DiGeorge syndrome

Summary

DiGeorge syndrome (MONDO:0008564) is a disease caused by TBX1 (GenCC Definitive), with 25 cohort genes and 31 clinical trials. Top therapeutic interventions include daclizumab, methylphenidate hydrochloride, and mycophenolate mofetil.

At a glance

• Causal gene: TBX1 (GenCC Definitive)
• Cohort genes: 25
• ClinVar variants: 879
• Clinical trials: 31

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	DiGeorge syndrome
Mondo ID	MONDO:0008564
MeSH	D004062
OMIM	188400
DOID	DOID:11198
ICD-10-CM	D82.1
NCIT	C2989
SNOMED CT	77128003
UMLS	C0012236
MedGen	4297
GARD	0015118
Anatomy (UBERON)	UBERON:0004117
Is cancer (heuristic)	no

Also known as: 22q deletion syndrome(s) · 22q11.2 deletion syndrome · DGS · DGS1 · Di-George syndrome · DiGeorge anomaly · DiGeorge syndrome · DiGeorge syndrome type 1 · DiGeorge’s syndrome · pharyngeal pouch syndrome · Shprintzen syndrome · Sphrintzen · VCF

Data availability: 879 ClinVar variants · 2 GenCC gene-disease records · 63 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › T-cell immunodeficiency › congenital T-cell immunodeficiency › DiGeorge syndrome

Related subtypes (1): Nezelof syndrome

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

600 retrieved; paginated sample, class counts are floors:

301 uncertain significance, 231 likely benign, 32 pathogenic, 15 conflicting classifications of pathogenicity, 11 benign, 5 likely pathogenic, 2 benign/likely benign, 2 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
2580313	GRCh37/hg19 22p13(chr22:135350-150557)x1		Pathogenic	criteria provided, single submitter
1703641	GRCh37/hg19 22q11.21(chr22:18916842-21798907)	C22orf39	Pathogenic	no assertion criteria provided
1077187	Single allele	CLTCL1	Pathogenic	criteria provided, single submitter
1703644	GRCh37/hg19 22q11.21(chr22:18893344-21650280)	CLTCL1	Pathogenic	no assertion criteria provided
14927	NM_000545.8(HNF1A):c.872dup (p.Gly292fs)	HNF1A	Pathogenic	reviewed by expert panel
2579266	GRCh38/hg38 22q11.21(chr22:18985739-21081116)x1	LRRC74B	Pathogenic	criteria provided, single submitter
1703640	GRCh37/hg19 22q11.21(chr22:18644790-21798907)	P2RX6	Pathogenic	no assertion criteria provided
1703642	GRCh37/hg19 22q11.21(chr22:18644790-21800471)	RANBP1	Pathogenic	no assertion criteria provided
1077190	Single allele	RIMBP3	Pathogenic	criteria provided, single submitter
1031062	NM_001379200.1(TBX1):c.1179_1180insAG (p.Leu394fs)	TBX1	Pathogenic	criteria provided, single submitter
1071027	NC_000022.10:g.(?19743226)(19755855_?)del	TBX1	Pathogenic	criteria provided, single submitter
1071028	NC_000022.10:g.(?19747167)(19754390_?)del	TBX1	Pathogenic	criteria provided, single submitter
1071029	NC_000022.10:g.(?_19748454)_19748649del	TBX1	Pathogenic	criteria provided, single submitter
1071222	NM_001379200.1(TBX1):c.1117del (p.Leu373fs)	TBX1	Pathogenic	criteria provided, single submitter
1354584	NM_001379200.1(TBX1):c.195_229del (p.Ala66fs)	TBX1	Pathogenic	criteria provided, single submitter
1378052	NM_001379200.1(TBX1):c.186C>A (p.Cys62Ter)	TBX1	Pathogenic	criteria provided, single submitter
1402928	NM_001379200.1(TBX1):c.794_798dup (p.Glu267fs)	TBX1	Pathogenic	criteria provided, single submitter
1432687	NM_001379200.1(TBX1):c.881del (p.Lys294fs)	TBX1	Pathogenic	criteria provided, single submitter
1445413	NM_001379200.1(TBX1):c.1063C>T (p.Gln355Ter)	TBX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1481145	NM_001379200.1(TBX1):c.711+1G>A	TBX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1967408	NM_001379200.1(TBX1):c.199_227del (p.Pro67fs)	TBX1	Pathogenic	criteria provided, single submitter
2133191	NM_001379200.1(TBX1):c.201dup (p.Gly68fs)	TBX1	Pathogenic	criteria provided, single submitter
2764419	NM_001379200.1(TBX1):c.1206_1207insGAACCCCGAGC (p.Ser403fs)	TBX1	Pathogenic	criteria provided, single submitter
2769601	NM_001379200.1(TBX1):c.1027del (p.Thr343fs)	TBX1	Pathogenic	criteria provided, single submitter
2803732	NM_001379200.1(TBX1):c.1015C>T (p.Gln339Ter)	TBX1	Pathogenic	criteria provided, single submitter
2848356	NM_001379200.1(TBX1):c.1252G>T (p.Glu418Ter)	TBX1	Pathogenic	criteria provided, single submitter
2866293	NM_001379200.1(TBX1):c.243del (p.Phe81fs)	TBX1	Pathogenic	criteria provided, single submitter
2917318	NM_001379200.1(TBX1):c.198_229dup (p.His77fs)	TBX1	Pathogenic	criteria provided, single submitter
3028918	NM_080647.1:g.(?19241636)(21349222_?)del	TBX1	Pathogenic	no assertion criteria provided
1703639	GRCh37/hg19 22q11.21(chr22:18645353-21800797)	TMEM191B	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 27 · 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
TBX1	Definitive	Autosomal dominant	DiGeorge syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
SLC25A1	Orphanet:356978	D,L-2-hydroxyglutaric aciduria
SLC25A1	Orphanet:98914	Presynaptic congenital myasthenic syndromes
HNF1A	Orphanet:319303	Chromophobe renal cell carcinoma
HNF1A	Orphanet:324575	Hyperinsulinism due to HNF1A deficiency
HNF1A	Orphanet:404511	Clear cell papillary renal cell carcinoma
HNF1A	Orphanet:552	MODY
TERT	Orphanet:146	Differentiated thyroid carcinoma
TERT	Orphanet:1501	Adrenocortical carcinoma
TERT	Orphanet:1775	Dyskeratosis congenita
TERT	Orphanet:2032	Idiopathic pulmonary fibrosis
TERT	Orphanet:2495	Meningioma
TERT	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
TERT	Orphanet:457246	Clear cell sarcoma of kidney
TERT	Orphanet:618	Familial melanoma
TERT	Orphanet:88	Idiopathic aplastic anemia
UFD1	Orphanet:567	22q11.2 deletion syndrome
TXNRD2	Orphanet:154	Familial isolated dilated cardiomyopathy
TXNRD2	Orphanet:361	Familial glucocorticoid deficiency
CLTCL1	Orphanet:453510	Congenital insensitivity to pain with severe intellectual disability
ARVCF	Orphanet:567	22q11.2 deletion syndrome
PRODH	Orphanet:419	Hyperprolinemia type 1

Cohort genes → proteins

25 cohort genes, 24 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	25

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TBX1	HGNC:11592	ENSG00000184058	O43435	T-box transcription factor TBX1	gencc,clinvar
SLC25A1	HGNC:10979	ENSG00000100075	P53007	Tricarboxylate transport protein, mitochondrial	clinvar
TSSK2	HGNC:11401	ENSG00000206203	Q96PF2	Testis-specific serine/threonine-protein kinase 2	clinvar
HNF1A	HGNC:11621	ENSG00000135100	P20823	Hepatocyte nuclear factor 1-alpha	clinvar
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	clinvar
UFD1	HGNC:12520	ENSG00000070010	Q92890	Ubiquitin recognition factor in ER-associated degradation protein 1	clinvar
FBXL7	HGNC:13604	ENSG00000183580	Q9UJT9	F-box/LRR-repeat protein 7	clinvar
MRPL40	HGNC:14491	ENSG00000185608	Q9NQ50	Large ribosomal subunit protein mL40	clinvar
TXNRD2	HGNC:18155	ENSG00000184470	Q9NNW7	Thioredoxin reductase 2, mitochondrial	clinvar
DGCR6L	HGNC:18551	ENSG00000128185	Q9BY27	Protein DGCR6L	clinvar
CLTCL1	HGNC:2093	ENSG00000070371	P53675	Clathrin heavy chain 2	clinvar
TRMT2A	HGNC:24974	ENSG00000099899	Q8IZ69	tRNA (uracil-5-)-methyltransferase homolog A	clinvar
AIFM3	HGNC:26398	ENSG00000183773	Q96NN9	Apoptosis-inducing factor 3	clinvar
C22orf39	HGNC:27012	ENSG00000242259	Q6P5X5	Synaptic plasticity regulator PANTS	clinvar
DGCR2	HGNC:2845	ENSG00000070413	P98153	Integral membrane protein DGCR2/IDD	clinvar
RIMBP3	HGNC:29344	ENSG00000275793	Q9UFD9	RIMS-binding protein 3A	clinvar
TMEM191B	HGNC:33600	ENSG00000278558	P0C7N4	Transmembrane protein 191B	clinvar
LRRC74B	HGNC:34301	ENSG00000187905	Q6ZQY2	Leucine-rich repeat-containing protein 74B	clinvar
FAM230A	HGNC:45045	ENSG00000277870		family with sequence similarity 230 member A	clinvar
GSC2	HGNC:4613	ENSG00000063515	O15499	Homeobox protein goosecoid-2	clinvar
ARVCF	HGNC:728	ENSG00000099889	O00192	Splicing regulator ARVCF	clinvar
P2RX6	HGNC:8538	ENSG00000099957	O15547	P2X purinoceptor 6	clinvar
SEPTIN5	HGNC:9164	ENSG00000184702	Q99719	Septin-5	clinvar
PRODH	HGNC:9453	ENSG00000100033	O43272	Proline dehydrogenase 1, mitochondrial	clinvar
RANBP1	HGNC:9847	ENSG00000099901	P43487	Ran-specific GTPase-activating protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBX1	T-box transcription factor TBX1	Transcription factor that plays a key role in cardiovascular development by promoting pharyngeal arch segmentation during embryonic development.
SLC25A1	Tricarboxylate transport protein, mitochondrial	Mitochondrial electroneutral antiporter that exports citrate from the mitochondria into the cytosol in exchange for malate.
TSSK2	Testis-specific serine/threonine-protein kinase 2	Testis-specific serine/threonine-protein kinase required during spermatid development.
HNF1A	Hepatocyte nuclear factor 1-alpha	Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver.
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
UFD1	Ubiquitin recognition factor in ER-associated degradation protein 1	Essential component of the ubiquitin-dependent proteolytic pathway which degrades ubiquitin fusion proteins.
FBXL7	F-box/LRR-repeat protein 7	Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex.
TXNRD2	Thioredoxin reductase 2, mitochondrial	Involved in the control of reactive oxygen species levels and the regulation of mitochondrial redox homeostasis.
DGCR6L	Protein DGCR6L	May play a role in neural crest cell migration into the third and fourth pharyngeal pouches.
CLTCL1	Clathrin heavy chain 2	Clathrin is the major protein of the polyhedral coat of coated pits and vesicles.
TRMT2A	tRNA (uracil-5-)-methyltransferase homolog A	S-adenosyl-L-methionine-dependent methyltransferase that catalyzes the formation of 5-methyl-uridine in tRNAs and some mRNAs.
AIFM3	Apoptosis-inducing factor 3	Induces apoptosis through a caspase dependent pathway.
C22orf39	Synaptic plasticity regulator PANTS	Negatively regulates long-term potentiation and modulates adult synaptic plasticity.
DGCR2	Integral membrane protein DGCR2/IDD	Putative adhesion receptor, that could be involved in cell-cell or cell-matrix interactions required for normal cell differentiation and migration.
RIMBP3	RIMS-binding protein 3A	Probable component of the manchette, a microtubule-based structure which plays a key role in sperm head morphogenesis during late stages of sperm development.
GSC2	Homeobox protein goosecoid-2	May have a role in development.
ARVCF	Splicing regulator ARVCF	Contributes to the regulation of alternative splicing of pre-mRNAs.
P2RX6	P2X purinoceptor 6	May act as a modulatory subunit rather than a functional channel.
SEPTIN5	Septin-5	Filament-forming cytoskeletal GTPase.
PRODH	Proline dehydrogenase 1, mitochondrial	Converts proline to delta-1-pyrroline-5-carboxylate.
RANBP1	Ran-specific GTPase-activating protein	Plays a role in RAN-dependent nucleocytoplasmic transport.

Protein-family classification

Druggable: 5 · Difficult: 3 · Unknown: 17 · Druggable fraction: 0.2

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
Enzyme (other)	3	1.4×	0.601
Other/Unknown	17	1.2×	0.601
Antibody/Immunoglobulin	1	1.2×	0.601
Kinase	1	1.1×	0.601
Transcription factor	3	1.0×	0.601

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBX1	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
SLC25A1	Other/Unknown	no		MCP, MCP_transmembrane, MCP_dom_sf
TSSK2	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
HNF1A	Transcription factor	no		HD, HNF1b_C, HNF1a_C
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
UFD1	Other/Unknown	no		UFD1-like, UFD1-like_Nn, UFD1_N1
FBXL7	Other/Unknown	no		F-box_dom, Leu-rich_rpt_Cys-con_subtyp, LRR_dom_sf
MRPL40	Other/Unknown	no		Ribosomal_mL40, Ribosomal_mL40_metazoa/plant
TXNRD2	Enzyme (other)	yes	1.8.1.9	Pyr_nuc-diS_OxRdtase, Pyr_nucl-diS_OxRdtase_dimer, Thioredoxin/glutathione_Rdtase
DGCR6L	Other/Unknown	no		Gonadal
CLTCL1	Other/Unknown	no		Clathrin_H-chain/VPS_repeat, TPR-like_helical_dom_sf, Clathrin_H-chain_linker_core
TRMT2A	Enzyme (other)	yes	2.1.1.35	RRM_dom, U5_MeTrfase_fam, Nucleotide-bd_a/b_plait_sf
AIFM3	Other/Unknown	no		FAD/NAD-linked_Rdtase_dimer_sf, Rieske_2Fe-2S, FAD/NAD-binding_dom
C22orf39	Other/Unknown	no		Pants/Emi1-like
DGCR2	Other/Unknown	no		VWF_dom, C-type_lectin-like, LDrepeatLR_classA_rpt
RIMBP3	Antibody/Immunoglobulin	yes		SH3_domain, FN3_dom, Ig-like_fold
TMEM191B	Other/Unknown	no		TMEM191B/C
LRRC74B	Other/Unknown	no		Leu-rich_rpt, LRR_dom_sf, LRR-containing
FAM230A	Other/Unknown	no
GSC2	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
ARVCF	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold
P2RX6	Other/Unknown	no		P2X_purnocptor, P2X6_purnocptor, P2X_extracellular_dom_sf
SEPTIN5	Other/Unknown	no		Septin, P-loop_NTPase, G_SEPTIN_dom
PRODH	Enzyme (other)	yes	1.5.5.2	Proline_DH_dom, Proline_oxidase, FAD-linked_oxidoreductase-like
RANBP1	Other/Unknown	no		Ran_bind_dom, PH-like_dom_sf, RanBP1-like

Expression context

Cohort genes with no expression data: 0.

18 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)	1
broad (>20)	24
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	5
right testis	5
testis	5
gastrocnemius	4
hindlimb stylopod muscle	4
muscle of leg	4
mucosa of transverse colon	3
right lobe of liver	3
male germ line stem cell (sensu Vertebrata) in testis	3
ventricular zone	2
right uterine tube	2
right frontal lobe	2
right hemisphere of cerebellum	2
endometrium epithelium	1
liver	1
olfactory bulb	1
stromal cell of endometrium	1
type B pancreatic cell	1
corpus epididymis	1
islet of Langerhans	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBX1	220	broad	marker	hindlimb stylopod muscle, gastrocnemius, muscle of leg
SLC25A1	284	ubiquitous	marker	endometrium epithelium, mucosa of transverse colon, right lobe of liver
TSSK2	129	tissue_specific	marker	left testis, right testis, male germ line stem cell (sensu Vertebrata) in testis
HNF1A	81	tissue_specific	yes	right lobe of liver, mucosa of transverse colon, liver
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
UFD1	295	ubiquitous	marker	tendon of biceps brachii, islet of Langerhans, corpus epididymis
FBXL7	277	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
MRPL40	292	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, heart right ventricle
TXNRD2	264	ubiquitous	marker	right lobe of liver, right adrenal gland cortex, apex of heart
DGCR6L	142	ubiquitous	marker	right testis, left testis, testis
CLTCL1	208	ubiquitous	marker	gastrocnemius, muscle of leg, hindlimb stylopod muscle
TRMT2A	206	ubiquitous	marker	granulocyte, right uterine tube, adenohypophysis
AIFM3	180	tissue_specific	marker	mucosa of transverse colon, right frontal lobe, right hemisphere of cerebellum
C22orf39	250	tissue_specific	marker	gastrocnemius, muscle of leg, hindlimb stylopod muscle
DGCR2	295	ubiquitous	marker	penis, nipple, lateral globus pallidus
RIMBP3	68		marker	left testis, testis, right testis
TMEM191B	126		yes	left testis, right testis, testis
LRRC74B	87	tissue_specific	marker	right uterine tube, olfactory segment of nasal mucosa, male germ line stem cell (sensu Vertebrata) in testis
FAM230A	80		yes	left testis, right testis, testis
GSC2	11		yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, testis
ARVCF	273	ubiquitous	yes	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
P2RX6	159		yes	gastrocnemius, muscle of leg, hindlimb stylopod muscle
SEPTIN5	189	ubiquitous	marker	right frontal lobe, cortical plate, anterior cingulate cortex
PRODH	135	broad	marker	skin of leg, zone of skin, skin of abdomen
RANBP1	279	ubiquitous	marker	ganglionic eminence, embryo, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 47.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TERT	5,717
TXNRD2	3,712
PRODH	3,653
CLTCL1	3,503
RANBP1	3,338
SLC25A1	2,949
HNF1A	2,491
TRMT2A	2,420
MRPL40	2,393
UFD1	2,294

Intra-cohort edges

A	B	Sources
AIFM3	P2RX6	string_interaction
AIFM3	TBX1	string_interaction
ARVCF	TRMT2A	string_interaction
ARVCF	TXNRD2	string_interaction
C22orf39	DGCR6L	string_interaction
C22orf39	SEPTIN5	string_interaction
C22orf39	TRMT2A	string_interaction
CLTCL1	DGCR2	string_interaction
CLTCL1	GSC2	string_interaction
CLTCL1	SLC25A1	string_interaction
DGCR2	DGCR6L	string_interaction
DGCR2	GSC2	string_interaction
DGCR2	MRPL40	string_interaction
DGCR2	PRODH	string_interaction
DGCR2	SLC25A1	string_interaction
DGCR2	TBX1	string_interaction
DGCR2	TRMT2A	string_interaction
DGCR2	UFD1	string_interaction
DGCR6L	GSC2	string_interaction
DGCR6L	MRPL40	string_interaction
DGCR6L	PRODH	string_interaction
DGCR6L	RIMBP3	biogrid_interaction, intact
DGCR6L	TBX1	string_interaction
DGCR6L	TMEM191B	string_interaction
DGCR6L	TSSK2	string_interaction
DGCR6L	UFD1	string_interaction
GSC2	PRODH	string_interaction
GSC2	RANBP1	string_interaction
GSC2	SEPTIN5	string_interaction
GSC2	SLC25A1	string_interaction
GSC2	TBX1	string_interaction
MRPL40	PRODH	string_interaction
MRPL40	SLC25A1	string_interaction
MRPL40	TRMT2A	string_interaction
MRPL40	TXNRD2	string_interaction
MRPL40	UFD1	string_interaction
PRODH	SEPTIN5	string_interaction
PRODH	SLC25A1	string_interaction
PRODH	TBX1	string_interaction
PRODH	TMEM191B	string_interaction
RANBP1	TRMT2A	string_interaction
RIMBP3	TMEM191B	string_interaction
SEPTIN5	TBX1	string_interaction
SEPTIN5	TSSK2	string_interaction
SLC25A1	UFD1	string_interaction
TMEM191B	TSSK2	string_interaction
TRMT2A	UFD1	string_interaction

Structural data

PDB: 10 · AlphaFold-only: 14 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPL40	Q9NQ50	82
TERT	O14746	23
UFD1	Q92890	9
AIFM3	Q96NN9	7
HNF1A	P20823	6
RANBP1	P43487	4
TRMT2A	Q8IZ69	2
TBX1	O43435	1
RIMBP3	Q9UFD9	1
SEPTIN5	Q99719	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C22orf39	Q6P5X5	89.97
DGCR6L	Q9BY27	87.10
PRODH	O43272	85.29
LRRC74B	Q6ZQY2	84.30
P2RX6	O15547	83.89
TSSK2	Q96PF2	82.84
FBXL7	Q9UJT9	82.67
CLTCL1	P53675	77.53
SLC25A1	P53007	75.09
TMEM191B	P0C7N4	74.28
GSC2	O15499	70.08
ARVCF	O00192	65.73
DGCR2	P98153	63.74
TXNRD2	Q9NNW7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 41. Enrichment computed across 25 evidence-associated genes (12 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 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Proline catabolism	1	317.2×	0.096	PRODH
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	135.9×	0.096	TERT
Organic anion transport by SLC5/17/25 transporters	1	119.0×	0.096	SLC25A1
Formation of annular gap junctions	1	86.5×	0.096	CLTCL1
Gap junction degradation	1	79.3×	0.096	CLTCL1
Elevation of cytosolic Ca2+ levels	1	59.5×	0.096	P2RX6
Translesion Synthesis by POLH	1	50.1×	0.096	UFD1
Extension of Telomeres	1	50.1×	0.096	TERT
Regulation of gene expression in beta cells	1	43.3×	0.096	HNF1A
Telomere Extension By Telomerase	1	38.1×	0.096	TERT
Cardiogenesis	1	35.2×	0.096	TBX1
Neddylation	2	7.9×	0.096	UFD1, FBXL7
Telomere Maintenance	1	30.7×	0.101	TERT
Rev-mediated nuclear export of HIV RNA	1	26.4×	0.101	RANBP1
Dengue Virus Genome Translation and Replication	1	26.4×	0.101	UFD1
Detoxification of Reactive Oxygen Species	1	25.0×	0.101	TXNRD2
Platelet homeostasis	1	23.2×	0.102	P2RX6
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	1	20.7×	0.108	FBXL7
EPH-ephrin mediated repulsion of cells	1	18.3×	0.113	CLTCL1
Chromosome Maintenance	1	17.6×	0.113	TERT
MITF-M-dependent gene expression	1	15.1×	0.125	TERT
Mitochondrial translation	1	11.5×	0.135	MRPL40
Mitochondrial translation initiation	1	10.6×	0.135	MRPL40
Mitochondrial translation elongation	1	10.6×	0.135	MRPL40
Mitochondrial ribosome-associated quality control	1	10.2×	0.135	MRPL40
Formation of the beta-catenin:TCF transactivating complex	1	10.0×	0.135	TERT
KEAP1-NFE2L2 pathway	1	10.0×	0.135	UFD1
TCF dependent signaling in response to WNT	1	9.8×	0.135	TERT
MITF-M-regulated melanocyte development	1	9.5×	0.135	TERT
Signaling by WNT	1	9.3×	0.135	TERT

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 21 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to oxygen radical	1	802.5×	0.024	TXNRD2
RNA-templated transcription	1	802.5×	0.024	TERT
DNA strand elongation	1	802.5×	0.024	TERT
siRNA transcription	1	802.5×	0.024	TERT
positive regulation of transdifferentiation	1	802.5×	0.024	TERT
regulation of animal organ morphogenesis	1	802.5×	0.024	TBX1
positive regulation of D-glucose import across plasma membrane	2	43.4×	0.024	TERT, CLTCL1
anatomical structure morphogenesis	3	19.9×	0.024	MRPL40, CLTCL1, GSC2
RNA-templated DNA biosynthetic process	1	401.2×	0.030	TERT
mitochondrial citrate transmembrane transport	1	401.2×	0.030	SLC25A1
vagus nerve morphogenesis	1	401.2×	0.030	TBX1
positive regulation of hair cycle	1	401.2×	0.030	TERT
positive regulation of tongue muscle cell differentiation	1	401.2×	0.030	TBX1
social behavior	2	25.9×	0.030	TBX1, SEPTIN5
L-proline metabolic process	1	267.5×	0.033	PRODH
obsolete L-proline catabolic process to L-glutamate	1	267.5×	0.033	PRODH
renal D-glucose absorption	1	267.5×	0.033	HNF1A
positive regulation of mitotic centrosome separation	1	267.5×	0.033	RANBP1
L-proline catabolic process	1	200.6×	0.037	PRODH
obsolete synaptic vesicle targeting	1	200.6×	0.037	SEPTIN5
ear morphogenesis	1	200.6×	0.037	TBX1
trans-4-hydroxy-L-proline catabolic process	1	160.5×	0.039	PRODH
tongue morphogenesis	1	160.5×	0.039	TBX1
soft palate development	1	160.5×	0.039	TBX1
regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway	1	160.5×	0.039	PRODH
muscle cell fate commitment	1	133.8×	0.043	TBX1
positive regulation of protein localization to nucleolus	1	133.8×	0.043	TERT
semicircular canal morphogenesis	1	114.6×	0.044	TBX1
parathyroid gland development	1	114.6×	0.044	TBX1
muscle tissue morphogenesis	1	114.6×	0.044	TBX1

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Teriparatide Acetate	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): NB-001.

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 21

Druggability breadth: 8 of 25 evidence-associated genes (32%) 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
TSSK2	BRIGATINIB
TERT	BERBERINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TERT	10	4
TSSK2	3	4
TXNRD2	3	3
RANBP1	1	2
TBX1	0	0
SLC25A1	0	0
HNF1A	0	0
UFD1	0	0
FBXL7	0	0
MRPL40	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BRIGATINIB	4	TSSK2
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
RESVERATROL	3	TERT
EPIGALOCATECHIN GALLATE	3	TERT
PERIFOSINE	3	TERT
CURCUMIN	3	TXNRD2
CENISERTIB	2	TSSK2
ISOMETAMIDIUM	2	TERT
HOMIDIUM BROMIDE	2	TERT
ALLICIN	2	TERT
OLEIC ACID	2	TERT
ETHACRIDINE	2	TERT
ELLAGIC ACID	2	TXNRD2
ELTANEXOR	2	RANBP1
RG-1530	1	TSSK2
ETHASELEN	1	TXNRD2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
TERT	391	Binding:389, Functional:2
TSSK2	150	Binding:149, Functional:1
TXNRD2	91	Binding:76, Functional:15
SLC25A1	5	Binding:5
P2RX6	4	Functional:2, Binding:2
RANBP1	4	Binding:4
HNF1A	1	Binding:1
SEPTIN5	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TSSK2	2.7.11.1	non-specific serine/threonine protein kinase
TXNRD2	1.8.1.9	thioredoxin-disulfide reductase (NADPH)
TRMT2A	2.1.1.35	tRNA (uracil54-C5)-methyltransferase
PRODH	1.5.5.2, 1.5.99.B2	proline dehydrogenase,

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TSSK2	150
TERT	391

Pharmacogenomics

Cohort genes with a PharmGKB record: 24; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

17 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)
BRIGATINIB	4	TSSK2
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
RESVERATROL	3	TERT
EPIGALOCATECHIN GALLATE	3	TERT
PERIFOSINE	3	TERT
CURCUMIN	3	TXNRD2
CENISERTIB	2	TSSK2
ISOMETAMIDIUM	2	TERT
HOMIDIUM BROMIDE	2	TERT
ALLICIN	2	TERT
OLEIC ACID	2	TERT
ETHACRIDINE	2	TERT
ELLAGIC ACID	2	TXNRD2
ELTANEXOR	2	RANBP1
RG-1530	1	TSSK2
ETHASELEN	1	TXNRD2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TSSK2, TERT
B	Phased (≥1) drug, not yet approved	2	TXNRD2, RANBP1
C	Druggable family + PDB, no drug	2	TRMT2A, RIMBP3
D	Druggable family + AlphaFold only, no drug	1	PRODH
E	Difficult family or no structure, no drug	18	TBX1, SLC25A1, HNF1A, UFD1, FBXL7, MRPL40, DGCR6L, CLTCL1, AIFM3, C22orf39 (+8 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TRMT2A	0	RANBP1
ARVCF	0	TXNRD2
TBX1	0	—
SLC25A1	5	—
HNF1A	1	—
UFD1	0	—
FBXL7	0	—
MRPL40	0	—
DGCR6L	0	—
CLTCL1	0	—
AIFM3	0	—
C22orf39	0	—
DGCR2	0	—
RIMBP3	0	—
TMEM191B	0	—
LRRC74B	0	—
FAM230A	0	—
GSC2	0	—
P2RX6	4	—
SEPTIN5	1	—
PRODH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 31.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	20
PHASE2	5
PHASE1	4
PHASE3	1
PHASE1/PHASE2	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
NCT00579527	PHASE1/PHASE2	COMPLETED	Phase I/II Thymus Transplantation With Immunosuppression #950
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
NCT00849888	PHASE1	TERMINATED	Serum-Free Thymus Transplantation in DiGeorge Anomaly
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
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
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
NCT04141540	Not specified	COMPLETED	Molecular Variants Associated With Schizophrenia: Differential Analysis of Monozygotic Twins With Variable Phenotypic 22q11
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
DACLIZUMAB	4	1
METHYLPHENIDATE HYDROCHLORIDE	4	1
MYCOPHENOLATE MOFETIL	4	1