Chromosome 22q11.2 deletion syndrome, distal

Summary

Chromosome 22q11.2 deletion syndrome, distal (MONDO:0012740) is a disease with 10 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 10
• ClinVar variants: 13
• Phenotypes (HPO): 60

Clinical features

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000319	Smooth philtrum	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001622	Premature birth	Very frequent (80-99%)
HP:0002463	Language impairment	Very frequent (80-99%)
HP:0002553	Highly arched eyebrow	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0000219	Thin upper lip vermilion	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000307	Pointed chin	Frequent (30-79%)
HP:0000363	Abnormality of earlobe	Frequent (30-79%)
HP:0000430	Underdeveloped nasal alae	Frequent (30-79%)
HP:0000490	Deeply set eye	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001660	Truncus arteriosus	Frequent (30-79%)
HP:0001763	Pes planus	Frequent (30-79%)
HP:0001802	Absent toenail	Frequent (30-79%)
HP:0001817	Absent fingernail	Frequent (30-79%)
HP:0002664	Neoplasm	Frequent (30-79%)
HP:0004209	Clinodactyly of the 5th finger	Frequent (30-79%)
HP:0000010	Recurrent urinary tract infections	Occasional (5-29%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000160	Narrow mouth	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000272	Malar flattening	Occasional (5-29%)
HP:0000276	Long face	Occasional (5-29%)
HP:0000324	Facial asymmetry	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000426	Prominent nasal bridge	Occasional (5-29%)
HP:0000453	Choanal atresia	Occasional (5-29%)
HP:0000581	Blepharophimosis	Occasional (5-29%)
HP:0000657	Oculomotor apraxia	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000722	Compulsive behaviors	Occasional (5-29%)
HP:0001166	Arachnodactyly	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0001659	Aortic regurgitation	Occasional (5-29%)
HP:0001770	Toe syndactyly	Occasional (5-29%)
HP:0001852	Sandal gap	Occasional (5-29%)
HP:0002021	Pyloric stenosis	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002607	Bowel incontinence	Occasional (5-29%)
HP:0002673	Coxa valga	Occasional (5-29%)
HP:0002705	High, narrow palate	Occasional (5-29%)
HP:0002721	Immunodeficiency	Occasional (5-29%)
HP:0003307	Hyperlordosis	Occasional (5-29%)
HP:0004279	Short palm	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	chromosome 22q11.2 deletion syndrome, distal
Mondo ID	MONDO:0012740
MeSH	C567511
OMIM	611867
Orphanet	261330
DOID	DOID:0060413
SNOMED CT	734029004
UMLS	C2678480
MedGen	395634
GARD	0017245
Is cancer (heuristic)	no

Also known as: chromosome 22q11.2 deletion syndrome, distal · distal 22q11.2 microdeletion syndrome · distal del(22)(q11.2) · distal monosomy 22q11.2

Data availability: 13 ClinVar variants.

Disease family

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

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

13 retrieved; paginated sample, class counts are floors:

11 pathogenic, 1 uncertain significance, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4820242	Single allele	AIFM3	Pathogenic	criteria provided, single submitter
599193	NC_000022.10:g.21808950_22963000del1154051	CCDC116	Pathogenic	criteria provided, single submitter
830215	NC_000022.10:g.(21822774_21914652)_(22922798_23025613)del	CCDC116	Pathogenic	criteria provided, single submitter
1330197	GRCh37/hg19 22q11.21(chr22:18660135-21737597)x1	DGCR6	Pathogenic	criteria provided, single submitter
625626	GRCh37/hg19 22q11.21-11.23(chr22:21797384-23630313)	IGLC1	Pathogenic	criteria provided, single submitter
2580309	GRCh37/hg19 22q11.21(chr22:18893838-21416074)x3	KLHL22	Pathogenic	criteria provided, single submitter
2580299	GRCh37/hg19 22q11.21(chr22:20609932-21576553)x1	LZTR1	Pathogenic	criteria provided, single submitter
1703235	Single allele	MRPL40	Pathogenic	criteria provided, single submitter
2580291	GRCh37/hg19 22q11.21(chr22:18893838-20508931)x3	MRPL40	Pathogenic	criteria provided, single submitter
2663782	NC_000022.10:g.(?21797384)(23630313_?)del	PRAME	Pathogenic	criteria provided, single submitter
973580	NC_000022.10:g.21514655_22986816del	RIMBP3B	Pathogenic	criteria provided, single submitter
3384223	GRCh37/hg19 22q11.22-11.23(chr22:22989174-23657759)x1	IGLC1	Likely pathogenic	no assertion criteria provided
1339957	NM_001089.3(ABCA3):c.4868C>T (p.Ala1623Val)	ABCA3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCA3	Orphanet:2032	Idiopathic pulmonary fibrosis
ABCA3	Orphanet:217563	Neonatal acute respiratory distress syndrome
ABCA3	Orphanet:440402	Interstitial lung disease due to ABCA3 deficiency
ABCA3	Orphanet:685082	Pediatric acute respiratory distress syndrome
LZTR1	Orphanet:251576	Gliosarcoma
LZTR1	Orphanet:251579	Giant cell glioblastoma
LZTR1	Orphanet:2678	Familial isolated café-au-lait macules
LZTR1	Orphanet:648	Noonan syndrome
LZTR1	Orphanet:93921	Full schwannomatosis

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MRPL40	HGNC:14491	ENSG00000185608	Q9NQ50	Large ribosomal subunit protein mL40	clinvar
KLHL22	HGNC:25888	ENSG00000099910	Q53GT1	Kelch-like protein 22	clinvar
AIFM3	HGNC:26398	ENSG00000183773	Q96NN9	Apoptosis-inducing factor 3	clinvar
CCDC116	HGNC:26688	ENSG00000161180	Q8IYX3	Coiled-coil domain-containing protein 116	clinvar
DGCR6	HGNC:2846	ENSG00000183628	Q14129	Protein DGCR6	clinvar
ABCA3	HGNC:33	ENSG00000167972	Q99758	Phospholipid-transporting ATPase ABCA3	clinvar
RIMBP3B	HGNC:33891	ENSG00000274600	A6NNM3	RIMS-binding protein 3B	clinvar
IGLC1	HGNC:5855	ENSG00000211675	P0CG04	Immunoglobulin lambda constant 1	clinvar
LZTR1	HGNC:6742	ENSG00000099949	Q8N653	Leucine-zipper-like transcriptional regulator 1	clinvar
PRAME	HGNC:9336	ENSG00000185686	P78395	Melanoma antigen preferentially expressed in tumors	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
DGCR6	Protein DGCR6	May play a role in neural crest cell migration into the third and fourth pharyngeal pouches.
ABCA3	Phospholipid-transporting ATPase ABCA3	Catalyzes the ATP-dependent transport of phospholipids such as phosphatidylcholine and phosphoglycerol from the cytoplasm into the lumen side of lamellar bodies, in turn participates in the lamellar bodies biogenesis and homeostasis of pul…
RIMBP3B	RIMS-binding protein 3B	Probable component of the manchette, a microtubule-based structure which plays a key role in sperm head morphogenesis during late stages of sperm development.
IGLC1	Immunoglobulin lambda constant 1	Constant region of immunoglobulin light chains.
LZTR1	Leucine-zipper-like transcriptional regulator 1	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination of Ras (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS).
PRAME	Melanoma antigen preferentially expressed in tumors	Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex, which mediates ubiquitination of target proteins, leading to their degradation.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 7 · Druggable fraction: 0.3

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	2	5.8×	0.132
Transporter	1	7.8×	0.182
Other/Unknown	7	1.2×	0.284

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MRPL40	Other/Unknown	no		Ribosomal_mL40, Ribosomal_mL40_metazoa/plant
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
CCDC116	Other/Unknown	no		DUF4702
DGCR6	Other/Unknown	no		Gonadal
ABCA3	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
RIMBP3B	Antibody/Immunoglobulin	yes		SH3_domain, FN3_dom, Ig-like_fold
IGLC1	Antibody/Immunoglobulin	yes		Ig/MHC_CS, Ig_C1-set, Ig-like_dom
LZTR1	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
PRAME	Other/Unknown	no		PRAME, LRR_dom_sf, LRRC14/PRAME

Expression context

Cohort genes with no expression data: 0.

8 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	3
right hemisphere of cerebellum	2
mucosa of transverse colon	2
male germ line stem cell (sensu Vertebrata) in testis	2
right testis	2
testis	2
biceps brachii	1
heart right ventricle	1
skeletal muscle tissue of rectus abdominis	1
cerebellar cortex	1
cerebellar hemisphere	1
right frontal lobe	1
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue	1
lower lobe of lung	1
upper lobe of left lung	1
upper lobe of lung	1
duodenum	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MRPL40	292	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, heart right ventricle
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
CCDC116	146	tissue_specific	yes	left testis, male germ line stem cell (sensu Vertebrata) in testis, right testis
DGCR6	134	ubiquitous	marker	skeletal muscle tissue, hindlimb stylopod muscle, gastrocnemius
ABCA3	222	ubiquitous	marker	lower lobe of lung, upper lobe of lung, upper lobe of left lung
RIMBP3B	37		marker	male germ line stem cell (sensu Vertebrata) in testis, left testis, testis
IGLC1	126	tissue_specific	marker	duodenum, rectum, mucosa of transverse colon
LZTR1	134	ubiquitous	marker	sural nerve, pituitary gland, adenohypophysis
PRAME	117	broad	marker	right testis, left testis, testis

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MRPL40	2,393
AIFM3	2,051
PRAME	1,804
LZTR1	1,562
ABCA3	1,436
KLHL22	1,428
CCDC116	633
DGCR6	581
RIMBP3B	485
IGLC1	18

Intra-cohort edges

A	B	Sources
AIFM3	KLHL22	string_interaction
AIFM3	LZTR1	biogrid_interaction, string_interaction
CCDC116	RIMBP3B	string_interaction
DGCR6	MRPL40	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPL40	Q9NQ50	82
AIFM3	Q96NN9	7
KLHL22	Q53GT1	4
IGLC1	P0CG04	3
LZTR1	Q8N653	3
ABCA3	Q99758	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DGCR6	Q14129	86.83
PRAME	P78395	81.29
RIMBP3B	A6NNM3	59.08
CCDC116	Q8IYX3	50.59

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 10 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
Defective ABCA3 causes SMDP3	1	3806.7×	0.003	ABCA3
Metabolism of proteins	3	12.4×	0.004	MRPL40, KLHL22, ABCA3
Diseases associated with surfactant metabolism	1	951.7×	0.006	ABCA3
ABC transporters in lipid homeostasis	1	200.3×	0.024	ABCA3
ABC transporter disorders	1	146.4×	0.027	ABCA3
Surfactant metabolism	1	122.8×	0.028	ABCA3
Disorders of transmembrane transporters	1	46.4×	0.045	ABCA3
Mitochondrial translation	1	45.9×	0.045	MRPL40
Mitochondrial translation initiation	1	42.3×	0.045	MRPL40
Mitochondrial translation elongation	1	42.3×	0.045	MRPL40
Mitochondrial ribosome-associated quality control	1	40.9×	0.045	MRPL40
ABC-family protein mediated transport	1	40.5×	0.045	ABCA3
Mitochondrial translation termination	1	36.6×	0.046	MRPL40
Diseases of metabolism	1	26.8×	0.059	ABCA3
Class I MHC mediated antigen processing & presentation	1	23.4×	0.063	KLHL22
Translation	1	20.7×	0.067	MRPL40
Neddylation	1	15.8×	0.083	KLHL22
Antigen processing: Ubiquitination & Proteasome degradation	1	12.4×	0.099	KLHL22
Adaptive Immune System	1	9.9×	0.117	KLHL22
Transport of small molecules	1	8.4×	0.131	ABCA3
Post-translational protein modification	1	6.4×	0.162	KLHL22
Disease	1	4.4×	0.214	ABCA3
Immune System	1	4.3×	0.214	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 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of protein homooligomerization	1	1872.4×	0.025	ABCA3
regulation of phosphatidylcholine metabolic process	1	936.2×	0.025	ABCA3
xenobiotic export from cell	1	624.1×	0.025	ABCA3
positive regulation of phospholipid efflux	1	468.1×	0.025	ABCA3
regulation of lipid biosynthetic process	1	312.1×	0.025	ABCA3
organelle assembly	1	312.1×	0.025	ABCA3
positive regulation of T cell mediated immune response to tumor cell	1	267.5×	0.025	KLHL22
positive regulation of phospholipid transport	1	267.5×	0.025	ABCA3
negative regulation of retinoic acid receptor signaling pathway	1	170.2×	0.031	PRAME
phosphatidylglycerol metabolic process	1	156.0×	0.031	ABCA3
cellular response to L-leucine	1	156.0×	0.031	KLHL22
phospholipid homeostasis	1	110.1×	0.034	ABCA3
xenobiotic transmembrane transport	1	104.0×	0.034	ABCA3
xenobiotic transport	1	93.6×	0.034	ABCA3
surfactant homeostasis	1	89.2×	0.034	ABCA3
phosphatidylcholine metabolic process	1	89.2×	0.034	ABCA3
execution phase of apoptosis	1	85.1×	0.034	AIFM3
phospholipid transport	1	78.0×	0.034	ABCA3
immunoglobulin mediated immune response	1	78.0×	0.034	IGLC1
negative regulation of Ras protein signal transduction	1	74.9×	0.034	LZTR1
proteasome-mediated ubiquitin-dependent protein catabolic process	2	11.6×	0.034	KLHL22, PRAME
positive regulation of cholesterol efflux	1	69.3×	0.035	ABCA3
mitotic spindle assembly checkpoint signaling	1	62.4×	0.037	KLHL22
negative regulation of type I interferon production	1	55.1×	0.040	KLHL22
mitotic sister chromatid segregation	1	53.5×	0.040	KLHL22
positive regulation of T cell activation	1	49.3×	0.042	KLHL22
B cell receptor signaling pathway	1	44.6×	0.044	IGLC1
protein monoubiquitination	1	38.2×	0.050	KLHL22
response to glucocorticoid	1	36.0×	0.051	ABCA3
fertilization	1	34.7×	0.051	RIMBP3B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 10

Druggability breadth: 0 of 10 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MRPL40	0	0
KLHL22	0	0
AIFM3	0	0
CCDC116	0	0
DGCR6	0	0
ABCA3	0	0
RIMBP3B	0	0
IGLC1	0	0
LZTR1	0	0
PRAME	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	ABCA3, IGLC1
D	Druggable family + AlphaFold only, no drug	1	RIMBP3B
E	Difficult family or no structure, no drug	7	MRPL40, KLHL22, AIFM3, CCDC116, DGCR6, LZTR1, PRAME

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MRPL40	0	—
KLHL22	0	—
AIFM3	0	—
CCDC116	0	—
DGCR6	0	—
ABCA3	0	—
RIMBP3B	0	—
IGLC1	0	—
LZTR1	0	—
PRAME	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.