title: Genetic analysis and clinical picture of severe congenital neutropenia in Israel.
abstract: BACKGROUND
  The relative frequency of mutated genes among patients with severe congenital neutropenia (SCN) may differ between various ethnic groups. To date, few population-based genetic studies have been reported. This study describes the genetic analysis of 32 Israeli patients with SCN.
  
  
  METHODS
  Clinical data were retrieved from the prospective Israeli Inherited Bone Marrow Failure Registry. Recruitment included living and deceased patients who were diagnosed between 1982 and 2012, for whom molecular diagnosis was performed. ELANE, HAX1 and G6PC3 genes were sequenced in all patients, and GFI-1 and WAS genes were sequenced if other genes were wildtype.
  
  
  RESULTS
  Eleven patients (34%) had heterozygous mutations in ELANE (10 kindreds), eight (25%) had homozygous mutations in G6PC3 (5 kindreds) and 13 (41%) had no detected mutations. No patients had mutations in HAX1 or WAS. Four of the eight patients with G6PC3 mutations had congenital anomalies. The probability of survival for all patients was 50% at age of 18. Deaths were mainly due to sepsis (5 patients, 4/5 not responding to G-CSF, none with G6PC3 mutation). Two patients developed acute myelogenous leukemia (AML) and one myelodysplastic syndrome (MDS), none with G6PC3 mutation.
  
  
  CONCLUSIONS
  We found a unique pattern of SCN mutations in Israel with homozygous G6PC3 mutations in eight (25%) patients, the highest frequency described so far. HAX1 mutations, reported mainly in Sweden and Iran, were absent. Patients with G6PC3 mutations had congenital anomalies, appeared to have a better response to G-CSF, and so far have not developed AML or MDS.
authors.affiliation: Department of Pediatrics B, Schneider Children's Medical Center of Israel, Petach Tikva, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Lebel
authors.forename: Joanne
authors.initials: J
authors.lastname: Yacobovich
authors.forename: Tanya
authors.initials: T
authors.lastname: Krasnov
authors.forename: Ariel
authors.initials: A
authors.lastname: Koren
authors.forename: Carina
authors.initials: C
authors.lastname: Levin
authors.forename: Chaim
authors.initials: C
authors.lastname: Kaplinsky
authors.forename: Shoshana
authors.initials: S
authors.lastname: Ravel-Vilk
authors.forename: Ruth
authors.initials: R
authors.lastname: Laor
authors.forename: Dina
authors.initials: D
authors.lastname: Attias
authors.forename: Ayelet
authors.initials: A
authors.lastname: Ben Barak
authors.forename: Dalia
authors.initials: D
authors.lastname: Shtager
authors.forename: Jerry
authors.initials: J
authors.lastname: Stein
authors.forename: Amir
authors.initials: A
authors.lastname: Kuperman
authors.forename: Hagit
authors.initials: H
authors.lastname: Miskin
authors.forename: Orly
authors.initials: O
authors.lastname: Dgany
authors.forename: Neelam
authors.initials: N
authors.lastname: Giri
authors.forename: Blanche P
authors.initials: BP
authors.lastname: Alter
authors.forename: Hannah
authors.initials: H
authors.lastname: Tamary
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D000080984:Congenital Bone Marrow Failure Syndromes; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005820:Genetic Testing; D005838:Genotype; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007557:Israel / Q000453:epidemiology; D015470:Leukemia, Myeloid, Acute / Q000453:epidemiology / Q000235:genetics / Q000628:therapy; D008297:Male; D009154:Mutation / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000453:epidemiology / Q000235:genetics / Q000628:therapy; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011446:Prospective Studies; D033581:Stem Cell Transplantation; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C498275:GFI1 protein, human; C104759:HAX1 protein, human; D014157:Transcription Factors; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D016179:Granulocyte Colony-Stimulating Factor; D005952:Glucose-6-Phosphatase; C492193:G6PC3 protein, human
keywords: bone marrow failure; molecular genetics; neutropenia