22q11.2 deletion syndrome

Summary

22q11.2 deletion syndrome (MONDO:0018923) is a disease with 6 cohort genes and 30 clinical trials. Top therapeutic interventions include melphalan and methylphenidate hydrochloride.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Cohort genes: 6
• ClinVar variants: 2
• Phenotypes (HPO): 131
• Clinical trials: 30

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Europe	Validated
Prevalence at birth	1-9 / 100 000	9.6	Europe	Validated
Prevalence at birth	1-5 / 10 000	16.8	United States	Validated
Prevalence at birth	1-5 / 10 000	37.5	Worldwide	Not yet validated
Prevalence at birth	1-5 / 10 000	10.3	France	Not yet validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000175	Cleft palate	Very frequent (80-99%)
HP:0000286	Epicanthus	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0000405	Conductive hearing impairment	Very frequent (80-99%)
HP:0000414	Bulbous nose	Very frequent (80-99%)
HP:0000426	Prominent nasal bridge	Very frequent (80-99%)
HP:0000431	Wide nasal bridge	Very frequent (80-99%)
HP:0000506	Telecanthus	Very frequent (80-99%)
HP:0000582	Upslanted palpebral fissure	Very frequent (80-99%)
HP:0000600	Abnormality of the pharynx	Very frequent (80-99%)
HP:0000778	Hypoplasia of the thymus	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001611	Hypernasal speech	Very frequent (80-99%)
HP:0001629	Ventricular septal defect	Very frequent (80-99%)
HP:0001631	Atrial septal defect	Very frequent (80-99%)
HP:0001636	Tetralogy of Fallot	Very frequent (80-99%)
HP:0001641	Abnormal pulmonary valve morphology	Very frequent (80-99%)
HP:0001660	Truncus arteriosus	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002381	Aphasia	Very frequent (80-99%)
HP:0002691	Platybasia	Very frequent (80-99%)
HP:0002721	Immunodeficiency	Very frequent (80-99%)
HP:0012303	Abnormal aortic arch morphology	Very frequent (80-99%)
HP:0030680	Abnormal cardiovascular system morphology	Very frequent (80-99%)
HP:0011840	Abnormality of T cell physiology	Frequent (30-79%)
HP:0000089	Renal hypoplasia	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000272	Malar flattening	Frequent (30-79%)
HP:0000276	Long face	Frequent (30-79%)
HP:0000343	Long philtrum	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000385	Small earlobe	Frequent (30-79%)
HP:0000389	Chronic otitis media	Frequent (30-79%)
HP:0000396	Overfolded helix	Frequent (30-79%)
HP:0000470	Short neck	Frequent (30-79%)
HP:0000492	Abnormal eyelid morphology	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000627	Posterior embryotoxon	Frequent (30-79%)
HP:0000670	Carious teeth	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0000829	Hypoparathyroidism	Frequent (30-79%)
HP:0000929	Abnormal skull morphology	Frequent (30-79%)
HP:0001051	Seborrheic dermatitis	Frequent (30-79%)
HP:0001061	Acne	Frequent (30-79%)
HP:0001166	Arachnodactyly	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001281	Tetany	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	22q11.2 deletion syndrome
Mondo ID	MONDO:0018923
Orphanet	567
ICD-11	1868156761
GARD	0010299
MedDRA	10012979, 10066430
NORD	853
Is cancer (heuristic)	no

Also known as: 22q11DS · catch 22 · Cayler cardiofacial syndrome · Chromosome 22q11.2 Deletion Syndrome · conotruncal anomaly face syndrome · DiGeorge sequence · DiGeorge syndrome · microdeletion 22q11.2 · monosomy 22q11 · Sedlackova syndrome · Shprintzen syndrome · Takao syndrome · VCFS

Data availability: 2 ClinVar variants · 4 GenCC gene-disease records · 63 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › 22q11.2 deletion 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, 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, 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, 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

Subtypes (4): congenital unilateral hypoplasia of depressor anguli oris, DiGeorge syndrome, velocardiofacial syndrome, chromosome 22q11.2 deletion syndrome, distal

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

2 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2498202	Single allele	AIFM3	Pathogenic	criteria provided, single submitter
17592	NM_000754.4(COMT):c.214G>T (p.Ala72Ser)	COMT	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 11 · 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
JMJD1C	Supportive	Autosomal dominant	22q11.2 deletion syndrome	4
RREB1	Supportive	Autosomal dominant	22q11.2 deletion syndrome	3
SEC24C	Supportive	Autosomal dominant	22q11.2 deletion syndrome
TBX1	Supportive	Autosomal dominant	22q11.2 deletion syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RREB1	Orphanet:567	22q11.2 deletion syndrome
SEC24C	Orphanet:567	22q11.2 deletion syndrome
TBX1	Orphanet:1727	22q11.2 duplication syndrome
TBX1	Orphanet:3303	Tetralogy of Fallot
TBX1	Orphanet:567	22q11.2 deletion syndrome
TBX1	Orphanet:665044	Common arterial trunk with aortic dominance
TBX1	Orphanet:665058	Common arterial trunk with pulmonary dominance and interrupted aortic arch
TBX1	Orphanet:685017	Combined immunodeficiency due to TBX1 deficiency
JMJD1C	Orphanet:567	22q11.2 deletion syndrome
JMJD1C	Orphanet:91352	Germinoma of the central nervous system
COMT	Orphanet:567	22q11.2 deletion syndrome

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RREB1	HGNC:10449	ENSG00000124782	Q92766	Ras-responsive element-binding protein 1	gencc
SEC24C	HGNC:10705	ENSG00000176986	P53992	Protein transport protein Sec24C	gencc
TBX1	HGNC:11592	ENSG00000184058	O43435	T-box transcription factor TBX1	gencc
JMJD1C	HGNC:12313	ENSG00000171988	Q15652	Jumonji domain-containing protein 1C	gencc
COMT	HGNC:2228	ENSG00000093010	P21964	Catechol O-methyltransferase	clinvar
AIFM3	HGNC:26398	ENSG00000183773	Q96NN9	Apoptosis-inducing factor 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RREB1	Ras-responsive element-binding protein 1	Transcription factor that binds specifically to the RAS-responsive elements (RRE) of gene promoters.
SEC24C	Protein transport protein Sec24C	Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER).
TBX1	T-box transcription factor TBX1	Transcription factor that plays a key role in cardiovascular development by promoting pharyngeal arch segmentation during embryonic development.
JMJD1C	Jumonji domain-containing protein 1C	Demethylates lysine in proteins, such as STAT3 or MDC1.
COMT	Catechol O-methyltransferase	Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones.
AIFM3	Apoptosis-inducing factor 3	Induces apoptosis through a caspase dependent pathway.

Protein-family classification

Druggable: 2 · Difficult: 3 · Unknown: 1 · 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
Transcription factor	3	4.1×	0.080
Enzyme (other)	2	4.0×	0.125
Other/Unknown	1	0.3×	0.993

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RREB1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, RREB1
SEC24C	Transcription factor	no		Znf_Sec23_Sec24, Sec23/24_trunk_dom, Sec23/24_helical_dom
TBX1	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
JMJD1C	Enzyme (other)	yes	1.14.11.65	JmjC_dom, LSDs-like, KDM3A/B_DUF7030
COMT	Enzyme (other)	yes	2.1.1.6	SAM_O-MeTrfase, Catechol_O-MeTrfase_euk, SAM-dependent_MTases_sf
AIFM3	Other/Unknown	no		FAD/NAD-linked_Rdtase_dimer_sf, Rieske_2Fe-2S, FAD/NAD-binding_dom

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right hemisphere of cerebellum	2
buccal mucosa cell	1
epithelium of nasopharynx	1
oral cavity	1
epithelium of esophagus	1
esophagus squamous epithelium	1
lower esophagus mucosa	1
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1
calcaneal tendon	1
cerebellar hemisphere	1
right adrenal gland	1
right adrenal gland cortex	1
stromal cell of endometrium	1
mucosa of transverse colon	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RREB1	278	ubiquitous	marker	buccal mucosa cell, epithelium of nasopharynx, oral cavity
SEC24C	290	ubiquitous	marker	lower esophagus mucosa, esophagus squamous epithelium, epithelium of esophagus
TBX1	220	broad	marker	hindlimb stylopod muscle, gastrocnemius, muscle of leg
JMJD1C	291	ubiquitous	marker	calcaneal tendon, right hemisphere of cerebellum, cerebellar hemisphere
COMT	296	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, stromal cell of endometrium
AIFM3	180	tissue_specific	marker	mucosa of transverse colon, right frontal lobe, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COMT	3,362
SEC24C	2,129
AIFM3	2,051
JMJD1C	1,641
RREB1	1,586
TBX1	1,256

Intra-cohort edges

A	B	Sources
AIFM3	TBX1	string_interaction
COMT	TBX1	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COMT	P21964	12
AIFM3	Q96NN9	7
SEC24C	P53992	3
JMJD1C	Q15652	3
TBX1	O43435	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RREB1	Q92766	48.28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 33. Enrichment computed across 6 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
Enzymatic degradation of Dopamine by monoamine oxidase	1	1427.5×	0.017	COMT
Enzymatic degradation of dopamine by COMT	1	951.7×	0.017	COMT
Methylation	1	203.9×	0.054	COMT
Cardiogenesis	1	105.7×	0.059	TBX1
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	1	98.5×	0.059	SEC24C
Cargo concentration in the ER	1	84.0×	0.059	SEC24C
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	79.3×	0.059	SEC24C
COPII-mediated vesicle transport	1	40.8×	0.095	SEC24C
Metabolism of steroids	1	34.4×	0.095	SEC24C
ER to Golgi Anterograde Transport	1	33.2×	0.095	SEC24C
SARS-CoV-2-host interactions	1	29.7×	0.095	SEC24C
Potential therapeutics for SARS	1	28.6×	0.095	COMT
Transport to the Golgi and subsequent modification	1	25.7×	0.097	SEC24C
MHC class II antigen presentation	1	22.3×	0.097	SEC24C
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	22.3×	0.097	SEC24C
SARS-CoV-2 Infection	1	20.1×	0.101	SEC24C
Class I MHC mediated antigen processing & presentation	1	17.5×	0.108	SEC24C
Factors involved in megakaryocyte development and platelet production	1	16.6×	0.108	JMJD1C
Asparagine N-linked glycosylation	1	15.0×	0.113	SEC24C
SARS-CoV Infections	1	13.9×	0.116	SEC24C
Membrane Trafficking	1	9.3×	0.158	SEC24C
Hemostasis	1	9.0×	0.158	JMJD1C
Vesicle-mediated transport	1	8.7×	0.158	SEC24C
Metabolism of lipids	1	7.9×	0.162	SEC24C
Viral Infection Pathways	1	7.7×	0.162	SEC24C
Adaptive Immune System	1	7.5×	0.162	SEC24C
Infectious disease	1	6.2×	0.185	SEC24C
Post-translational protein modification	1	4.8×	0.227	SEC24C
Developmental Biology	1	3.6×	0.284	TBX1
Disease	1	3.3×	0.292	SEC24C

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
norepinephrine secretion	1	2808.7×	0.012	COMT
response to dopamine	1	2808.7×	0.012	COMT
regulation of animal organ morphogenesis	1	2808.7×	0.012	TBX1
vagus nerve morphogenesis	1	1404.3×	0.012	TBX1
catecholamine catabolic process	1	1404.3×	0.012	COMT
positive regulation of tongue muscle cell differentiation	1	1404.3×	0.012	TBX1
dopamine secretion	1	936.2×	0.012	COMT
renal filtration	1	936.2×	0.012	COMT
renin secretion into blood stream	1	702.2×	0.012	COMT
cellular response to phosphate starvation	1	702.2×	0.012	COMT
renal sodium excretion	1	702.2×	0.012	COMT
ear morphogenesis	1	702.2×	0.012	TBX1
habituation	1	702.2×	0.012	COMT
mastication	1	702.2×	0.012	COMT
tongue morphogenesis	1	561.7×	0.012	TBX1
soft palate development	1	561.7×	0.012	TBX1
renal albumin absorption	1	561.7×	0.012	COMT
positive regulation of wound healing, spreading of epidermal cells	1	561.7×	0.012	RREB1
cerebellar cortex morphogenesis	1	468.1×	0.012	COMT
positive regulation of mammary gland epithelial cell proliferation	1	468.1×	0.012	RREB1
muscle cell fate commitment	1	468.1×	0.012	TBX1
semicircular canal morphogenesis	1	401.2×	0.012	TBX1
parathyroid gland development	1	401.2×	0.012	TBX1
muscle tissue morphogenesis	1	401.2×	0.012	TBX1
negative regulation of mesenchymal cell apoptotic process	1	401.2×	0.012	TBX1
synaptic transmission, dopaminergic	1	351.1×	0.012	COMT
response to salt	1	351.1×	0.012	COMT
positive regulation of lamellipodium morphogenesis	1	351.1×	0.012	RREB1
lymph vessel development	1	312.1×	0.012	TBX1
muscle organ morphogenesis	1	312.1×	0.012	TBX1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 3 of 6 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
COMT	OPICAPONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COMT	3	4
RREB1	0	0
SEC24C	0	0
TBX1	0	0
JMJD1C	0	0
AIFM3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OPICAPONE	4	COMT
TOLCAPONE	4	COMT
ENTACAPONE	4	COMT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
COMT	55	Binding:47, ADMET:8
JMJD1C	2	Binding:2
SEC24C	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
JMJD1C	1.14.11.65	[histone H3]-dimethyl-L-lysine9 demethylase
COMT	2.1.1.6	catechol O-methyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
COMT	1

Chemical tractability of cohort targets

3 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)
OPICAPONE	4	COMT
TOLCAPONE	4	COMT
ENTACAPONE	4	COMT

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	COMT
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	JMJD1C
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	RREB1, SEC24C, TBX1, AIFM3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RREB1	0	—
SEC24C	1	—
TBX1	0	—
JMJD1C	2	—
AIFM3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 30.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	21
PHASE2	5
PHASE1	3
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00395538	PHASE3	TERMINATED	Effects of PTH Replacement on Bone in Hypoparathyroidism
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT07284641	PHASE2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT00576407	PHASE2	COMPLETED	Thymus Transplantation in DiGeorge Syndrome #668
NCT00576836	PHASE2	COMPLETED	Thymus Transplantation Dose in DiGeorge #932
NCT05149898	PHASE2	COMPLETED	Open-Label Study of ZYN002 Administered as a Transdermal Gel to Children and Adolescents With 22q11.2 Deletion Syndrome (INSPIRE)
NCT00566488	PHASE1	COMPLETED	Parathyroid and Thymus Transplantation in DiGeorge #931
NCT00579709	PHASE1	COMPLETED	Thymus Transplantation With Immunosuppression
NCT02895906	PHASE1	COMPLETED	Safety and Efficacy Study of NFC-1 in Subjects Aged 12-17 Years With 22q11.2DS & Associated Neuropsychiatric Conditions
NCT00556530	Not specified	RECRUITING	Examining Genetic Factors That Affect the Severity of 22q11.2 Deletion Syndrome
NCT03836300	Not specified	ENROLLING_BY_INVITATION	Parent and Infant Inter(X)Action Intervention (PIXI)
NCT04639388	Not specified	RECRUITING	Understanding of Psychotic Disorders in Children With 22q11.2DS
NCT05924347	Not specified	RECRUITING	Early Scoliotic Changes in Children at Increased Risk for Scoliosis Development
NCT07493096	Not specified	RECRUITING	Intensive Multimodal Neurorehabilitation Targeting Neuroplasticity in Pediatric Neurodevelopmental and Chromosomal Disorders
NCT00004351	Not specified	COMPLETED	Study of Phenotype and Genotype Correlations in Patients With Contiguous Gene Deletion Syndromes
NCT00005102	Not specified	UNKNOWN	Immunologic Evaluation in Patients With DiGeorge Syndrome or Velocardiofacial Syndrome
NCT00105274	Not specified	COMPLETED	Velocardiofacial (VCFS; 22q11.2; DiGeorge) Syndrome Study
NCT00161109	Not specified	UNKNOWN	Genetics and Psychopathology in the 22q11 Deletion Syndrome
NCT00278005	Not specified	TERMINATED	Infection in DiGeorge Following CHD Surgery
NCT00916955	Not specified	COMPLETED	Genetic Modifiers for 22q11.2 Syndrome
NCT01220531	Not specified	COMPLETED	Thymus Transplantation Safety-Efficacy
NCT01781923	Not specified	COMPLETED	Cognitive Remediation in 22q11DS
NCT02381457	Not specified	COMPLETED	SNP-based Microdeletion and Aneuploidy RegisTry (SMART)
NCT02430584	Not specified	UNKNOWN	Whole Blood Specimen Collection From Pregnant Subjects
NCT02460328	Not specified	COMPLETED	Resolution of Primary Immune Defect in 22q11.2 Deletion Syndrome
NCT02787486	Not specified	COMPLETED	Expanded Noninvasive Genomic Medical Assessment: The Enigma Study
NCT03284060	Not specified	TERMINATED	Social Cognition Training and Cognitive Remediation
NCT04373226	Not specified	TERMINATED	Arithmetic Abilities in Children With 22q11.2DS
NCT04639960	Not specified	TERMINATED	Neuroprotective Effects of Risperdal on Brain and Cognition in 22q11 Deletion Syndrome
NCT04647500	Not specified	COMPLETED	Effects of Methylphenidate on Brain and Cognition in 22q11 Deletion Syndrome

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MELPHALAN	4	1
METHYLPHENIDATE HYDROCHLORIDE	4	1