Velocardiofacial syndrome

Summary

Velocardiofacial syndrome (MONDO:0008644) is a disease caused by TBX1 (GenCC Strong), with 6 cohort genes and 12 clinical trials. Top therapeutic interventions include methylphenidate, risperidone, and nb-001.

At a glance

• Causal gene: TBX1 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 40
• Clinical trials: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	velocardiofacial syndrome
Mondo ID	MONDO:0008644
OMIM	192430
DOID	DOID:12583
UMLS	C0220704
MedGen	65085
GARD	0015123
Is cancer (heuristic)	no

Also known as: 22q11 deletion syndrome · deletion 22q11.2 syndrome · Shprintzen syndrome · Shprintzen VCF syndrome · VCF syndrome · velocardiofacial syndrome

Data availability: 40 ClinVar variants · 1 GenCC gene-disease record.

Disease family

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

Related subtypes (3): congenital unilateral hypoplasia of depressor anguli oris, DiGeorge 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

40 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 12 pathogenic, 9 conflicting classifications of pathogenicity, 4 likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
636280	GRCh37/hg19 22q11.21(chr22:18912231-21465672)x1	AIFM3	Pathogenic	no assertion criteria provided
636282	GRCh37/hg19 22q11.21(chr22:18922151-21449911)x1	AIFM3	Pathogenic	no assertion criteria provided
636283	GRCh37/hg19 22q11.21(chr22:18636749-21800471)x1	AIFM3	Pathogenic	no assertion criteria provided
636284	GRCh37/hg19 22q11.21(chr22:18919477-21800471)x1	AIFM3	Pathogenic	no assertion criteria provided
666443	GRCh37/hg19 22q11.21(chr22:18661724-21505417)x1	DGCR6L	Pathogenic	criteria provided, single submitter
2580309	GRCh37/hg19 22q11.21(chr22:18893838-21416074)x3	KLHL22	Pathogenic	criteria provided, single submitter
2574134	NC_000022.11:g.18948676_21110520del	LOC129391266	Pathogenic	criteria provided, single submitter
636281	GRCh37/hg19 22q11.21(chr22:18631364-21800471)x1	RANBP1	Pathogenic	no assertion criteria provided
1684640	Single allele	SNORA77B	Pathogenic	criteria provided, single submitter
1378052	NM_001379200.1(TBX1):c.186C>A (p.Cys62Ter)	TBX1	Pathogenic	criteria provided, single submitter
7566	NM_001379200.1(TBX1):c.1326_1348del (p.Pro444fs)	TBX1	Pathogenic	no assertion criteria provided
7567	NM_001379200.1(TBX1):c.609C>G (p.His203Gln)	TBX1	Pathogenic	no assertion criteria provided
2441780	NM_001379200.1(TBX1):c.437+1G>C	TBX1	Likely pathogenic	criteria provided, single submitter
3235917	NM_001379200.1(TBX1):c.61G>A (p.Ala21Thr)	TBX1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3777108	NM_001379200.1(TBX1):c.215_234del (p.Pro72fs)	TBX1	Likely pathogenic	criteria provided, single submitter
973222	NM_001379200.1(TBX1):c.503T>C (p.Leu168Pro)	TBX1	Likely pathogenic	criteria provided, single submitter
1114796	NM_001379200.1(TBX1):c.941G>A (p.Arg314Gln)	TBX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1934268	NM_001379200.1(TBX1):c.1004C>T (p.Ala335Val)	TBX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2001091	NM_001379200.1(TBX1):c.1342C>A (p.Pro448Thr)	TBX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2086566	NM_001379200.1(TBX1):c.170_229del (p.Pro57_Pro76del)	TBX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
518715	NM_001379200.1(TBX1):c.1076G>A (p.Gly359Asp)	TBX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
598931	NM_001379200.1(TBX1):c.1401C>G (p.Pro467=)	TBX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626178	NM_001379200.1(TBX1):c.351C>T (p.Ala117=)	TBX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
800274	NM_001379200.1(TBX1):c.1178C>A (p.Pro393Gln)	TBX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
934486	NM_001379200.1(TBX1):c.823G>A (p.Glu275Lys)	TBX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1023859	NM_001379200.1(TBX1):c.97G>T (p.Ala33Ser)	TBX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1060987	NM_001379200.1(TBX1):c.1153GCCGGCGGC[1] (p.385AGG[1])	TBX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1213748	NM_001379200.1(TBX1):c.623C>T (p.Ser208Leu)	TBX1	Uncertain significance	criteria provided, single submitter
1382862	NM_001379200.1(TBX1):c.740A>G (p.Gln247Arg)	TBX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1414844	NM_001379200.1(TBX1):c.711+3G>A	TBX1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 6 · 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	Strong	Autosomal dominant	velocardiofacial 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

Cohort genes → proteins

6 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TBX1	HGNC:11592	ENSG00000184058	O43435	T-box transcription factor TBX1	gencc,clinvar
DGCR6L	HGNC:18551	ENSG00000128185	Q9BY27	Protein DGCR6L	clinvar
KLHL22	HGNC:25888	ENSG00000099910	Q53GT1	Kelch-like protein 22	clinvar
AIFM3	HGNC:26398	ENSG00000183773	Q96NN9	Apoptosis-inducing factor 3	clinvar
SNORA77B	HGNC:52221	ENSG00000264346		small nucleolar RNA, H/ACA box 77B	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.
DGCR6L	Protein DGCR6L	May play a role in neural crest cell migration into the third and fourth pharyngeal pouches.
KLHL22	Kelch-like protein 22	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex required for chromosome alignment and localization of PLK1 at kinetochores.
AIFM3	Apoptosis-inducing factor 3	Induces apoptosis through a caspase dependent pathway.
RANBP1	Ran-specific GTPase-activating protein	Plays a role in RAN-dependent nucleocytoplasmic transport.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 5 · 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	5	1.5×	0.348
Transcription factor	1	1.4×	0.539

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
DGCR6L	Other/Unknown	no		Gonadal
KLHL22	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
AIFM3	Other/Unknown	no		FAD/NAD-linked_Rdtase_dimer_sf, Rieske_2Fe-2S, FAD/NAD-binding_dom
SNORA77B	Other/Unknown	no
RANBP1	Other/Unknown	no		Ran_bind_dom, PH-like_dom_sf, RanBP1-like

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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right hemisphere of cerebellum	2
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1
left testis	1
right testis	1
testis	1
cerebellar cortex	1
cerebellar hemisphere	1
mucosa of transverse colon	1
right frontal lobe	1
adrenal tissue	1
liver	1
sural nerve	1
embryo	1
ganglionic eminence	1
ventricular zone	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
DGCR6L	142	ubiquitous	marker	right testis, left testis, testis
KLHL22	246	ubiquitous	yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
AIFM3	180	tissue_specific	marker	mucosa of transverse colon, right frontal lobe, right hemisphere of cerebellum
SNORA77B	81		yes	adrenal tissue, sural nerve, liver
RANBP1	279	ubiquitous	marker	ganglionic eminence, embryo, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RANBP1	3,338
AIFM3	2,051
KLHL22	1,428
TBX1	1,256
DGCR6L	683
SNORA77B	0

Intra-cohort edges

A	B	Sources
AIFM3	KLHL22	string_interaction
AIFM3	TBX1	string_interaction
DGCR6L	TBX1	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AIFM3	Q96NN9	7
KLHL22	Q53GT1	4
RANBP1	P43487	4
TBX1	O43435	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DGCR6L	Q9BY27	87.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 6 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cardiogenesis	1	141.0×	0.047	TBX1
Rev-mediated nuclear export of HIV RNA	1	105.7×	0.047	RANBP1
Class I MHC mediated antigen processing & presentation	1	23.4×	0.141	KLHL22
Neddylation	1	15.8×	0.155	KLHL22
Antigen processing: Ubiquitination & Proteasome degradation	1	12.4×	0.157	KLHL22
Adaptive Immune System	1	9.9×	0.162	KLHL22
Post-translational protein modification	1	6.4×	0.212	KLHL22
Developmental Biology	1	4.8×	0.223	TBX1
Immune System	1	4.3×	0.223	KLHL22
Metabolism of proteins	1	4.1×	0.223	KLHL22

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
regulation of animal organ morphogenesis	1	4213.0×	0.010	TBX1
vagus nerve morphogenesis	1	2106.5×	0.010	TBX1
positive regulation of tongue muscle cell differentiation	1	2106.5×	0.010	TBX1
positive regulation of mitotic centrosome separation	1	1404.3×	0.010	RANBP1
ear morphogenesis	1	1053.2×	0.010	TBX1
tongue morphogenesis	1	842.6×	0.010	TBX1
soft palate development	1	842.6×	0.010	TBX1
muscle cell fate commitment	1	702.2×	0.010	TBX1
positive regulation of T cell mediated immune response to tumor cell	1	601.9×	0.010	KLHL22
semicircular canal morphogenesis	1	601.9×	0.010	TBX1
parathyroid gland development	1	601.9×	0.010	TBX1
muscle tissue morphogenesis	1	601.9×	0.010	TBX1
negative regulation of mesenchymal cell apoptotic process	1	601.9×	0.010	TBX1
lymph vessel development	1	468.1×	0.010	TBX1
muscle organ morphogenesis	1	468.1×	0.010	TBX1
coronary artery morphogenesis	1	468.1×	0.010	TBX1
embryonic viscerocranium morphogenesis	1	421.3×	0.011	TBX1
outer ear morphogenesis	1	383.0×	0.011	TBX1
mesenchymal cell apoptotic process	1	383.0×	0.011	TBX1
cellular response to L-leucine	1	351.1×	0.011	KLHL22
enamel mineralization	1	300.9×	0.012	TBX1
aorta morphogenesis	1	221.7×	0.016	TBX1
blood vessel morphogenesis	1	200.6×	0.016	TBX1
pharyngeal system development	1	200.6×	0.016	TBX1
execution phase of apoptosis	1	191.5×	0.016	AIFM3
middle ear morphogenesis	1	175.5×	0.016	TBX1
artery morphogenesis	1	168.5×	0.016	TBX1
outflow tract septum morphogenesis	1	162.0×	0.016	TBX1
retinoic acid receptor signaling pathway	1	162.0×	0.016	TBX1
positive regulation of mesenchymal cell proliferation	1	150.5×	0.016	TBX1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 1 of 6 evidence-associated genes (17%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RANBP1	1	2
TBX1	0	0
DGCR6L	0	0
KLHL22	0	0
AIFM3	0	0
SNORA77B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ELTANEXOR	2	RANBP1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RANBP1	4	Binding:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
ELTANEXOR	2	RANBP1

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	RANBP1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	TBX1, DGCR6L, KLHL22, AIFM3, SNORA77B

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)
TBX1	0	—
DGCR6L	0	—
KLHL22	0	—
AIFM3	0	—
SNORA77B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	8
PHASE2	2
PHASE4	1
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00768820	PHASE4	RECRUITING	The Psychiatric and Cognitive Phenotypes in Velocardiofacial Syndrome
NCT02070211	PHASE2/PHASE3	UNKNOWN	Indicated Prevention With Long-chain Polyunsaturated Omega-3 Fatty Acids in Patients With 22q11 Microdeletion Syndrome.
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT05290493	PHASE2	COMPLETED	NB-001 in Children and Adolescents With 22q11 Deletion Syndrome
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT05664412	Not specified	RECRUITING	Using Transcranial Alternating Current Stimulation to Improve Executive Function in 22q11.2 Deletion Syndrome
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
NCT00917189	Not specified	COMPLETED	Computerized Cognitive Skills Training for Adolescents With Velocardiofacial Syndrome
NCT02381457	Not specified	COMPLETED	SNP-based Microdeletion and Aneuploidy RegisTry (SMART)
NCT05849441	Not specified	COMPLETED	Mindfulness Program for Adolescents With 22q11DS

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
METHYLPHENIDATE	4	1
RISPERIDONE	4	1
NB-001	3	1
OMEGA-3 FATTY ACIDS	3	1