List of genes and phenotypes associated with GNs (2022)
| Neutropenia subgroup . | Gene, disease name . | OMIM code . | Main hematological features . | Extrahematopoietic features . | Inheritance, gene localization . | Normal function of the gene-encoded protein . |
|---|---|---|---|---|---|---|
| Congenital neutropenia usually without extrahematopoietic manifestation | ELANE, severe congenital or cyclic neutropenia | 202700 162800 | Severe and permanent neutropenia, maturation arrest, intermittent/cyclic with variable BM features | No | Dominant, 19q13.3 | Protease activity Antagonism with α-1 antitrypsin |
| CSF3R | 202700 | Permanent maturation arrest, unresponsive to GCSF | No | Recessive, 1p35-p34.3 | Transmembrane GCSF receptor/intracellular signaling | |
| WAS | 301000 | Severe permanent neutropenia, maturation arrest, monocytopenia | No | X-linked, Xp11.4-p11.21 | Cytoskeleton homeostasis | |
| CXCR2 | Severe permanent neutropenia, no maturation arrest | No | Recessive, 2q35 | Chemokine receptor (CXCL12) | ||
| SEC61A1 | No maturation arrest | No | Dominant, 3q21.3 | The translocon complex of proteins transports nascent polypeptides with a targeting signal sequence into the interior space of the ER | ||
| SRP54 | Maturation arrest | Some mutations are associated with exocrine pancreas deficiency, mental retardation | Dominant, 14q13.2 | SRP is a protein-RNA complex that recognizes and targets proteins specific to the ER. SRP54 and SRP68 proteins are components of that complex. | ||
| SRP68 | Maturation arrest | No | Recessive, 17q25.1 | |||
| Congenital neutropenia with frequent extrahematopoietic manifestations, including innate-immunity deficiencies | SBDS, Shwachman–Diamond syndrome | 260400 | Mild neutropenia, dysgranulopoiesis, mild dysmegakaryopoiesis | Exocrine pancreas deficiency, metaphyseal dysplasia, mental retardation, cardiomyopathy | Recessive, 7q11.22 | Ribosomal protein that regulates RNA expression |
| EFL1, syndrome | 260400 | Mild neutropenia, dyserythropoiesis | Exocrine pancreas deficiency, metaphyseal dysplasia, mental retardation | Recessive, 15q25.2 | Ribosomal protein that regulates RNA expression | |
| GATA2, syndrome | 614038 614172 | Mild neutropenia, monocytopenia, macrocytosis | Lymphedema, deafness, mycobacterial, HPV infections | Dominant, 3q21.3 | Transcription factor | |
| G6PC3, severe congenital neutropenia | 202700 | Maturation arrest | Skin-prominent superficial venous network, atrial defect, uropathy | Recessive, 17q21 | 1,5AG6P hydrolysis | |
| SLC37A4, Glycogen Storage Disease Type Ib | 232220 | No maturation arrest | Hypoglycemia, fasting hyperlactacidemia, and glycogen overload in the liver | Recessive, 11q23.3 | glucose-6-phosphate or 1,5AG6P transport to the ER | |
| TAFAZIN, Barth disease | 302060 | No maturation arrest | Hypertrophic cardiomyopathy, myopathic syndrome, 3-methylglutaconic aciduria | X-linked, Xq28 | Tafazzin, phospholipid membrane homeostasis | |
| CXCR4, WHIM syndrome | 193670 | No maturation arrest, myelokathexis | Lymphopenia, thrombocytopenia, cardiopathy type tetralogy of Fallot | Dominant, 2q21 | Chemokine receptor (ligand CXCL12) | |
| JAGN1, severe congenital neutropenia | 616022 | Variable | Bone abnormalities, exocrine pancreatic deficiency | Recessive, 3p25.3 | ER protein | |
| VPS13B, Cohen syndrome | 216550 | No maturation arrest | Psychomotor retardation, clumsiness, microcephaly, characteristic facial features, hypotonia, joint laxity, progressive retinochoroidal dystrophy, myopia | Recessive, 8q22-q23 | Sorting and transporting proteins in the ER | |
| GFI1, severe congenital neutropenia | 202700 | Permanent/severe or mild neutropenia, sometimes maturation arrest | Internal ear (in mouse model), lymphopenia | Dominant, p22 | Transcription factor regulating oncoproteins | |
| HAX1, Kostmann's disease | 202700 | Maturation arrest | Central nervous system: mental retardation or seizures | Recessive, 1q21.3 | Antiapoptotic protein located in mitochondria and cytosol | |
| AP3B1, Hermansky-Pudlak syndrome type 2 | 608233 | No maturation arrest | Albinism | Recessive, 5q14.1 | Cargo protein or ER trafficking | |
| LAMTOR2, chronic neutropenia | 610389 | No maturation arrest | Albinism | Recessive, 1q21 | Lysosome packaging | |
| USB1, poikiloderma with Clericuzio-type neutropenia | 604173 | No maturation arrest, minor dysgranulopoietic features | Poikiloderma | Recessive, 16q21 | Unelucidated | |
| VPS45, severe congenital neutropenia | 615285 | Maturation arrest/myelofibrosis | Nephromegaly, hepatosplenomegaly, mental retardation | Recessive, 1q21.2 | Role in segregation of intracellular molecules into distinct organelles | |
| TCIRG1, severe congenital neutropenia | 202700 | Variable | Skin angiomatosis | Dominant, 11q13.2 | Unelucidated | |
| EIF2AK3, Wolcott-Rallison syndrome | 604032 | Maturation arrest | Insulin-dependent neonatal diabetes | Recessive, 2p11.2 | ER stress | |
| CLPB syndrome | 616254 | Maturation arrest | Mental retardation, congenital cataracts, 3-methylglutaconic aciduria | Recessive/ Dominant, 11q13.4 | Unelucidated | |
| STK4 (MST1) syndrome | 614868 | Intermittent or autoimmune neutropenia | Atrial defect | Recessive, 20q13 | Serine/threonine protein kinase | |
| SMARCD2 | Dysplastic syndrome, no granules in neutrophils | Chronic diarrhea, bone abnormalities, low-set ears | Recessive, 17q23 | Unelucidated | ||
| SASH3 | Maturation arrest | Autoimmune disease, viral infection(s) | X-linked, Xq26 | Unelucidated | ||
| CARD11 | Maturation arrest, hyperlymphocytosis | Skin disorders | Dominant, 7p22.2 | Unelucidated | ||
| Mitochondrial DNA, Pearson syndrome | 557000 | Vacuolization of BM precursors, Perls staining reveals ring sideroblasts | Exocrine pancreatic insufficiency, sideroblastic anemia and thrombocytopenia usually later in life, delayed development with Kearns-Sayre syndrome; elevated lactate/pyruvate ratio | Complex inheritance | Deletion(s) in mitochondrial DNA |
| Neutropenia subgroup . | Gene, disease name . | OMIM code . | Main hematological features . | Extrahematopoietic features . | Inheritance, gene localization . | Normal function of the gene-encoded protein . |
|---|---|---|---|---|---|---|
| Congenital neutropenia usually without extrahematopoietic manifestation | ELANE, severe congenital or cyclic neutropenia | 202700 162800 | Severe and permanent neutropenia, maturation arrest, intermittent/cyclic with variable BM features | No | Dominant, 19q13.3 | Protease activity Antagonism with α-1 antitrypsin |
| CSF3R | 202700 | Permanent maturation arrest, unresponsive to GCSF | No | Recessive, 1p35-p34.3 | Transmembrane GCSF receptor/intracellular signaling | |
| WAS | 301000 | Severe permanent neutropenia, maturation arrest, monocytopenia | No | X-linked, Xp11.4-p11.21 | Cytoskeleton homeostasis | |
| CXCR2 | Severe permanent neutropenia, no maturation arrest | No | Recessive, 2q35 | Chemokine receptor (CXCL12) | ||
| SEC61A1 | No maturation arrest | No | Dominant, 3q21.3 | The translocon complex of proteins transports nascent polypeptides with a targeting signal sequence into the interior space of the ER | ||
| SRP54 | Maturation arrest | Some mutations are associated with exocrine pancreas deficiency, mental retardation | Dominant, 14q13.2 | SRP is a protein-RNA complex that recognizes and targets proteins specific to the ER. SRP54 and SRP68 proteins are components of that complex. | ||
| SRP68 | Maturation arrest | No | Recessive, 17q25.1 | |||
| Congenital neutropenia with frequent extrahematopoietic manifestations, including innate-immunity deficiencies | SBDS, Shwachman–Diamond syndrome | 260400 | Mild neutropenia, dysgranulopoiesis, mild dysmegakaryopoiesis | Exocrine pancreas deficiency, metaphyseal dysplasia, mental retardation, cardiomyopathy | Recessive, 7q11.22 | Ribosomal protein that regulates RNA expression |
| EFL1, syndrome | 260400 | Mild neutropenia, dyserythropoiesis | Exocrine pancreas deficiency, metaphyseal dysplasia, mental retardation | Recessive, 15q25.2 | Ribosomal protein that regulates RNA expression | |
| GATA2, syndrome | 614038 614172 | Mild neutropenia, monocytopenia, macrocytosis | Lymphedema, deafness, mycobacterial, HPV infections | Dominant, 3q21.3 | Transcription factor | |
| G6PC3, severe congenital neutropenia | 202700 | Maturation arrest | Skin-prominent superficial venous network, atrial defect, uropathy | Recessive, 17q21 | 1,5AG6P hydrolysis | |
| SLC37A4, Glycogen Storage Disease Type Ib | 232220 | No maturation arrest | Hypoglycemia, fasting hyperlactacidemia, and glycogen overload in the liver | Recessive, 11q23.3 | glucose-6-phosphate or 1,5AG6P transport to the ER | |
| TAFAZIN, Barth disease | 302060 | No maturation arrest | Hypertrophic cardiomyopathy, myopathic syndrome, 3-methylglutaconic aciduria | X-linked, Xq28 | Tafazzin, phospholipid membrane homeostasis | |
| CXCR4, WHIM syndrome | 193670 | No maturation arrest, myelokathexis | Lymphopenia, thrombocytopenia, cardiopathy type tetralogy of Fallot | Dominant, 2q21 | Chemokine receptor (ligand CXCL12) | |
| JAGN1, severe congenital neutropenia | 616022 | Variable | Bone abnormalities, exocrine pancreatic deficiency | Recessive, 3p25.3 | ER protein | |
| VPS13B, Cohen syndrome | 216550 | No maturation arrest | Psychomotor retardation, clumsiness, microcephaly, characteristic facial features, hypotonia, joint laxity, progressive retinochoroidal dystrophy, myopia | Recessive, 8q22-q23 | Sorting and transporting proteins in the ER | |
| GFI1, severe congenital neutropenia | 202700 | Permanent/severe or mild neutropenia, sometimes maturation arrest | Internal ear (in mouse model), lymphopenia | Dominant, p22 | Transcription factor regulating oncoproteins | |
| HAX1, Kostmann's disease | 202700 | Maturation arrest | Central nervous system: mental retardation or seizures | Recessive, 1q21.3 | Antiapoptotic protein located in mitochondria and cytosol | |
| AP3B1, Hermansky-Pudlak syndrome type 2 | 608233 | No maturation arrest | Albinism | Recessive, 5q14.1 | Cargo protein or ER trafficking | |
| LAMTOR2, chronic neutropenia | 610389 | No maturation arrest | Albinism | Recessive, 1q21 | Lysosome packaging | |
| USB1, poikiloderma with Clericuzio-type neutropenia | 604173 | No maturation arrest, minor dysgranulopoietic features | Poikiloderma | Recessive, 16q21 | Unelucidated | |
| VPS45, severe congenital neutropenia | 615285 | Maturation arrest/myelofibrosis | Nephromegaly, hepatosplenomegaly, mental retardation | Recessive, 1q21.2 | Role in segregation of intracellular molecules into distinct organelles | |
| TCIRG1, severe congenital neutropenia | 202700 | Variable | Skin angiomatosis | Dominant, 11q13.2 | Unelucidated | |
| EIF2AK3, Wolcott-Rallison syndrome | 604032 | Maturation arrest | Insulin-dependent neonatal diabetes | Recessive, 2p11.2 | ER stress | |
| CLPB syndrome | 616254 | Maturation arrest | Mental retardation, congenital cataracts, 3-methylglutaconic aciduria | Recessive/ Dominant, 11q13.4 | Unelucidated | |
| STK4 (MST1) syndrome | 614868 | Intermittent or autoimmune neutropenia | Atrial defect | Recessive, 20q13 | Serine/threonine protein kinase | |
| SMARCD2 | Dysplastic syndrome, no granules in neutrophils | Chronic diarrhea, bone abnormalities, low-set ears | Recessive, 17q23 | Unelucidated | ||
| SASH3 | Maturation arrest | Autoimmune disease, viral infection(s) | X-linked, Xq26 | Unelucidated | ||
| CARD11 | Maturation arrest, hyperlymphocytosis | Skin disorders | Dominant, 7p22.2 | Unelucidated | ||
| Mitochondrial DNA, Pearson syndrome | 557000 | Vacuolization of BM precursors, Perls staining reveals ring sideroblasts | Exocrine pancreatic insufficiency, sideroblastic anemia and thrombocytopenia usually later in life, delayed development with Kearns-Sayre syndrome; elevated lactate/pyruvate ratio | Complex inheritance | Deletion(s) in mitochondrial DNA |
AP3B1, adaptor-related protein complex-3 subunit-β1; CARD11, caspase recruitment domain family member-11; CLPB, caseinolytic peptidase-B protein homolog; EFL1, elongation factor-like GTPase-1; EIF2AK3, eukaryotic translation initiation factor-2 alpha kinase-1; GATA2, transcription factor binding to the DNA sequence “GATA”; GF1, gold furrows of hull 1, GATA1 transcription factor; HAX1, encodes hematopoietic cell-specific Lyn substrate-1 protein; JAGN1, Jagunal homolog-1; LAMTOR2, late endosomal/lysosomal adaptor, MAPK and MTOR activator-2; SASH3, sterile alpha motif (SAM) and Src homology-3 (SH3) domain containing-3; SEC61A1, SEC61 translocon-subunit alpha-1; SLC3, solute carrier family-3; SMARCD2, SWItch/sucrose nonfermentable (SWI/SNF)-related, matrix associated, actin dependent regulator of chromatin, subfamily D, member 2; SRP, signal-recognition particle; STK4 (MST1), serine/threonine kinase-4 (macrophage stimulating-1; TAZ, tafazzin; TCIRG1, T-cell immune regulator 1, ATPase H+ transporting V0 subunit a3; USB1, U6 SnRNA biogenesis phosphodiesterase-1; VPS13B, vacuolar protein sorting– associated protein 13B; WAS, Wiskott-Aldrich syndrome.
Data reproduced with permission from Donadieu.6