Chromosome 4q21 deletion syndrome

Summary

Chromosome 4q21 deletion syndrome (MONDO:0013292) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 2
• Phenotypes (HPO): 42

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		14	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

42 HPO clinical features (Orphanet curated; top 42 by frequency):

HPO ID	Term	Frequency
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0011344	Severe global developmental delay	Very frequent (80-99%)
HP:0000293	Full cheeks	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000322	Short philtrum	Frequent (30-79%)
HP:0000337	Broad forehead	Frequent (30-79%)
HP:0000369	Low-set ears	Frequent (30-79%)
HP:0000470	Short neck	Frequent (30-79%)
HP:0001773	Short foot	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0002983	Micromelia	Frequent (30-79%)
HP:0004279	Short palm	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0200055	Small hand	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Occasional (5-29%)
HP:0000233	Thin vermilion border	Occasional (5-29%)
HP:0000239	Large fontanelles	Occasional (5-29%)
HP:0000348	High forehead	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000527	Long eyelashes	Occasional (5-29%)
HP:0000664	Synophrys	Occasional (5-29%)
HP:0000717	Autism	Occasional (5-29%)
HP:0000733	Abnormal repetitive mannerisms	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001274	Agenesis of corpus callosum	Occasional (5-29%)
HP:0001321	Cerebellar hypoplasia	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001770	Toe syndactyly	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002230	Generalized hirsutism	Occasional (5-29%)
HP:0002360	Sleep abnormality	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002714	Downturned corners of mouth	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0100716	Self-injurious behavior	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	chromosome 4q21 deletion syndrome
Mondo ID	MONDO:0013292
OMIM	613509
Orphanet	238750
DOID	DOID:0060420
SNOMED CT	719660008
UMLS	C3150756
MedGen	462106
GARD	0017181
Is cancer (heuristic)	no

Also known as: 4q21 microdeletion syndrome · chromosome 4q21 deletion syndrome · chromosome 4q21 deletion syndrome, isolated cases · Del(4)(q21) · monosomy 4q21

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › chromosomal disorder › syndrome caused by partial chromosomal deletion › partial deletion of chromosome 4 › partial deletion of the long arm of chromosome 4 › chromosome 4q21 deletion syndrome

Related subtypes (2): distal monosomy 4q, 4q25 proximal deletion 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

2 retrieved; paginated sample, class counts are floors:

2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2579270	GRCh38/hg38 4q21.21-23(chr4:79123548-99457773)x1	ABCG2	Pathogenic	criteria provided, single submitter
830313	Single allele	HNRNPDL	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HNRNPDL	Orphanet:55596	HNRNPDL-related limb-girdle muscular dystrophy D3

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HNRNPDL	HGNC:5037	ENSG00000152795	O14979	Heterogeneous nuclear ribonucleoprotein D-like	clinvar
ABCG2	HGNC:74	ENSG00000118777	Q9UNQ0	Broad substrate specificity ATP-binding cassette transporter ABCG2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HNRNPDL	Heterogeneous nuclear ribonucleoprotein D-like	Acts as a transcriptional regulator.
ABCG2	Broad substrate specificity ATP-binding cassette transporter ABCG2	Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transporter	1	38.9×	0.051
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HNRNPDL	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, hnRPDL_RRM1
ABCG2	Transporter	yes	7.6.2.2	ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
embryo	1
primordial germ cell in gonad	1
tendon of biceps brachii	1
endothelial cell	1
ileal mucosa	1
jejunal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HNRNPDL	306	ubiquitous	marker	primordial germ cell in gonad, tendon of biceps brachii, embryo
ABCG2	245	broad	marker	jejunal mucosa, ileal mucosa, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HNRNPDL	4,869
ABCG2	3,743

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCG2	Q9UNQ0	29
HNRNPDL	O14979	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Abacavir transmembrane transport	1	1142.0×	0.007	ABCG2
Ciprofloxacin ADME	1	1142.0×	0.007	ABCG2
Metabolism of porphyrins	1	713.8×	0.007	ABCG2
Abacavir ADME	1	713.8×	0.007	ABCG2
NFE2L2 regulating MDR associated enzymes	1	713.8×	0.007	ABCG2
Heme degradation	1	407.9×	0.009	ABCG2
Heme biosynthesis	1	380.7×	0.009	ABCG2
Paracetamol ADME	1	211.5×	0.013	ABCG2
Iron uptake and transport	1	173.0×	0.013	ABCG2
Nuclear events mediated by NFE2L2	1	167.9×	0.013	ABCG2
Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation	1	150.3×	0.013	HNRNPDL
Sphingolipid de novo biosynthesis	1	142.8×	0.013	ABCG2
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	139.3×	0.013	ABCG2
Drug ADME	1	114.2×	0.014	ABCG2
Developmental Cell Lineages	1	112.0×	0.014	ABCG2
Sphingolipid metabolism	1	84.0×	0.018	ABCG2
Cellular response to chemical stress	1	71.4×	0.020	ABCG2
KEAP1-NFE2L2 pathway	1	60.1×	0.022	ABCG2
Cellular responses to stress	1	18.4×	0.068	ABCG2
Metabolism of lipids	1	15.8×	0.072	ABCG2
Cellular responses to stimuli	1	15.7×	0.072	ABCG2
Transport of small molecules	1	12.6×	0.085	ABCG2
Developmental Biology	1	7.2×	0.139	ABCG2
Metabolism	1	5.8×	0.165	ABCG2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
biotin transport	1	2808.7×	0.002	ABCG2
renal urate salt excretion	1	2808.7×	0.002	ABCG2
riboflavin transport	1	2106.5×	0.002	ABCG2
xenobiotic transport across blood-brain barrier	1	1404.3×	0.002	ABCG2
export across plasma membrane	1	842.6×	0.003	ABCG2
urate metabolic process	1	766.0×	0.003	ABCG2
transepithelial transport	1	601.9×	0.003	ABCG2
cellular detoxification	1	561.7×	0.003	ABCG2
obsolete organic anion transport	1	401.2×	0.004	ABCG2
sphingolipid biosynthetic process	1	179.3×	0.008	ABCG2
RNA processing	1	109.4×	0.012	HNRNPDL
transport across blood-brain barrier	1	89.6×	0.013	ABCG2
transmembrane transport	1	84.3×	0.013	ABCG2
regulation of gene expression	1	41.7×	0.024	HNRNPDL

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
ABCG2	CANDESARTAN CILEXETIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABCG2	92	4
HNRNPDL	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANDESARTAN CILEXETIL	4	ABCG2
TELMISARTAN	4	ABCG2
SAQUINAVIR	4	ABCG2
ATAZANAVIR	4	ABCG2
FEBUXOSTAT	4	ABCG2
PONATINIB	4	ABCG2
RABEPRAZOLE	4	ABCG2
DOLUTEGRAVIR	4	ABCG2
TIVOZANIB	4	ABCG2
CLOFAZIMINE	4	ABCG2
SORAFENIB	4	ABCG2
POSACONAZOLE	4	ABCG2
ESTRONE	4	ABCG2
NIMODIPINE	4	ABCG2
ATOVAQUONE	4	ABCG2
NICARDIPINE	4	ABCG2
ATORVASTATIN	4	ABCG2
PANTOPRAZOLE	4	ABCG2
OMEPRAZOLE	4	ABCG2
KETOCONAZOLE	4	ABCG2
CYCLOSPORINE	4	ABCG2
RITONAVIR	4	ABCG2
CASPOFUNGIN	4	ABCG2
ALECTINIB	4	ABCG2
RILPIVIRINE	4	ABCG2
LOSARTAN	4	ABCG2
NIFEDIPINE	4	ABCG2
REGORAFENIB	4	ABCG2
COBICISTAT	4	ABCG2
FOSTAMATINIB	4	ABCG2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ABCG2	878	Binding:651, ADMET:115, Functional:111, Toxicity:1
HNRNPDL	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCG2	7.6.2.2, 7.6.2.3	ABC-type xenobiotic transporter, ABC-type glutathione-S-conjugate transporter

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ABCG2	878

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
ABCG2	1

Chemical tractability of cohort targets

30 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)
CANDESARTAN CILEXETIL	4	ABCG2
TELMISARTAN	4	ABCG2
SAQUINAVIR	4	ABCG2
ATAZANAVIR	4	ABCG2
FEBUXOSTAT	4	ABCG2
PONATINIB	4	ABCG2
RABEPRAZOLE	4	ABCG2
DOLUTEGRAVIR	4	ABCG2
TIVOZANIB	4	ABCG2
CLOFAZIMINE	4	ABCG2
SORAFENIB	4	ABCG2
POSACONAZOLE	4	ABCG2
ESTRONE	4	ABCG2
NIMODIPINE	4	ABCG2
ATOVAQUONE	4	ABCG2
NICARDIPINE	4	ABCG2
ATORVASTATIN	4	ABCG2
PANTOPRAZOLE	4	ABCG2
OMEPRAZOLE	4	ABCG2
KETOCONAZOLE	4	ABCG2
CYCLOSPORINE	4	ABCG2
RITONAVIR	4	ABCG2
CASPOFUNGIN	4	ABCG2
ALECTINIB	4	ABCG2
RILPIVIRINE	4	ABCG2
LOSARTAN	4	ABCG2
NIFEDIPINE	4	ABCG2
REGORAFENIB	4	ABCG2
COBICISTAT	4	ABCG2
FOSTAMATINIB	4	ABCG2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ABCG2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	HNRNPDL

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HNRNPDL	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.