Neutropenia in the age of genetic testing: Advances and challenges

Identification of genetic causes of neutropenia informs precision medicine approaches to medical management and treatment. Accurate diagnosis of genetic neutropenia disorders informs treatment options, enables risk stratification, cancer surveillance, and attention to associated medical complications. The rapidly expanding genetic testing options for the evaluation of neutropenia have led to exciting advances but also new challenges. This review provides a practical guide to germline genetic testing for neutropenia.

[1]  D. Bidwell,et al.  Formation , 2006, Revue Francophone d'Orthoptie.

[2]  F. Xia,et al.  PSTPIP1‐associated myeloid‐related proteinemia inflammatory syndrome: A rare cause of childhood neutropenia associated with systemic inflammation and hyperzincemia , 2018, Pediatric blood & cancer.

[3]  J. Klco,et al.  Donor-derived MDS/AML in families with germline GATA2 mutation. , 2018, Blood.

[4]  É. Oksenhendler,et al.  Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome. , 2018, Blood.

[5]  Donald P. Frush,et al.  Further evidence for the involvement of EFL1 in a Shwachman–Diamond-like syndrome and expansion of the phenotypic features , 2018, Cold Spring Harbor molecular case studies.

[6]  L. Notarangelo,et al.  CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN‐&ggr; , 2018, The Journal of allergy and clinical immunology.

[7]  U. Pannicke,et al.  Recent advances in understanding the pathogenesis and management of reticular dysgenesis , 2018, British journal of haematology.

[8]  J. Soulier,et al.  A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. , 2018, Blood.

[9]  G. Bagby.  Recent advances in understanding hematopoiesis in Fanconi Anemia , 2018, F1000Research.

[10]  J. Churpek,et al.  Old and new tools in the clinical diagnosis of inherited bone marrow failure syndromes. , 2017, Hematology. American Society of Hematology. Education Program.

[11]  S. Corey,et al.  New monogenic disorders identify more pathways to neutropenia: from the clinic to next-generation sequencing. , 2017, Hematology. American Society of Hematology. Education Program.

[12]  R. Badolato,et al.  How I treat warts, hypogammaglobulinemia, infections, and myelokathexis syndrome. , 2017, Blood.

[13]  M. Boerries,et al.  Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7 , 2017, Haematologica.

[14]  E. Nexo,et al.  Long-term Outcome of 4 Patients With Transcobalamin Deficiency Caused by 2 Novel TCN2 Mutations , 2017, Journal of pediatric hematology/oncology.

[15]  Magalie S Leduc,et al.  Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond–like features , 2017, The Journal of clinical investigation.

[16]  D. Dale,et al.  Elastase inhibitors as potential therapies for ELANE‐associated neutropenia , 2017, Journal of leukocyte biology.

[17]  C. Bellanné-Chantelot,et al.  Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history , 2017, British journal of haematology.

[18]  P. Newburger,et al.  A novel homozygous VPS45 p.P468L mutation leading to severe congenital neutropenia with myelofibrosis , 2017, Pediatric blood & cancer.

[19]  D. Dale.  How I manage children with neutropenia , 2017, British journal of haematology.

[20]  A. Shimamura,et al.  Genetic predisposition to hematologic malignancies: management and surveillance. , 2017, Blood.

[21]  C. Bellanné-Chantelot,et al.  How to differentiate congenital from noncongenital chronic neutropenia at the first medical examination? Proposal of score: A pilot study from the French Severe Chronic Neutropenia registry , 2017, Pediatric blood & cancer.

[22]  A. Schambach,et al.  Gene correction of HAX1 reversed Kostmann disease phenotype in patient-specific induced pluripotent stem cells. , 2017, Blood advances.

[23]  S. Scherer,et al.  Biallelic mutations in DNAJC21 cause Shwachman-Diamond syndrome. , 2017, Blood.

[24]  A. Shimamura,et al.  Germline Genetic Predisposition to Hematologic Malignancy. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  D. Neuberg,et al.  Prognostic Mutations in Myelodysplastic Syndrome after Stem‐Cell Transplantation , 2017, The New England journal of medicine.

[26]  J. Chou,et al.  Glycogen storage disease type Ib neutrophils exhibit impaired cell adhesion and migration. , 2017, Biochemical and biophysical research communications.

[27]  L. Marshall,et al.  Severe congenital neutropenias , 2017, Nature Reviews Disease Primers.

[28]  C. Klein.  Children with rare diseases of neutrophil granulocytes: from therapeutic orphans to pioneers of individualized medicine. , 2016, Hematology. American Society of Hematology. Education Program.

[29]  R. Brodsky,et al.  Genetic panels in young patients with bone marrow failure: are they clinically relevant? , 2016, Haematologica.

[30]  T. Walsh,et al.  Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients , 2016, Haematologica.

[31]  Deborah Nickerson,et al.  Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L. , 2016, American journal of human genetics.

[32]  H. Okano,et al.  SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7 , 2016, Nature Genetics.

[33]  L. Foster,et al.  Jagn1 Is Induced in Response to ER Stress and Regulates Proinsulin Biosynthesis , 2016, PloS one.

[34]  P. Ng,et al.  SIFT missense predictions for genomes , 2015, Nature Protocols.

[35]  M. Pillon,et al.  Pearson Syndrome: A Retrospective Cohort Study from the Marrow Failure Study Group of A.I.E.O.P. (Associazione Italiana Emato-Oncologia Pediatrica). , 2016, JIMD reports.

[36]  C. Klein.  Kostmann’s Disease and HCLS1-Associated Protein X-1 (HAX1) , 2016, Journal of Clinical Immunology.

[37]  T. Möröy,et al.  From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation. , 2015, Blood.

[38]  C. Klein,et al.  Severe congenital neutropenia with neurological impairment due to a homozygous VPS45 p.E238K mutation: A case report suggesting a genotype–phenotype correlation , 2015, American journal of medical genetics. Part A.

[39]  Christopher A. Miller,et al.  Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. , 2015, Blood.

[40]  I. Barlan,et al.  G6PC3 Deficiency: Primary Immune Deficiency Beyond Just Neutropenia. , 2015, Journal of pediatric hematology/oncology.

[41]  K. Welte,et al.  GM-CSF stimulates granulopoiesis in a congenital neutropenia patient with loss-of-function biallelic heterozygous CSF3R mutations. , 2015, Blood.

[42]  É. Oksenhendler,et al.  Severe chronic primary neutropenia in adults: report on a series of 108 patients. , 2015, Blood.

[43]  J. Beyene,et al.  Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes , 2015, Journal of Medical Genetics.

[44]  F. Cardinale,et al.  Lethal sepsis and malignant transformation in severe congenital neutropenia: Report from the Italian Neutropenia Registry , 2015, Pediatric blood & cancer.

[45]  E. de la Mora,et al.  Defective Guanine Nucleotide Exchange in the Elongation Factor-like 1 (EFL1) GTPase by Mutations in the Shwachman-Diamond Syndrome Protein* , 2015, The Journal of Biological Chemistry.

[46]  Laurie D. Smith,et al.  CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria. , 2015, American journal of human genetics.

[47]  T. Meitinger,et al.  CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder. , 2015, American journal of human genetics.

[48]  S. Holland,et al.  GATA2 deficiency , 2015, Current opinion in allergy and clinical immunology.

[49]  David A. Williams,et al.  Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity , 2015, Haematologica.

[50]  C. Picard,et al.  Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French severe congenital neutropenia registry , 2014, Orphanet Journal of Rare Diseases.

[51]  B. Alter.  Fanconi anemia and the development of leukemia. , 2014, Best practice & research. Clinical haematology.

[52]  A. Schäffer,et al.  JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia , 2014, Nature Genetics.

[53]  D. Nickerson,et al.  TCIRG1‐Associated Congenital Neutropenia , 2014, Human mutation.

[54]  S. Pittaluga,et al.  A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor. , 2014, Blood.

[55]  A. Shimamura,et al.  Variable clinical presentation of Shwachman-Diamond syndrome: update from the North American Shwachman-Diamond Syndrome Registry. , 2014, The Journal of pediatrics.

[56]  Jana Marie Schwarz,et al.  MutationTaster2: mutation prediction for the deep-sequencing age , 2014, Nature Methods.

[57]  J. Orange,et al.  GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. , 2014, Blood.

[58]  J. Shendure,et al.  A general framework for estimating the relative pathogenicity of human genetic variants , 2014, Nature Genetics.

[59]  C. Klein,et al.  Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes , 2013, Current opinion in allergy and clinical immunology.

[60]  S. Kingsmore,et al.  Clinical, laboratory and molecular signs of immunodeficiency in patients with partial oculo-cutaneous albinism , 2013, Orphanet Journal of Rare Diseases.

[61]  N. Sánchez-Puig,et al.  Guanine nucleotide exchange in the ribosomal GTPase EFL1 is modulated by the protein mutated in the Shwachman-Diamond syndrome. , 2013, Biochemical and biophysical research communications.

[62]  J. Mullikin,et al.  A congenital neutrophil defect syndrome associated with mutations in VPS45. , 2013, The New England journal of medicine.

[63]  P. Newburger,et al.  Evaluation and management of patients with isolated neutropenia. , 2013, Seminars in hematology.

[64]  W. Newman,et al.  A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations , 2013, Orphanet Journal of Rare Diseases.

[65]  P. Campbell,et al.  Aberrant 3' oligoadenylation of spliceosomal U6 small nuclear RNA in poikiloderma with neutropenia. , 2013, Blood.

[66]  C. Bellanné-Chantelot,et al.  Epidemiology of congenital neutropenia. , 2013, Hematology/oncology clinics of North America.

[67]  S. Corey,et al.  ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. , 2013, Hematology/oncology clinics of North America.

[68]  J. Finsterer,et al.  Haematological features in Barth syndrome , 2013, Current opinion in hematology.

[69]  Nicholas J. Dobbins,et al.  Variable Clinical Presentation of Shwachman-Diamond Syndrome: Update From the North-American Shwachman-Diamond Syndrome Registry. , 2012 .

[70]  J. Palmblad,et al.  Incidence of severe congenital neutropenia in Sweden and risk of evolution to myelodysplastic syndrome/leukaemia , 2012, British journal of haematology.

[71]  M. Odero,et al.  The role of the GATA2 transcription factor in normal and malignant hematopoiesis. , 2012, Critical reviews in oncology/hematology.

[72]  A. Schäffer,et al.  The phenotype of human STK4 deficiency. , 2011, Blood.

[73]  J. Rommens,et al.  Draft consensus guidelines for diagnosis and treatment of Shwachman‐Diamond syndrome , 2011, Annals of the New York Academy of Sciences.

[74]  B. Wood,et al.  The CXCR4 antagonist plerixafor is a potential therapy for myelokathexis, WHIM syndrome. , 2011, Blood.

[75]  T. Fleisher,et al.  The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome. , 2011, Blood.

[76]  Smita Y. Patel,et al.  Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. , 2011, Blood.

[77]  A. Schäffer,et al.  HAX1 mutations causing severe congenital neuropenia and neurological disease lead to cerebral microstructural abnormalities documented by quantitative MRI , 2010, American journal of medical genetics. Part A.

[78]  S. Savage,et al.  The genetics and clinical manifestations of telomere biology disorders , 2010, Genetics in Medicine.

[79]  P. Newburger,et al.  Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE mutation and paternal haplotype: Evidence for phenotype determination by modifying genes , 2010, Pediatric blood & cancer.

[80]  Fabio Macciardi,et al.  Targeted next-generation sequencing appoints c16orf57 as clericuzio-type poikiloderma with neutropenia gene. , 2010, American journal of human genetics.

[81]  J. Chou,et al.  Neutropenia in type Ib glycogen storage disease , 2010, Current opinion in hematology.

[82]  Bodo Grimbacher,et al.  A syndrome with congenital neutropenia and mutations in G6PC3. , 2009, The New England journal of medicine.

[83]  D. Link,et al.  Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia , 2009, British journal of haematology.

[84]  A. Shimamura,et al.  Shwachman-Diamond syndrome: a review of the clinical presentation, molecular pathogenesis, diagnosis, and treatment. , 2009, Hematology/oncology clinics of North America.

[85]  D. Link,et al.  The many causes of severe congenital neutropenia. , 2009, New England Journal of Medicine.

[86]  L. Notarangelo,et al.  Cartilage-hair hypoplasia: molecular basis and heterogeneity of the immunological phenotype , 2008, Current opinion in allergy and clinical immunology.

[87]  O. Mäkitie,et al.  Extended follow‐up of the Finnish cartilage‐hair hypoplasia cohort confirms high incidence of non‐Hodgkin lymphoma and basal cell carcinoma , 2008, American journal of medical genetics. Part A.

[88]  R. Christensen,et al.  Expected ranges for blood neutrophil concentrations of neonates: the Manroe and Mouzinho charts revisited , 2008, Journal of Perinatology.

[89]  J. Finsterer,et al.  Hematological Manifestations of Primary Mitochondrial Disorders , 2007, Acta Haematologica.

[90]  Bengt Fadeel,et al.  HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease) , 2007, Nature Genetics.

[91]  Laurence Boxer,et al.  The Severe Chronic Neutropenia International Registry: 10-Year Follow-up Report. , 2006, Supportive cancer therapy.

[92]  George Eliopoulos,et al.  Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2 , 2003, Nature Genetics.

[93]  R. Norio,et al.  Cohen syndrome: essential features, natural history, and heterogeneity. , 2001, American journal of medical genetics.

[94]  Koenraad Devriendt,et al.  Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia , 2001, Nature Genetics.