WHIM syndrome 1

Summary

WHIM syndrome 1 (MONDO:8000006) is a disease caused by CXCR4 (GenCC Definitive), with 1 cohort gene and 3 clinical trials. Top therapeutic interventions include mavorixafor.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CXCR4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 31
• Phenotypes (HPO): 34
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		65	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated
Prevalence at birth	<1 / 1 000 000	0.023	France	Validated

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0001875	Decreased total neutrophil count	Very frequent (80-99%)
HP:0001888	Lymphopenia	Very frequent (80-99%)
HP:0011992	Abnormality of neutrophil morphology	Very frequent (80-99%)
HP:0031020	Bone marrow hypercellularity	Very frequent (80-99%)
HP:0031160	Myelokathexis	Very frequent (80-99%)
HP:0002090	Pneumonia	Frequent (30-79%)
HP:0002718	Recurrent bacterial infections	Frequent (30-79%)
HP:0002788	Recurrent upper respiratory tract infections	Frequent (30-79%)
HP:0004313	Decreased circulating antibody level	Frequent (30-79%)
HP:0006532	Recurrent pneumonia	Frequent (30-79%)
HP:0011947	Respiratory tract infection	Frequent (30-79%)
HP:0012740	Papilloma	Frequent (30-79%)
HP:0200043	Verrucae	Frequent (30-79%)
HP:0000246	Sinusitis	Occasional (5-29%)
HP:0000388	Otitis media	Occasional (5-29%)
HP:0001636	Tetralogy of Fallot	Occasional (5-29%)
HP:0002070	Limb ataxia	Occasional (5-29%)
HP:0002110	Bronchiectasis	Occasional (5-29%)
HP:0002167	Abnormality of speech or vocalization	Occasional (5-29%)
HP:0002172	Postural instability	Occasional (5-29%)
HP:0002244	Abnormality of the small intestine	Occasional (5-29%)
HP:0007010	Poor fine motor coordination	Occasional (5-29%)
HP:0025439	Pharyngitis	Occasional (5-29%)
HP:0030079	Cervix cancer	Occasional (5-29%)
HP:0000166	Severe periodontitis	Very rare (<1-4%)
HP:0001045	Vitiligo	Very rare (<1-4%)
HP:0001250	Seizure	Very rare (<1-4%)
HP:0001287	Meningitis	Very rare (<1-4%)
HP:0002840	Lymphadenitis	Very rare (<1-4%)
HP:0011850	Parotitis	Very rare (<1-4%)
HP:0012056	Cutaneous melanoma	Very rare (<1-4%)
HP:0100658	Cellulitis	Very rare (<1-4%)
HP:0100750	Atelectasis	Very rare (<1-4%)
HP:0100806	Sepsis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	WHIM syndrome 1
Mondo ID	MONDO:8000006
MeSH	C536697
OMIM	193670
Orphanet	51636
DOID	DOID:0060591
SNOMED CT	234571003
UMLS	C5542296
MedGen	1778124
GARD	0009297
NORD	1849
Is cancer (heuristic)	no

Also known as: Warts-hypogammaglobulinemia-infections-myelokathexis syndrome · Warts-infections-leukopenia-myelokatexis syndrome · WHIM Syndrome · WHIMS · WILM

Data availability: 31 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › leukocyte disorder › leukopenia › agranulocytosis › neutropenia › constitutional neutropenia › WHIM syndrome 1

Related subtypes (12): cyclic hematopoiesis, Chediak-Higashi syndrome, Cohen syndrome, glycogen storage disease Ib, Lichtenstein syndrome, Barth syndrome, poikiloderma with neutropenia, Griscelli syndrome type 2, Hermansky-Pudlak syndrome 2, primary immunodeficiency syndrome due to p14 deficiency, neutropenia-monocytopenia-deafness syndrome, severe congenital neutropenia

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

31 retrieved; paginated sample, class counts are floors:

19 pathogenic, 4 likely pathogenic, 4 uncertain significance, 2 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1036381	NM_003467.3(CXCR4):c.969dup (p.Ser324fs)	CXCR4	Pathogenic	criteria provided, single submitter
1338437	NM_003467.3(CXCR4):c.1012_1015dup (p.Ser339fs)	CXCR4	Pathogenic	criteria provided, multiple submitters, no conflicts
14020	NM_003467.3(CXCR4):c.1000C>T (p.Arg334Ter)	CXCR4	Pathogenic	criteria provided, multiple submitters, no conflicts
14021	NM_003467.3(CXCR4):c.1016_1017del (p.Ser339fs)	CXCR4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14022	NM_003467.3(CXCR4):c.1027G>T (p.Glu343Ter)	CXCR4	Pathogenic	no assertion criteria provided
14023	NM_003467.3(CXCR4):c.1013C>G (p.Ser338Ter)	CXCR4	Pathogenic	criteria provided, multiple submitters, no conflicts
3901266	NM_003467.3(CXCR4):c.1037_1040del (p.Glu345_Ser346insTer)	CXCR4	Pathogenic	criteria provided, single submitter
3902802	NM_003467.3(CXCR4):c.1032_1033del (p.Glu345fs)	CXCR4	Pathogenic	criteria provided, single submitter
3902803	NM_003467.3(CXCR4):c.976dup (p.Leu326fs)	CXCR4	Pathogenic	criteria provided, single submitter
3902804	NM_003467.3(CXCR4):c.970del (p.Ser324fs)	CXCR4	Pathogenic	criteria provided, single submitter
3902805	NM_003467.3(CXCR4):c.970_971insTCCT (p.Ser324fs)	CXCR4	Pathogenic	criteria provided, single submitter
3902806	NM_003467.3(CXCR4):c.969del (p.Ser324fs)	CXCR4	Pathogenic	criteria provided, single submitter
3902807	NM_003467.3(CXCR4):c.966_967del (p.Gly323fs)	CXCR4	Pathogenic	criteria provided, single submitter
3902808	NM_003467.3(CXCR4):c.954del (p.Ser319fs)	CXCR4	Pathogenic	criteria provided, single submitter
3902809	NM_003467.3(CXCR4):c.951del (p.Thr318fs)	CXCR4	Pathogenic	criteria provided, single submitter
3902811	NM_003467.3(CXCR4):c.1021del (p.Ser341fs)	CXCR4	Pathogenic	criteria provided, single submitter
3902812	NM_003467.3(CXCR4):c.1016_1017dup (p.Val340fs)	CXCR4	Pathogenic	criteria provided, single submitter
3902814	NM_003467.3(CXCR4):c.986_990del (p.Leu329fs)	CXCR4	Pathogenic	criteria provided, single submitter
3902815	NM_003467.3(CXCR4):c.979_980insG (p.Lys327fs)	CXCR4	Pathogenic	criteria provided, single submitter
3902816	NM_003467.3(CXCR4):c.977_978del (p.Leu326fs)	CXCR4	Pathogenic	criteria provided, single submitter
827702	NM_003467.3(CXCR4):c.950_953del (p.Leu317fs)	CXCR4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685294	NM_003467.3(CXCR4):c.1013C>A (p.Ser338Ter)	CXCR4	Likely pathogenic	criteria provided, single submitter
3900754	NM_003467.3(CXCR4):c.1027G>A (p.Glu343Lys)	CXCR4	Likely pathogenic	criteria provided, single submitter
3902810	NM_003467.3(CXCR4):c.1032dup (p.Glu345Ter)	CXCR4	Likely pathogenic	criteria provided, single submitter
3902813	NM_003467.3(CXCR4):c.997A>T (p.Lys333Ter)	CXCR4	Likely pathogenic	criteria provided, single submitter
709395	NM_003467.3(CXCR4):c.157A>C (p.Ile53Leu)	CXCR4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
808804	NM_003467.3(CXCR4):c.250G>C (p.Asp84His)	CXCR4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2431876	NM_003467.3(CXCR4):c.175G>A (p.Val59Ile)	CXCR4	Uncertain significance	criteria provided, single submitter
3893085	NM_003467.3(CXCR4):c.857T>A (p.Ile286Asn)	CXCR4	Uncertain significance	criteria provided, single submitter
4277816	NM_003467.3(CXCR4):c.356A>G (p.Asn119Ser)	CXCR4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
CXCR4	Definitive	Autosomal dominant	WHIM syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CXCR4	Orphanet:51636	WHIM syndrome

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
CXCR4	HGNC:2561	ENSG00000121966	P61073	C-X-C chemokine receptor type 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CXCR4	C-X-C chemokine receptor type 4	Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
GPCR	1	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CXCR4	GPCR	yes		GPCR_Rhodpsn, Chemokine_rcpt, CXCR4/ACKR2

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
bone marrow	1
lymph node	1
thymus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CXCR4	281	ubiquitous	marker	bone marrow, thymus, lymph node

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CXCR4	402

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CXCR4	P61073	33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Binding and entry of HIV virion	1	2855.0×	0.002	CXCR4
Specification of primordial germ cells	1	878.5×	0.003	CXCR4
Formation of definitive endoderm	1	713.8×	0.003	CXCR4
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	601.0×	0.003	CXCR4
Chemokine receptors bind chemokines	1	187.2×	0.007	CXCR4
Signaling by ROBO receptors	1	124.1×	0.009	CXCR4
G alpha (i) signalling events	1	39.0×	0.026	CXCR4

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
positive regulation of macrophage migration inhibitory factor signaling pathway	1	8426.0×	0.002	CXCR4
positive regulation of vasculature development	1	4213.0×	0.002	CXCR4
CXCL12-activated CXCR4 signaling pathway	1	3370.4×	0.002	CXCR4
myelin maintenance	1	2808.7×	0.002	CXCR4
dendritic cell chemotaxis	1	991.3×	0.004	CXCR4
positive regulation of oligodendrocyte differentiation	1	674.1×	0.005	CXCR4
cellular response to cytokine stimulus	1	543.6×	0.006	CXCR4
regulation of cell adhesion	1	306.4×	0.009	CXCR4
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	218.9×	0.010	CXCR4
neurogenesis	1	208.1×	0.010	CXCR4
cell chemotaxis	1	185.2×	0.010	CXCR4
calcium-mediated signaling	1	183.2×	0.010	CXCR4
positive regulation of cold-induced thermogenesis	1	163.6×	0.010	CXCR4
response to virus	1	144.0×	0.011	CXCR4
positive regulation of cytosolic calcium ion concentration	1	117.0×	0.013	CXCR4
response to hypoxia	1	95.8×	0.014	CXCR4
brain development	1	79.5×	0.016	CXCR4
positive regulation of cell migration	1	61.7×	0.020	CXCR4
immune response	1	47.1×	0.025	CXCR4
inflammatory response	1	37.7×	0.029	CXCR4
G protein-coupled receptor signaling pathway	1	36.2×	0.029	CXCR4
apoptotic process	1	28.7×	0.035	CXCR4

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
CXCR4	PLERIXAFOR

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CXCR4	5	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PLERIXAFOR	4	CXCR4
MAVORIXAFOR	4	CXCR4
CHLOROQUINE	4	CXCR4
ZALCITABINE	4	CXCR4
APLAVIROC HYDROCHLORIDE	3	CXCR4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CXCR4	560	Binding:386, Functional:174

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CXCR4	560

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

4 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)
PLERIXAFOR	4	CXCR4
CHLOROQUINE	4	CXCR4
ZALCITABINE	4	CXCR4
APLAVIROC HYDROCHLORIDE	3	CXCR4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CXCR4
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: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1
PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03995108	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy and Safety Study of Mavorixafor in Participants With Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) Syndrome
NCT03005327	PHASE2	COMPLETED	A Dose Determination and Safety Study of X4P-001 (Mavorixafor) in Participants With Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) Syndrome
NCT03087370	Not specified	WITHDRAWN	A Retrospective and Prospective Natural History Study of Patients With WHIM Syndrome

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MAVORIXAFOR	4	2