	Pathogenic	criteria provided, multiple submitters, no conflicts
280623	NM_001282531.3(ADNP):c.2157C>A (p.Tyr719Ter)	ADNP	Pathogenic	criteria provided, multiple submitters, no conflicts
3033209	NM_001282531.3(ADNP):c.2189del (p.Arg730fs)	ADNP	Pathogenic	criteria provided, single submitter
3235197	NM_001282531.3(ADNP):c.2301del (p.Ser769fs)	ADNP	Pathogenic	criteria provided, single submitter
3238820	NM_001282531.3(ADNP):c.2450dup (p.Tyr818fs)	ADNP	Pathogenic	criteria provided, single submitter
338748	NM_001282531.3(ADNP):c.1102C>T (p.Gln368Ter)	ADNP	Pathogenic	criteria provided, single submitter
3704491	NM_001282531.3(ADNP):c.2317_2318del (p.Lys773fs)	ADNP	Pathogenic	criteria provided, multiple submitters, no conflicts
373314	NM_001282531.3(ADNP):c.539_542del (p.Val180fs)	ADNP	Pathogenic	criteria provided, multiple submitters, no conflicts
374212	NM_001282531.3(ADNP):c.2318dup (p.Tyr774fs)	ADNP	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
ADNP	Definitive	Autosomal dominant	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADNP	Orphanet:404448	Helsmoortel-Van der Aa syndrome
CNOT2	Orphanet:289513	12q15q21 microdeletion syndrome
CNOT2	Orphanet:697764	Intellectual disability-nasal speech-craniofacial dysmorphism syndrome due to CNOT2 mutation

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ADNP	HGNC:15766	ENSG00000101126	Q9H2P0	Activity-dependent neuroprotector homeobox protein	gencc,clinvar
CD38	HGNC:1667	ENSG00000004468	P28907	ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1	clinvar
MDGA2	HGNC:19835	ENSG00000139915	Q7Z553	MAM domain-containing glycosylphosphatidylinositol anchor protein 2	clinvar
CNOT2	HGNC:7878	ENSG00000111596	Q9NZN8	CCR4-NOT transcription complex subunit 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADNP	Activity-dependent neuroprotector homeobox protein	May be involved in transcriptional regulation.
CD38	ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1	Multifunctional transmembrane glycoprotein able to exert enzymatic activities and also to mobilize calcium, to transduce signals, to adhere to hyaluronan and to other ligands.
MDGA2	MAM domain-containing glycosylphosphatidylinositol anchor protein 2	May be involved in cell-cell interactions.
CNOT2	CCR4-NOT transcription complex subunit 2	Component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational in…

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

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
Antibody/Immunoglobulin	1	7.3×	0.521
Enzyme (other)	1	3.0×	0.538
Transcription factor	1	2.1×	0.538
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADNP	Transcription factor	no		HD, Homeodomain-like_sf, Znf_C2H2_type
CD38	Enzyme (other)	yes	2.4.99.20	ADP-ribosyl_cyclase
MDGA2	Antibody/Immunoglobulin	yes		MAM_dom, Ig_sub2, Ig_sub
CNOT2	Other/Unknown	no		NOT2/3/5_C, CCR4-NOT_su2/3/5_C_sf, Not2/3/5

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	2
ganglionic eminence	1
ventricular zone	1
bone marrow cell	1
lymph node	1
seminal vesicle	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
cervix squamous epithelium	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADNP	295	ubiquitous	marker	ganglionic eminence, cortical plate, ventricular zone
CD38	207	broad	marker	seminal vesicle, bone marrow cell, lymph node
MDGA2	85	broad	marker	cortical plate, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
CNOT2	296	ubiquitous	marker	oocyte, secondary oocyte, cervix squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CD38	2,718
CNOT2	2,409
ADNP	2,228
MDGA2	1,351

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CD38	P28907	56
CNOT2	Q9NZN8	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MDGA2	Q7Z553	84.96
ADNP	Q9H2P0	57.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	1	129.8×	0.034	CNOT2
Deadenylation of mRNA	1	109.8×	0.034	CNOT2
Nicotinate metabolism	1	98.5×	0.034	CD38
M-decay: degradation of maternal mRNAs by maternally stored factors	1	81.6×	0.034	CNOT2
ChAHP complex assembly	1	46.0×	0.037	ADNP
Metabolism of water-soluble vitamins and cofactors	1	45.3×	0.037	CD38
Post-translational modification: synthesis of GPI-anchored proteins	1	42.0×	0.037	MDGA2
Metabolism of vitamins and cofactors	1	29.1×	0.047	CD38
Post-translational protein modification	1	4.8×	0.236	MDGA2
Metabolism of proteins	1	3.1×	0.302	MDGA2
Metabolism	1	2.9×	0.302	CD38

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intracellular nitric oxide homeostasis	1	1404.3×	0.015	ADNP
positive regulation of cytoplasmic mRNA processing body assembly	1	601.9×	0.015	CNOT2
artery smooth muscle contraction	1	468.1×	0.015	CD38
response to carbohydrate	1	421.3×	0.015	ADNP
response to hydroperoxide	1	421.3×	0.015	CD38
negative regulation of synaptic transmission	1	421.3×	0.015	ADNP
estrous cycle	1	351.1×	0.015	ADNP
nicotinate metabolic process	1	351.1×	0.015	CD38
regulation of stem cell population maintenance	1	351.1×	0.015	CNOT2
short-term memory	1	324.1×	0.015	ADNP
negative regulation of intracellular estrogen receptor signaling pathway	1	280.9×	0.015	CNOT2
trophectodermal cell differentiation	1	247.8×	0.015	CNOT2
negative regulation of bone resorption	1	247.8×	0.015	CD38
spinal cord motor neuron differentiation	1	234.1×	0.015	MDGA2
long-term synaptic depression	1	221.7×	0.015	CD38
nuclear-transcribed mRNA poly(A) tail shortening	1	200.6×	0.015	CNOT2
obsolete cGMP-mediated signaling	1	200.6×	0.015	ADNP
regulatory ncRNA-mediated gene silencing	1	168.5×	0.017	CNOT2
positive regulation of vasoconstriction	1	150.5×	0.018	CD38
positive regulation of axon extension	1	127.7×	0.018	ADNP
response to interleukin-1	1	127.7×	0.018	CD38
response to progesterone	1	123.9×	0.018	CD38
B cell proliferation	1	120.4×	0.018	CD38
B cell receptor signaling pathway	1	100.3×	0.021	CD38
response to retinoic acid	1	95.8×	0.021	CD38
positive regulation of B cell proliferation	1	86.0×	0.023	CD38
positive regulation of insulin secretion	1	63.8×	0.029	CD38
positive regulation of synapse assembly	1	61.1×	0.029	ADNP
negative regulation of neuron projection development	1	59.3×	0.029	CD38
apoptotic signaling pathway	1	56.2×	0.030	CD38

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
CD38	2	3
ADNP	0	0
MDGA2	0	0
CNOT2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
QUERCETIN	3	CD38
LUTEOLIN	2	CD38

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CD38	28	Binding:22, ADMET:6
CNOT2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CD38	2.4.99.20, 3.2.2.5, 3.2.2.6	2’-phospho-ADP-ribosyl cyclase/2’-phospho-cyclic-ADP-ribose transferase, NAD+ glycohydrolase, ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 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)
QUERCETIN	3	CD38
LUTEOLIN	2	CD38

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	1	CD38
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	MDGA2
E	Difficult family or no structure, no drug	2	ADNP, CNOT2

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)
ADNP	0	—
MDGA2	0	—
CNOT2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04388774	PHASE1/PHASE2	COMPLETED	Low-Dose Ketamine in Children With ADNP Syndrome
NCT03718936	Not specified	RECRUITING	ADNP Syndrome: The Seaver Autism Center for Research and Treatment is Characterizing ADNP-related Neurodevelopmental Disorders Using Genetic, Medical, and Neuropsychological Measures.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
KETAMINE	4	1