Neutrophil immunodeficiency syndrome

Summary

Neutrophil immunodeficiency syndrome (MONDO:0011988) is a disease caused by RAC2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RAC2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 196
• Phenotypes (HPO): 4

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

4 HPO clinical features (Orphanet curated; top 4 by frequency):

HPO ID	Term	Frequency
HP:0001058	Poor wound healing	Very frequent (80-99%)
HP:0001974	Leukocytosis	Very frequent (80-99%)
HP:0002721	Immunodeficiency	Very frequent (80-99%)
HP:0011990	Abnormality of neutrophil physiology	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neutrophil immunodeficiency syndrome
Mondo ID	MONDO:0011988
MeSH	C564275
OMIM	608203
Orphanet	183707
DOID	DOID:0112064
ICD-11	1459690929
SNOMED CT	723443003
UMLS	C1842398
MedGen	374920
GARD	0017087
Is cancer (heuristic)	no

Also known as: immunodeficiency 73A with defective neutrophil chemotaxix and leukocytosis · neutrophil immunodeficiency syndrome

Data availability: 196 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › leukocyte disorder › functional neutrophil defect › neutrophil immunodeficiency syndrome

Related subtypes (4): Papillon-Lefevre disease, specific granule deficiency, myeloperoxidase deficiency, leukocyte adhesion deficiency

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

196 retrieved; paginated sample, class counts are floors:

113 likely benign, 66 uncertain significance, 9 benign, 2 likely pathogenic, 2 benign/likely benign, 2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
464885	NM_002872.5(RAC2):c.184G>A (p.Glu62Lys)	RAC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7575	NM_002872.5(RAC2):c.169G>A (p.Asp57Asn)	RAC2	Pathogenic	criteria provided, single submitter
2052978	NM_002872.5(RAC2):c.181C>A (p.Gln61Lys)	RAC2	Likely pathogenic	criteria provided, single submitter
977224	NM_002872.5(RAC2):c.101C>A (p.Pro34His)	RAC2	Likely pathogenic	criteria provided, single submitter
577450	NM_002872.5(RAC2):c.545C>T (p.Thr182Met)	RAC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
803686	NM_002872.5(RAC2):c.562G>A (p.Ala188Thr)	RAC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3377823	NM_002872.5(RAC2):c.35+3A>G	LOC130067357	Uncertain significance	criteria provided, single submitter
4712163	NM_002872.5(RAC2):c.34G>T (p.Gly12Trp)	LOC130067357	Uncertain significance	criteria provided, single submitter
4735673	NM_002872.5(RAC2):c.20_24del (p.Val7fs)	LOC130067357	Uncertain significance	criteria provided, single submitter
4803198	NM_002872.5(RAC2):c.5A>G (p.Gln2Arg)	LOC130067357	Uncertain significance	criteria provided, single submitter
657624	NM_002872.5(RAC2):c.32A>T (p.Asp11Val)	LOC130067357	Uncertain significance	criteria provided, single submitter
663023	NM_002872.5(RAC2):c.31G>A (p.Asp11Asn)	LOC130067357	Uncertain significance	criteria provided, single submitter
1006066	NM_002872.5(RAC2):c.560G>A (p.Arg187His)	RAC2	Uncertain significance	criteria provided, single submitter
1027219	NM_002872.5(RAC2):c.379G>A (p.Glu127Lys)	RAC2	Uncertain significance	criteria provided, single submitter
1042756	NM_002872.5(RAC2):c.511G>A (p.Glu171Lys)	RAC2	Uncertain significance	criteria provided, single submitter
1056472	NM_002872.5(RAC2):c.544A>G (p.Thr182Ala)	RAC2	Uncertain significance	criteria provided, single submitter
1301643	NM_002872.5(RAC2):c.328A>G (p.Ile110Val)	RAC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333551	NM_002872.5(RAC2):c.97A>G (p.Ile33Val)	RAC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1349653	NM_002872.5(RAC2):c.574C>T (p.Leu192Phe)	RAC2	Uncertain significance	criteria provided, single submitter
1364327	NM_002872.5(RAC2):c.559C>T (p.Arg187Cys)	RAC2	Uncertain significance	criteria provided, single submitter
1375066	NM_002872.5(RAC2):c.517A>C (p.Ile173Leu)	RAC2	Uncertain significance	criteria provided, single submitter
1382760	NM_002872.5(RAC2):c.305G>A (p.Arg102Gln)	RAC2	Uncertain significance	criteria provided, single submitter
1410696	NC_000022.10:g.(?37622713)(37640188_?)dup	RAC2	Uncertain significance	criteria provided, single submitter
1445460	NM_002872.5(RAC2):c.520C>T (p.Arg174Trp)	RAC2	Uncertain significance	criteria provided, single submitter
1445776	NM_002872.5(RAC2):c.347A>G (p.Lys116Arg)	RAC2	Uncertain significance	criteria provided, single submitter
1447690	NM_002872.5(RAC2):c.175G>T (p.Ala59Ser)	RAC2	Uncertain significance	criteria provided, single submitter
1478191	NM_002872.5(RAC2):c.304C>T (p.Arg102Trp)	RAC2	Uncertain significance	criteria provided, single submitter
1521799	NM_002872.5(RAC2):c.283G>A (p.Ala95Thr)	RAC2	Uncertain significance	criteria provided, single submitter
1524605	NM_002872.5(RAC2):c.54C>G (p.Cys18Trp)	RAC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1903909	NM_002872.5(RAC2):c.569G>C (p.Ser190Thr)	RAC2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
RAC2	Definitive	Autosomal dominant	immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAC2	Orphanet:183707	Infantile LAD-like disease due to RAC2 deficiency
RAC2	Orphanet:688543	Reticular dysgenesis-like severe combined immunodeficiency
RAC2	Orphanet:692812	RAC2-related combined immunodeficiency-bronchiectasis-cancer-predisposing 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
RAC2	HGNC:9802	ENSG00000128340	P15153	Ras-related C3 botulinum toxin substrate 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAC2	Ras-related C3 botulinum toxin substrate 2	Plasma membrane-associated small GTPase which cycles between an active GTP-bound and inactive GDP-bound state.

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RAC2	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTPase_Rho, Small_GTP-bd

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
blood	1
granulocyte	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAC2	242	ubiquitous	marker	granulocyte, blood, spleen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAC2	6,478

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAC2	P15153	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
RHO GTPases Activate NADPH Oxidases	1	456.8×	0.007	RAC2
ROS and RNS production in phagocytes	1	335.9×	0.007	RAC2
GPVI-mediated activation cascade	1	308.6×	0.007	RAC2
PCP/CE pathway	1	300.5×	0.007	RAC2
Constitutive Signaling by Aberrant PI3K in Cancer	1	126.9×	0.011	RAC2
RAC2 GTPase cycle	1	126.9×	0.011	RAC2
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	96.8×	0.012	RAC2
PIP3 activates AKT signaling	1	66.8×	0.015	RAC2

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
regulation of mast cell chemotaxis	1	16852.0×	0.001	RAC2
regulation of cell-substrate adhesion	1	5617.3×	0.001	RAC2
lymphocyte aggregation	1	5617.3×	0.001	RAC2
regulation of respiratory burst	1	4213.0×	0.001	RAC2
regulation of neutrophil migration	1	4213.0×	0.001	RAC2
erythrocyte enucleation	1	3370.4×	0.001	RAC2
mast cell proliferation	1	3370.4×	0.001	RAC2
positive regulation of mast cell proliferation	1	3370.4×	0.001	RAC2
regulation of hydrogen peroxide metabolic process	1	2808.7×	0.001	RAC2
regulation of mast cell degranulation	1	1872.4×	0.001	RAC2
cortical cytoskeleton organization	1	1685.2×	0.001	RAC2
respiratory burst	1	1296.3×	0.002	RAC2
regulation of T cell proliferation	1	1053.2×	0.002	RAC2
cell projection assembly	1	936.2×	0.002	RAC2
superoxide anion generation	1	674.1×	0.003	RAC2
positive regulation of neutrophil chemotaxis	1	648.1×	0.003	RAC2
positive regulation of lamellipodium assembly	1	601.9×	0.003	RAC2
bone resorption	1	581.1×	0.003	RAC2
obsolete positive regulation of protein targeting to mitochondrion	1	495.6×	0.003	RAC2
establishment or maintenance of cell polarity	1	401.2×	0.003	RAC2
small GTPase-mediated signal transduction	1	183.2×	0.007	RAC2
regulation of actin cytoskeleton organization	1	157.5×	0.008	RAC2
chemotaxis	1	135.9×	0.009	RAC2
regulation of cell shape	1	123.0×	0.009	RAC2
actin filament organization	1	118.7×	0.009	RAC2
G protein-coupled receptor signaling pathway	1	36.2×	0.029	RAC2
signal transduction	1	16.1×	0.062	RAC2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RAC2	1	1

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MBQ-167	1	RAC2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RAC2	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RAC2	3.6.5.2	small monomeric GTPase

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

1 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)
MBQ-167	1	RAC2

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	1	RAC2
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.