pancytopenia due to IKZF1 mutations

Summary

pancytopenia due to IKZF1 mutations (MONDO:0014810) is a disease caused by IKZF1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IKZF1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 39

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		39	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	pancytopenia due to IKZF1 mutations
Mondo ID	MONDO:0014810
OMIM	616873
Orphanet	317473
DOID	DOID:0081155
ICD-11	1240674590
UMLS	C4225173
MedGen	905078
GARD	0017442
Is cancer (heuristic)	no

Also known as: Cid due to IKAROS deficiency · combined immunodeficiency due to IKAROS deficiency · CVID13 · IKZF1 syndrome with combined immunodeficiency · immunodeficiency, common variable, 13 · immunodeficiency, common variable, type 13 · syndrome with combined immunodeficiency caused by mutation in IKZF1

Data availability: 39 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic agammaglobulinemia › common variable immunodeficiency › pancytopenia due to IKZF1 mutations

Related subtypes (15): immune deficiency, familial variable, immunodeficiency, common variable, 2, immunodeficiency, common variable, 1, immunodeficiency, common variable, 3, immunodeficiency, common variable, 4, immunodeficiency, common variable, 5, immunodeficiency, common variable, 6, immunodeficiency, common variable, 7, combined immunodeficiency due to LRBA deficiency, immunodeficiency, common variable, 10, IL21-related infantile inflammatory bowel disease, immunodeficiency, common variable, 12, immunodeficiency, common variable, 14, immunodeficiency, common variable, due to APRIL deficiency, immunodeficiency, common variable, 15

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

39 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 9 conflicting classifications of pathogenicity, 6 benign, 5 pathogenic, 4 likely pathogenic, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
224777	NM_006060.6(IKZF1):c.629A>G (p.Tyr210Cys)	IKZF1	Pathogenic	no assertion criteria provided
224779	NM_006060.6(IKZF1):c.485G>A (p.Arg162Gln)	IKZF1	Pathogenic	criteria provided, single submitter
224782	NM_006060.5(IKZF1):c.161-8388_589+2308del	IKZF1	Pathogenic	no assertion criteria provided
692112	NM_006060.6(IKZF1):c.546C>A (p.Cys182Ter)	IKZF1	Pathogenic	criteria provided, single submitter
827709	NM_006060.6(IKZF1):c.476A>G (p.Asn159Ser)	IKZF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1285540	NM_006060.6(IKZF1):c.530T>C (p.Leu177Pro)	IKZF1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2444367	NM_006060.6(IKZF1):c.1275dup (p.Leu426fs)	IKZF1	Likely pathogenic	criteria provided, single submitter
3779761	NM_006060.6(IKZF1):c.10_40+46del	IKZF1	Likely pathogenic	criteria provided, single submitter
4279067	NM_006060.6(IKZF1):c.266G>A (p.Gly89Glu)	IKZF1	Likely pathogenic	no assertion criteria provided
2030696	NM_006060.6(IKZF1):c.499C>T (p.His167Tyr)	IKZF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
224778	NM_006060.6(IKZF1):c.485G>T (p.Arg162Leu)	IKZF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
224780	NM_006060.6(IKZF1):c.500A>G (p.His167Arg)	IKZF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
423249	NM_006060.6(IKZF1):c.825G>A (p.Lys275=)	IKZF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
428611	NM_006060.6(IKZF1):c.584A>G (p.His195Arg)	IKZF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
548705	NM_006060.6(IKZF1):c.814G>A (p.Ala272Thr)	IKZF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
548932	NM_006060.6(IKZF1):c.64G>A (p.Asp22Asn)	IKZF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
827712	NM_006060.6(IKZF1):c.550C>T (p.Arg184Trp)	IKZF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
977104	NM_006060.6(IKZF1):c.548G>A (p.Arg183His)	IKZF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032403	NM_006060.6(IKZF1):c.715+167C>T	IKZF1	Uncertain significance	criteria provided, single submitter
1320280	NM_006060.6(IKZF1):c.1047G>C (p.Gln349His)	IKZF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1342336	NM_006060.6(IKZF1):c.1076C>T (p.Pro359Leu)	IKZF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1683635	NM_006060.6(IKZF1):c.369G>A (p.Gly123=)	IKZF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
224781	NM_006060.6(IKZF1):c.551G>A (p.Arg184Gln)	IKZF1	Uncertain significance	criteria provided, single submitter
2432839	NM_006060.6(IKZF1):c.589+1G>A	IKZF1	Uncertain significance	criteria provided, single submitter
2444881	NM_006060.6(IKZF1):c.880G>C (p.Asp294His)	IKZF1	Uncertain significance	criteria provided, single submitter
2921139	NM_006060.6(IKZF1):c.863T>G (p.Leu288Arg)	IKZF1	Uncertain significance	criteria provided, single submitter
3242021	NM_006060.6(IKZF1):c.1288G>C (p.Glu430Gln)	IKZF1	Uncertain significance	criteria provided, single submitter
3594723	NM_006060.6(IKZF1):c.1346T>G (p.Leu449Arg)	IKZF1	Uncertain significance	criteria provided, single submitter
4078996	NM_006060.6(IKZF1):c.665G>A (p.Arg222His)	IKZF1	Uncertain significance	criteria provided, single submitter
996848	NM_006060.6(IKZF1):c.161-15019A>G	IKZF1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 5 · 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
IKZF1	Definitive	Autosomal dominant	pancytopenia due to IKZF1 mutations	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IKZF1	Orphanet:317473	Common variable immunodeficiency phenotype due to IKAROS functional haploinsufficiency
IKZF1	Orphanet:36426	Stevens-Johnson syndrome
IKZF1	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
IKZF1	Orphanet:695172	Combined immunodeficiency due to dimerization defective IKAROS mutation
IKZF1	Orphanet:697414	Early-onset combined immunodeficiency with low Ig due to dominant negative IKAROS mutation

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IKZF1	HGNC:13176	ENSG00000185811	Q13422	DNA-binding protein Ikaros	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IKZF1	DNA-binding protein Ikaros	Transcription regulator of hematopoietic cell differentiation.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IKZF1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Ikaros_C2H2-ZF

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IKZF1	225	broad	marker	leukocyte, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IKZF1	4,096

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IKZF1	Q13422	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
NOTCH3 Intracellular Domain Regulates Transcription	1	439.2×	0.005	IKZF1
Interaction of NuRD complexes with transcription factors	1	126.9×	0.008	IKZF1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lymphocyte differentiation	1	2808.7×	0.002	IKZF1
mesoderm development	1	526.6×	0.006	IKZF1
erythrocyte differentiation	1	267.5×	0.007	IKZF1
chromatin organization	1	99.1×	0.015	IKZF1
negative regulation of DNA-templated transcription	1	31.6×	0.038	IKZF1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	IKZF1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
IKZF1	POMALIDOMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IKZF1	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
POMALIDOMIDE	4	IKZF1
LENALIDOMIDE	4	IKZF1
IBERDOMIDE	3	IKZF1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
IKZF1	106	Binding:105, Functional:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
IKZF1	106

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

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)
POMALIDOMIDE	4	IKZF1
LENALIDOMIDE	4	IKZF1
IBERDOMIDE	3	IKZF1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	IKZF1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.