Invitae Severe Congenital Neutropenia Panel



Test description

This test analyzes 23 genes that are associated with severe congenital neutropenia. Disorders that can cause severe congenital neutropenia are primary hematologic disorders that are characterized by episodes of neutropenia and recurrent infections.

Genetic testing of these genes may confirm a clinical diagnosis and guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives.

Genes tested

AK2

AP3B1

CD40LG

CLPB

CSF3R

CXCR4

ELANE

G6PC3

GATA2

GFI1

HAX1

JAGN1

LAMTOR2

LYST

RAB27A

RMRP

SLC37A4

STK4

TAZ

TCN2

VPS13B

VPS45

WAS

Clinical sensitivity

The clinical sensitivity of this test is dependent on the patient’s underlying genetic condition. This test covers some of the common genetic causes of congenital neutropenia-related disorders. Of the 60-75% of neutropenia-related disorders attributed to genetic etiology, a minimum of 82% of individuals are expected to have a pathogenic variant identified in one of the genes on this panel, although exact estimates are unknown (PMID: 28593997, 30661651, 28875503).

Gene*

% of severe neutropenia attributed to this gene

AK2

rare

AP3B1

rare

CD40LG

rare

CLPB

rare

CSF3R

rare

CXCR4

2%

ELANE

45%

G6PC3

2%

GATA2

rare

GFI1

rare

HAX1

7%

JAGN1

rare

LAMTOR2

rare

LYST

rare

RAB27A

rare

RMRP

rare

SLC37A4

12%

STK4

rare

TAZ

4%

TCN2

rare

VPS13B

2%

VPS45

rare

WAS

2%

*Please note that this test does not include analysis of the SBDS gene, which is estimated to account for 14% of genetic severe congenital neutropenia (PMID: 28593997)

DISORDERS TESTED

Gene

Disorder

Protein Name

Protein Symbol

AK2

Reticular dysgenesis, AK2 deficiency

adenylate kinase-2

AK2

AP3B1

Hermansky-Pudlak syndrome, type 2

adaptor-related protein complex-3, B1 subunit

AP3B1

CD40LG

CD40 ligand deficiency

CD40 ligand

CD40LG

CLPB

3-Methylglutaconic aciduria

caseinolytic peptidase B

CLPB

CSF3R

G-CSF receptor deficiency

granulocyte colony-stimulating factor receptor

CSF3R

CXCR4

WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome

chemokine, CXC motif, receptor 4

CXCR4

ELANE

Elastase deficiency (SCN1), cyclic neutropenia

elastase

ELANE

G6PC3

G6PC3 deficiency (SCN4)

glucose-6-phosphatase beta

G6PC3

GATA2

GATA2 deficiency

GATA-binding protein 2

GATA2

GFI1

GFI 1 deficiency (SCN2)

growth factor-independent 1

GFI1

HAX1

Kostmann disease (SCN3)

HCLS-associated protein X1

HAX1

JAGN1

JAGN1 deficiency

homolog of drosophila jagunal 1

JAGN1

LAMTOR2

P14/LAMTOR2 deficiency

p14

P14

LYST

Chediak-Higashi syndrome

lysosomal trafficking regulator

LYST

RAB27A

Griscelli syndrome, type 2

Ras-associated protein RAB27A

RAB27A

RMRP

Cartilage hair hypoplasia

mitochondrial RNA-processing endoribonuclease (RNase MRP) RNA

RNAse MRP (RNA)

SLC37A4

Glycogen storage disease type 1b

glucose-6-phosphate transporter 1

G6PT1

STK4

MST1 deficiency

mammalian sterile 20-like 1

MST1

TAZ

Barth syndrome

tafazzin

TAZ

TCN2

Transcobalamin 2 deficiency

transcobalamin 2

TCN2

VPS13B

Cohen syndrome

vacuolar protein sorting 13 homolog B

COH1

VPS45

VPS45 deficiency (SCN5)

vacuolar protein sorting 45

VPS45

WAS

Wiskott-Aldrich syndrome, X-linked neutropenia/myelodysplasia

WAS protein

WASP

Clinical description

Genetic disorders causing severe congenital neutropenia are rare primary hematologic disorders that are characterized by episodes of neutropenia and recurrent infections. There are numerous primary genetic defects that can result in severe chronic neutropenia with or without additional immune deficiencies. Clinical manifestations vary considerably depending on the underlying genetic condition. Many of these disorders demonstrate decreased bone marrow myeloid cell production, resulting in neutropenia and an increased propensity to infection. For some disorders, the neutropenia may occur secondary to underlying immune dysregulation rather than a primary defect in neutrophil production. The symptoms of these disorders typically present at or shortly after birth. Common clinical manifestations include respiratory infections, otitis media, oropharyngeal problems (painful gingivitis, stomatitis, oral ulcerations), cellulitis, and skin infections.

Determination of an underlying genetic predisposition in an individual with a personal or family history of these disorders may be critical for the selection of therapy regimens, consideration of bone marrow or stem cell transplant, and counseling of the individual and their family.

Inheritance

The following genes confer an increased risk of severe congenital neutropenia in:

  • an autosomal dominant inheritance pattern: CXCR4, ELANE, GATA2, GFI1
  • an autosomal recessive inheritance pattern: AK2, AP3B1, CLPB, G6PC3, HAX1, JAGN1, LAMTOR2, LYST, RAB27A, RMRP, SLC37A4, STK4, TCN2, VSP13B, VPS45
  • an autosomal dominant or autosomal recessive inheritance pattern: CSF3R
  • an X-linked inheritance pattern: CD40LG, TAZ, WAS

Considerations for testing

This panel may be considered for individuals whose personal and/or family history is suggestive of a hereditary predisposition to severe congenital neutropenia, including (but not limited to) any of the following:

  • chronic common bacterial and fungal infections
  • unusual bacterial and fungal infections
  • omphalitis in infants
  • oropharyngeal problems (painful gingivitis, stomatitis, oral ulcerations)
  • congenital neutropenia
  • cyclic neutropenia

If the patient has undergone a bone marrow transplant prior to genetic testing, a sample type not derived from blood (such as skin biopsy) is warranted.  While we do not accept this sample type directly, we can accept gDNA derived from skin or muscle, but deletion/duplication analysis is not guaranteed for gDNA samples because the success rate varies based on sample qualify.  Please see our Specimen Requirements for more details.

References

  1. Lagresle-Peyrou C et al. Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness. Nat Genet. 2009;41(1):106-11. PMID: 19043416
  2. Fontana S et al. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood. 2006;15;107(12):4857-64. PMID:16507770
  3. Etzioni A et. al. The hyper IgM syndrome--an evolving story. Pediatr Res. 2004;56(4):519-25. PMID:15319456
  4. Capo-Chichi JM et. al. Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria. J Med Genet. 2015;52(5):303-11. PMID: 25650066
  5. Wortmann SB et. al. CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder. Am J Hum Genet. 2015;96(2):245-57. PMID: 25597510
  6. Saunders C et al. CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria. Am J Hum Genet. 2015;96(2):258-65. PMID: 25597511
  7. Triot A et al. Inherited biallelic CSF3R mutations in severe congenital neutropenia. Blood. 2014;123(24):3811-7. PMID: 24753537
  8. Klimiankou M et al. GM-CSF stimulates granulopoiesis in a congenital neutropenia patient with loss-of-function biallelic heterozygous CSF3R mutations. Blood. 2015;126(15):1865-7. PMID: 26324699
  9. McCormick PJ et al. Impaired recruitment of Grk6 and beta-Arrestin 2 causes delayed internalization and desensitization of a WHIM syndrome-associated CXCR4 mutant receptor. PLoS One. 2009;4(12):e8102. PMID: 19956569
  10. Makaryan V et al. The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Curr Opin Hematol. 2015;22(1):3-11. PMID: 25427142
  11. Banka S et al. A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations. Orphanet J Rare Dis. 2013;8:84. PMID: 23758768
  12. Boztug K et al. A syndrome with congenital neutropenia and mutations in G6PC3. N Engl J Med. 2009;360(1):32-43. PMID: 19118303
  13. Dursun A et al. Familial pulmonary arterial hypertension, leucopenia, and atrial septal defect: a probable new familial syndrome with multisystem involvement. Clin Dysmorphol. 2009;18(1):19-23. PMID: 19011569
  14. Banka S et al. Mutations in the G6PC3 gene cause Dursun syndrome. Am J Med Genet A. 2010;152A(10):2609-11. PMID: 20799326
  15. Hsu AP et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome.Blood. 2011;118(10):2653-5. PMID: 21670465
  16. Pasquet M et al. High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia. Blood. 2013;121(5):822-9. PMID: 23223431
  17. Person RE et al. Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nat Genet. 2003;34(3):308-12. PMID: 12778173
  18. Zarebski A et al. Mutations in growth factor independent-1 associated with human neutropenia block murine granulopoiesis through colony stimulating factor-1. Immunity. 2008;28(3):370-80. PMID: 18328744
  19. Velu CS et al. Gfi1 regulates miR-21 and miR-196b to control myelopoiesis. Blood. 2009;113(19):4720-8. PMID: 19278956
  20. Liu Q et al. Gfi-1 inhibits the expression of eosinophil major basic protein (MBP) during G-CSF-induced neutrophilic differentiation. Int J Hematol. 2012;95(6):640-7. PMID: 22552881
  21. Mamishi S et al. Severe congenital neutropenia in 2 siblings of consanguineous parents. The role of HAX1 deficiency. J Investig Allergol Clin Immunol. 2009;19(6):500-3. PMID: 20128427
  22. Eghbali A et al. HAX1 mutation in an infant with severe congenital neutropenia. Turk J Pediatr. 2010;52(1):81-4. PMID: 20402072
  23. Patiroglu T et al. Severe congenital neutropenia in two siblings related to HAX1 mutation without neurodevelopmental disorders. Genet Couns. 2013;24(3):253-8. PMID: 24341138
  24. Germeshausen M et al. Novel HAX1 mutations in patients with severe congenital neutropenia reveal isoform-dependent genotype-phenotype associations. Blood. 2008;111(10):4954-7. PMID: 18337561
  25. Carlsson G et al. Central nervous system involvement in severe congenital neutropenia: neurological and neuropsychological abnormalities associated with specific HAX1 mutations. J Intern Med. 2008;264(4):388-400. PMID: 18513342
  26. Boztug K et al. HAX1 mutations causing severe congenital neuropenia and neurological disease lead to cerebral microstructural abnormalities documented by quantitative MRI. Am J Med Genet A. 2010;152A(12):3157-63. PMID: 21108402
  27. Boztug K et al. JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia. Nat Genet. 2014;46(9):1021-7. PMID: 25129144
  28. Baris S et al. JAGN1 Deficient Severe Congenital Neutropenia: Two Cases from the Same Family. J Clin Immunol. 2015;35(4):339-43. PMID: 25851723
  29. Bohn G et al. A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nat Med. 2007;13(1):38-45. PMID: 17195838
  30. Karim MA et al. Mutations in the Chediak-Higashi syndrome gene (CHS1) indicate requirement for the complete 3801 amino acid CHS protein. Hum Mol Genet. 1997;6(7):1087-9. PMID: 9215679
  31. Catz SD. The role of Rab27a in the regulation of neutrophil function. Cell Microbiol. 2014;16(9):1301-10. PMID: 24964030
  32. Hermanns P et al. RMRP mutations in cartilage-hair hypoplasia. Am J Med Genet A. 2006;140(19):2121-30. PMID: 16838329
  33. Steward CG et al. Barth syndrome: an X-linked cause of fetal cardiomyopathy and stillbirth. Prenat Diagn. 2010;30(10):970-6. PMID: 20812380
  34. Clarke SL et al. Barth syndrome. Orphanet J Rare Dis. 2013;8:23. PMID: 23398819
  35. Saric A et al. Barth Syndrome: From Mitochondrial Dysfunctions Associated with Aberrant Production of Reactive Oxygen Species to Pluripotent Stem Cell Studies. Front Genet. 2016;20;6:359. PMID: 26834781
  36. van Werkhoven MA et al. Monolysocardiolipin in cultured fibroblasts is a sensitive and specific marker for Barth Syndrome. J Lipid Res. 2006;47(10):2346-51. PMID: 16873891
  37. Angelini R et al. Cardiolipin fingerprinting of leukocytes by MALDI-TOF/MS as a screening tool for Barth syndrome. J Lipid Res. 2015;56(9):1787-94. PMID: 26144817
  38. Roberts AE et al. The Barth Syndrome Registry: distinguishing disease characteristics and growth data from a longitudinal study. Am J Med Genet A. 2012 Nov;158A(11):2726-32. PMID: 23045169
  39. Nashabat M et al. Long-term Outcome of 4 Patients With Transcobalamin Deficiency Caused by 2 Novel TCN2 Mutations. J Pediatr Hematol Oncol. 2017;39(8):e430-e436. PMID: 28538514
  40. Kolehmainen J et al. Delineation of Cohen syndrome following a large-scale genotype-phenotype screen. Am J Hum Genet. 2004;75(1):122-7. PMID: 15141358
  41. Parri V et al. High frequency of COH1 intragenic deletions and duplications detected by MLPA in patients with Cohen syndrome. Eur J Hum Genet. 2010;18(10):1133-40. PMID: 20461111
  42. Seifert W et al. Mutational spectrum of COH1 and clinical heterogeneity in Cohen syndrome. J Med Genet. 2006;43(5):e22. PMID: 16648375
  43. Vilboux T et al. A congenital neutrophil defect syndrome associated with mutations in VPS45. N Engl J Med. 2013;369(1):54-65. PMID: 23738510
  44. Stepensky P et al. The Thr224Asn mutation in the VPS45 gene is associated with the congenital neutropenia and primary myelofibrosis of infancy. Blood. 2013;121(25):5078-87. PMID: 23599270
  45. Meerschaut I et al. Severe congenital neutropenia with neurological impairment due to a homozygous VPS45 p.E238K mutation: A case report suggesting a genotype-phenotype correlation. Am J Med Genet A. 2015;167A(12):3214-8. PMID: 26358756
  46. Buchbinder D et al. Wiskott-Aldrich syndrome: diagnosis, current management, and emerging treatments. Appl Clin Genet. 2014;7:55-66. PMID: 24817816
  47. Boonyawat B et al. Combined de-novo mutation and non-random X-chromosome inactivation causing Wiskott-Aldrich syndrome in a female with thrombocytopenia. J Clin Immunol. 2013 Oct;33(7):1150-5. PMID: 23943155
  48. Skokowa J et al. Severe congenital neutropenias. Nat Rev Dis Primers. 2017;3:17032. PMID: 28593997
  49. Spoor J et al. Congenital neutropenia and primary immunodeficiency diseases. Crit Rev Oncol Hematol. 2019;133:149-162. PMID: 30661651
  50. Donadieu J et al. Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history. Br J Haematol. 2017;179(4):557-574. PMID: 28875503
  51. Klein C. Congenital neutropenia. Hematology Am Soc Hematol Educ Program. 2009:344-50. PMID: 20008220
  52. Welte K et al. Severe congenital neutropenia. Semin Hematol. 2006;43(3):189-95. PMID: 16822461
  53. Klein C. Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes. Annu Rev Immunol. 2011;29:399-413. PMID: 21219176

Assay

There are no limitations for any of these genes and no special targets.

Gene

Transcript Reference

Sequencing Analysis

Deletion/Duplication Analysis

AK2

NM_001625.3

x

x

AP3B1

NM_003664.4

x

x

CD40LG

NM_000074.2

x

x

CLPB

NM_030813.5

x

x

CSF3R

NM_000760.3

x

x

CXCR4

NM_003467.2

x

x

ELANE

NM_001972.2

x

x

G6PC3

NM_138387.3

x

x

GATA2

NM_032638.4

x

x

GFI1

NM_005263.3

x

x

HAX1

NM_006118.3

x

x

JAGN1

NM_032492.3

x

x

LAMTOR2

NM_014017.3

x

x

LYST

NM_000081.3

x

x

RAB27A

NM_004580.4

x

x

RMRP

NR_003051.3

x

x

SLC37A4

NM_001164277.1

x

x

STK4

NM_006282.3

x

x

TAZ

NM_000116.4

x

x

TCN2

NM_000355.3

x

x

VPS13B

NM_017890.4

x

x

VPS45

NM_007259.4

x

x

WAS

NM_000377.2

x

x