X-linked severe congenital neutropenia

Summary

X-linked severe congenital neutropenia (MONDO:0010294) is a disease caused by WAS (GenCC Strong), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: WAS (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 612
• Phenotypes (HPO): 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		45	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

3 HPO clinical features (Orphanet curated; top 3 by frequency):

HPO ID	Term	Frequency
HP:0001875	Decreased total neutrophil count	Very frequent (80-99%)
HP:0002718	Recurrent bacterial infections	Very frequent (80-99%)
HP:0012312	Monocytopenia	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked severe congenital neutropenia
Mondo ID	MONDO:0010294
MeSH	C564539
OMIM	300299
Orphanet	86788
DOID	DOID:0112128
SNOMED CT	718882006
UMLS	C1845987
MedGen	335314
GARD	0003981
Is cancer (heuristic)	no

Also known as: neutropenia, severe congenital, X-linked · neutropenia, severe congenital, X-linked, X-linked recessive · SCNX · severe congenital neutropenia X-linked · severe congenital neutropenia, X-linked · X-linked severe congenital neutropenia

Data availability: 612 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › X-linked severe congenital neutropenia

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked lissencephaly with abnormal genitalia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked erythropoietic protoporphyria, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

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

600 retrieved; paginated sample, class counts are floors:

237 likely benign, 169 uncertain significance, 99 pathogenic, 34 conflicting classifications of pathogenicity, 26 benign, 17 benign/likely benign, 10 likely pathogenic, 8 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2422978	NC_000023.10:g.(?46618120)(48549553_?)del	LINC01560	Pathogenic	criteria provided, single submitter
1073358	NM_000377.3(WAS):c.753dup (p.Trp252fs)	WAS	Pathogenic	criteria provided, single submitter
1074326	NM_000377.3(WAS):c.827_828insGGGCCTTCTCCAGGGCAGGAAT (p.Ile276fs)	WAS	Pathogenic	criteria provided, single submitter
1074601	NM_000377.3(WAS):c.1453+2T>G	WAS	Pathogenic	criteria provided, single submitter
1074623	NM_000377.3(WAS):c.539dup (p.His180fs)	WAS	Pathogenic	criteria provided, single submitter
1076500	NM_000377.3(WAS):c.723del (p.Ser242fs)	WAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11115	NM_000377.3(WAS):c.257G>A (p.Arg86His)	WAS	Pathogenic	criteria provided, multiple submitters, no conflicts
11116	NM_000377.3(WAS):c.167C>T (p.Ala56Val)	WAS	Pathogenic	criteria provided, multiple submitters, no conflicts
11119	NM_000377.3(WAS):c.100C>T (p.Arg34Ter)	WAS	Pathogenic	criteria provided, single submitter
11123	NM_000377.3(WAS):c.134C>T (p.Thr45Met)	WAS	Pathogenic	criteria provided, multiple submitters, no conflicts
11125	NM_000377.3(WAS):c.809T>C (p.Leu270Pro)	WAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11132	NM_000377.3(WAS):c.11del (p.Gly4fs)	WAS	Pathogenic	criteria provided, single submitter
1338374	NM_000377.3(WAS):c.192G>A (p.Trp64Ter)	WAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1360224	NM_000377.3(WAS):c.176del (p.Pro59fs)	WAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1410526	NM_000377.3(WAS):c.382T>C (p.Phe128Leu)	WAS	Pathogenic	criteria provided, single submitter
1418621	NM_000377.3(WAS):c.1021_1022insT (p.Pro341fs)	WAS	Pathogenic	criteria provided, single submitter
1441543	NM_000377.3(WAS):c.1085del (p.Pro362fs)	WAS	Pathogenic	criteria provided, single submitter
1466589	NM_000377.3(WAS):c.777+3_777+6del	WAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1493038	NM_000377.3(WAS):c.1339-2A>G	WAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686299	NM_000377.3(WAS):c.190T>C (p.Trp64Arg)	WAS	Pathogenic	criteria provided, single submitter
1810240	NM_000377.3(WAS):c.383T>C (p.Phe128Ser)	WAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2005814	NM_000377.3(WAS):c.701del (p.Ser234fs)	WAS	Pathogenic	criteria provided, single submitter
2013847	NM_000377.3(WAS):c.964G>T (p.Gly322Ter)	WAS	Pathogenic	criteria provided, single submitter
2022929	NM_000377.3(WAS):c.1266del (p.Gly424fs)	WAS	Pathogenic	criteria provided, single submitter
2029720	NM_000377.3(WAS):c.412dup (p.Arg138fs)	WAS	Pathogenic	criteria provided, single submitter
2030805	NM_000377.3(WAS):c.19_41del (p.Gly7fs)	WAS	Pathogenic	criteria provided, single submitter
2033777	NM_000377.3(WAS):c.295del (p.Gln99fs)	WAS	Pathogenic	criteria provided, single submitter
2091421	NM_000377.3(WAS):c.735-2A>T	WAS	Pathogenic	criteria provided, single submitter
2094231	NM_000377.3(WAS):c.619_623del (p.Ile207fs)	WAS	Pathogenic	criteria provided, single submitter
2113185	NM_000377.3(WAS):c.1203del (p.Pro402fs)	WAS	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
WAS	Strong	X-linked	X-linked severe congenital neutropenia	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WAS	Orphanet:852	X-linked thrombocytopenia with normal platelets
WAS	Orphanet:86788	X-linked severe congenital neutropenia
WAS	Orphanet:906	Wiskott-Aldrich syndrome
ELANE	Orphanet:2686	Cyclic neutropenia
ELANE	Orphanet:486	Autosomal dominant severe congenital neutropenia

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WAS	HGNC:12731	ENSG00000015285	P42768	Actin nucleation-promoting factor WAS	gencc,clinvar
CCNB3	HGNC:18709	ENSG00000147082	Q8WWL7	G2/mitotic-specific cyclin-B3	clinvar
LINC01560	HGNC:27333	ENSG00000196741	Q8TB33	Putative uncharacterized protein encoded by LINC01560	clinvar
ELANE	HGNC:3309	ENSG00000197561	P08246	Neutrophil elastase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WAS	Actin nucleation-promoting factor WAS	Effector protein for Rho-type GTPases that regulates actin filament reorganization via its interaction with the Arp2/3 complex.
CCNB3	G2/mitotic-specific cyclin-B3	Cyclins are positive regulatory subunits of the cyclin-dependent kinases (CDKs), and thereby play an essential role in the control of the cell cycle, notably via their destruction during cell division.
ELANE	Neutrophil elastase	Serine protease that modifies the functions of natural killer cells, monocytes and granulocytes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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
Protease	1	9.2×	0.210
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WAS	Other/Unknown	no		CRIB_dom, WH1/EVH1_dom, WH2_dom
CCNB3	Other/Unknown	no		Cyclin_C-dom, Cyclin_N, Cyclin-like_dom
LINC01560	Other/Unknown	no
ELANE	Protease	yes	3.4.21.37	Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
granulocyte	1
leukocyte	1
mononuclear cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
secondary oocyte	1
buccal mucosa cell	1
ganglionic eminence	1
bone marrow	1
bone marrow cell	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WAS	246	broad	marker	granulocyte, leukocyte, mononuclear cell
CCNB3	156	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte
LINC01560	207	ubiquitous	yes	buccal mucosa cell, primordial germ cell in gonad, ganglionic eminence
ELANE	124	tissue_specific	marker	bone marrow, bone marrow cell, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WAS	3,320
ELANE	2,758
CCNB3	2,576
LINC01560	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ELANE	P08246	38
WAS	P42768	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CCNB3	Q8WWL7	42.25
LINC01560	Q8TB33	40.36

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 4 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
Expression of NOTCH2NL genes	1	1142.0×	0.013	ELANE
Pyroptosis	1	211.5×	0.015	ELANE
Generation of second messenger molecules	1	173.0×	0.015	WAS
RHO GTPases Activate WASPs and WAVEs	1	158.6×	0.015	WAS
Activation of Matrix Metalloproteinases	1	154.3×	0.015	ELANE
Regulation of Complement cascade	1	116.5×	0.015	ELANE
Antimicrobial peptides	1	112.0×	0.015	ELANE
RHOJ GTPase cycle	1	100.2×	0.015	WAS
FCGR3A-mediated phagocytosis	1	93.6×	0.015	WAS
Regulation of actin dynamics for phagocytic cup formation	1	92.1×	0.015	WAS
Collagen degradation	1	87.8×	0.015	ELANE
Degradation of the extracellular matrix	1	58.9×	0.021	ELANE
CDC42 GTPase cycle	1	36.1×	0.032	WAS
RAC1 GTPase cycle	1	30.5×	0.035	WAS
Neutrophil degranulation	1	11.5×	0.085	ELANE

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of T cell antigen processing and presentation	1	5617.3×	0.004	WAS
biosynthetic process of antibacterial peptides active against Gram-negative bacteria	1	5617.3×	0.004	ELANE
neutrophil-mediated killing of fungus	1	2808.7×	0.006	ELANE
negative regulation of chemotaxis	1	1872.4×	0.006	ELANE
Cdc42 protein signal transduction	1	1404.3×	0.006	WAS
neutrophil-mediated killing of gram-negative bacterium	1	1123.5×	0.006	ELANE
acute inflammatory response to antigenic stimulus	1	936.2×	0.006	ELANE
regulation of actin polymerization or depolymerization	1	936.2×	0.006	WAS
response to yeast	1	702.2×	0.007	ELANE
negative regulation of chemokine production	1	702.2×	0.007	ELANE
regulation of lamellipodium assembly	1	624.1×	0.007	WAS
positive regulation of leukocyte tethering or rolling	1	510.7×	0.008	ELANE
negative regulation of cell motility	1	432.1×	0.009	WAS
leukocyte migration involved in inflammatory response	1	401.2×	0.009	ELANE
negative regulation of interleukin-8 production	1	330.4×	0.009	ELANE
regulation of stress fiber assembly	1	330.4×	0.009	WAS
actin filament-based movement	1	267.5×	0.010	WAS
actin polymerization or depolymerization	1	255.3×	0.010	WAS
positive regulation of MAP kinase activity	1	216.1×	0.012	ELANE
negative regulation of stress fiber assembly	1	193.7×	0.012	WAS
pyroptotic inflammatory response	1	170.2×	0.013	ELANE
actin filament polymerization	1	160.5×	0.013	WAS
positive regulation of immune response	1	160.5×	0.013	ELANE
positive regulation of double-strand break repair via homologous recombination	1	127.7×	0.015	WAS
response to UV	1	122.1×	0.015	ELANE
extracellular matrix disassembly	1	122.1×	0.015	ELANE
positive regulation of smooth muscle cell proliferation	1	110.1×	0.016	ELANE
T cell activation	1	86.4×	0.018	WAS
endosomal transport	1	81.4×	0.018	WAS
positive regulation of interleukin-8 production	1	81.4×	0.018	ELANE

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 2

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
CCNB3	PALBOCICLIB
ELANE	BOCEPREVIR

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CCNB3	17	4
ELANE	11	4
WAS	0	0
LINC01560	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PALBOCICLIB	4	CCNB3
BOCEPREVIR	4	ELANE
TELAPREVIR	4	ELANE
BORTEZOMIB	4	ELANE
DINACICLIB	3	CCNB3
ALVOCIDIB	3	CCNB3
QUERCETIN	3	CCNB3, ELANE
EPIGALOCATECHIN GALLATE	3	ELANE
SIVELESTAT	3	ELANE
SILMITASERTIB	2	CCNB3
INDIRUBIN	2	CCNB3
SELICICLIB	2	CCNB3
LUTEOLIN	2	CCNB3, ELANE
ASNUCICLIB	2	CCNB3
FISETIN	2	CCNB3
RIVICICLIB	2	CCNB3
AT-7519	2	CCNB3
MIDESTEINE	2	ELANE
FRESELESTAT	2	ELANE
DELANZOMIB	2	ELANE
ALVELESTAT	2	ELANE
KAEMPFEROL	1	CCNB3
SU-9516	1	CCNB3
HARMINE	1	CCNB3
BMS-387032	1	CCNB3
LADUVIGLUSIB	1	CCNB3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ELANE	801	Binding:758, Functional:35, ADMET:6, Toxicity:2
CCNB3	148	Binding:147, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ELANE	3.4.21.37	leukocyte elastase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CCNB3	148
ELANE	801

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

26 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)
PALBOCICLIB	4	CCNB3
BOCEPREVIR	4	ELANE
TELAPREVIR	4	ELANE
BORTEZOMIB	4	ELANE
DINACICLIB	3	CCNB3
ALVOCIDIB	3	CCNB3
QUERCETIN	3	CCNB3, ELANE
EPIGALOCATECHIN GALLATE	3	ELANE
SIVELESTAT	3	ELANE
SILMITASERTIB	2	CCNB3
INDIRUBIN	2	CCNB3
SELICICLIB	2	CCNB3
LUTEOLIN	2	CCNB3, ELANE
ASNUCICLIB	2	CCNB3
FISETIN	2	CCNB3
RIVICICLIB	2	CCNB3
AT-7519	2	CCNB3
MIDESTEINE	2	ELANE
FRESELESTAT	2	ELANE
DELANZOMIB	2	ELANE
ALVELESTAT	2	ELANE
KAEMPFEROL	1	CCNB3
SU-9516	1	CCNB3
HARMINE	1	CCNB3
BMS-387032	1	CCNB3
LADUVIGLUSIB	1	CCNB3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CCNB3, ELANE
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	2	WAS, LINC01560

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
WAS	0	—
LINC01560	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.