Table 1 Monogenic diseases that affect neutrophils.

AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive.

Gene
Protein
Disease nameInheritance patternMolecular mechanisms
Disorders with primarily neutropenia
ELANE
Neutrophil elastase
Congenital neutropenia or cyclic
neutropenia
AD or somaticMaturation arrest, premature
apoptosis
Unfolded protein response, ER stress
JAGN1
Jagunal homolog 1
Congenital neutropeniaARDifferentiation defect, premature
apoptosis
ER secretory pathway
CSF3R
Colony stimulating factor receptor
Congenital neutropeniaAR and ADBone marrow production and release
signaling defect
GFI1
Growth factor independence 1
Congenital neutropeniaADMyeloid cell differentiation
Transcription repressor
G6PC3
Glucose-6-phosphatase
Congenital neutropeniaARBone marrow retention, apoptosis
ER stress, glycosylation defect
HAX1
HS1-associated protein X1
Kostmann syndromeARBone marrow production and release
G-CSF signaling defect
Multisystemic syndromes with neutropenia
AK2
Adenylate kinase 2
Reticular dysgenesisARDifferentiation defect
Mitochondrial metabolism dysfunction
RMRP
RNAase mitochondrial RNA processing
Cartilage hair hypoplasiaARBone marrow dysfunction
Preribosomal RNA processing
SBDS
Schwachman-Bodian-Diamond
syndrome protein
Schwachman-Bodian-Diamond
syndrome
ARDifferentiation defect, premature
apoptosis
Ribosome biogenesis
DNM2
Dynamin 2
Charcot-Marie-Tooth diseaseADMembrane trafficking, microtubules
TAZ1
Tafazzin
Barth syndromeXLRMitochondrial membrane dynamics
G6PT
Glucose-6-phosphate transporter
Glycogen storage disease type 1bARPremature apoptosis
ER stress, mitochondrial dysfunction
Immunodeficiency syndromes with neutropenia
BTK
Bruton’s tyrosine kinase
X-linked agammaglobulinemiaXLRChemotaxis defect, reactive oxygen
defect
WAS
Wiskott-Aldrich syndrome
X-linked neutropenia
Wiskott-Aldrich syndrome
XLRDecreased proliferation, increased
apoptosis
Actin polymerization
CD40L
CD40 ligand
Hyper-IgM syndromeXLRAdhesion and transmigration
CXCR4
Chemokine receptor CXCR4
WHIM (warts,
hypogammaglobulinemia,
immunodeficiency, and
myelokathexis)
ADBone marrow and tissue homing
abnormality
Defective chemokine receptor
function
STK4
Serine/threonine kinase 4
STK4 deficiencyARIncreased apoptosis
Mitochondrial dysfunction
GINS1
Go-ichi-ni-san complex subunit 1
GINS1 deficiencyARImpaired cell cycle
Defective DNA repair
Neutrophil dysfunction disorders
ITGB2
Leukocyte integrin β2 chain
LAD-IARNeutrophil adhesion/migration defects
Adhesion molecule deficiency
GFTP
GDP fucose transporter
LAD-IIARSelectin deficiency
Defect in fucose transport
FERMT3
Kindlin-3
LAD-IIIARNeutrophil adhesion defect
CYBB
Cytochrome b-245β; gp91phox
Chronic granulomatous diseaseXLRDefective oxidative burst
NADPH oxidase enzyme defect
CYBA
Cytochrome b-245α; p22phox
Chronic granulomatous diseaseARDefective oxidative burst
NADPH oxidase enzyme defect
NCF1
Neutrophil cytosolic factor-1; p47phox
Chronic granulomatous diseaseARDefective oxidative burst
NADPH oxidase enzyme defect
NCF2
Neutrophil cytosolic factor-2; p67phox
Chronic granulomatous diseaseARDefective oxidative burst
NADPH oxidase enzyme defect
NCF4
Neutrophil cytosolic factor-4; p40phox
Chronic granulomatous diseaseARDefective oxidative burst
NADPH oxidase enzyme defect
G6PD
Glucose-6-phosphate dehydrogenase
G6PD deficiencyARDefective oxidative burst, NETosis defect
Enzyme deficiency
RAC2
Ras-related C3 botulinum toxin 3
Neutrophil immunodeficiency syndromeARGTPase deficiency, defective oxidative burst
Secretory and phagocytosis defect
MYD88
Myeloid differentiation 88
MyD88 deficiencyARNeutrophil aging
TLR and IL-1R signaling defect
IRAK4
Interleukin-1 receptor associated kinase 4
IRAK4 deficiencyARDefective migration and phagocytosis
Impaired TLR and IL-1 receptor responses
Secretory lysosome/granule defects
LYST
Lysosomal trafficking regulator
Chediak-Higashi syndromeARNeutrophil signaling defect
Abnormal lysosome and melanosome trafficking
RAB27A
RAB27a
Griscelli syndrome type 2ARReduced mature neutrophils
Membrane trafficking/phagosome secretion defect
UNC13D
MUNC13-4
Familial hemophagocytic lymphohistiocytosis type 3ARNeutropenia, vesicular trafficking, and secretion defects
STXBP2
Syntaxin binding protein 2 (MUNC18-2)
Familial hemophagocytic lymphohistiocytosis type 5ARSecretion and bactericidal defects
WDR1
Actin-interacting protein 1 (Aip1)
WDR1 deficiencyARMild neutropenia, impaired chemotaxis
Normal bacterial killing and increased oxidative burst
MLK1
Megakaryoblastic leukemia 1 (MKL1)
MLK1 deficiencyARDecreased phagocytosis and impaired migration
AP3B1
Adaptor-related protein complex β1
Hermansky-Pudlack syndromeARReduced mature neutrophils
Abnormal vesicular trafficking of proteins
LAMTOR2
Late endosomal/lysosomal adaptor, MAPK and MTOR activator 2
Immunodeficiency due to defect in MAPBP-interacting protein
(p14 deficiency)
ARAbnormal neutrophil maturation and function
Late endosome biogenesis
CEBPE
CCAAT enhancer binding protein ε
Specific granule deficiencyARNeutrophil chemotaxis defect
Abnormal or absent granule formation
Autoinflammatory disorders
NLPR3
Cryopyrin
Cryopyrin-associated periodic syndromes (CAPS)AD or somaticNeutrophil homeostasis dysregulation
Inflammasome mediated IL-1β release/cell death
MEFV
Pyrin
Familial Mediterranean feverAR or rarely ADNeutrophil chemotaxis and phagocytosis defect
Enhanced apoptosis and altered adhesion
Hyperactive inflammasome-mediated IL-1β release
Alterations in F-actin dynamics
MVK
Mevalonate kinase
Mevalonic aciduria and hyper-IgD syndromeARPyrin inflammasome activation due to RhoA inactivation and compromised phosphatidylinositol 3-kinase activity secondary to prenylation defect
TNFRSF1A
Tumor necrosis factor receptor–1A
Tumor necrosis factor receptor–associated periodic syndromeADNeutrophil apoptosis resistance
TNFR signaling or shedding defect
NOD2
Nucleotide oligomerization domain 2
Blau syndromeADIncreased ocular neutrophil rolling and adherence
Activation of nuclear factor κB/IL-1B–mediated inflammation
IL1RN
Interleukin-1 receptor antagonist
Deficiency of IL-1 receptor antagonistARNeutrophil mobilization and activation
Unregulated IL-1 receptor activation
CD2BP1
CD2 binding protein 1
Pyogenic arthritis pyoderma gangrenosum and acne (PAPA)ADNeutrophil mobilization and activation
Defective actin dynamics
PSMB8
Proteasome subunit β type 8
Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE)ARNeutrophil mobilization and activation
IFN dysregulation
TMEM173
Stimulator of interferon genes (STING)
STING-associated vasculopathy with onset in infancy (SAVI)ADNeutrophil mobilization and activation
IFN dysregulation
Other disorders
DNASE1
Deoxyribonuclease 1
Monogenic systemic lupus erythematosusARDefective NET degradation
Increased ROS production
IFN dysregulation
DNASE1L3
Deoxyribonuclease 1L3
Monogenic systemic lupus erythematosusADDefective NET degradation
Increased ROS production
IFN dysregulation
CFTR
Cystic fibrosis transmembrane regulator
Cystic fibrosisARDelayed neutrophil apoptosis
Impaired MPO activity