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.

PROCEDURES:

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: Asaf Lebel, Joanne Yacobovich, Tanya Krasnov, Ariel Koren, Carina Levin, Chaim Kaplinsky, Shoshana Ravel-Vilk, Ruth Laor, Dina Attias, Ayelet Ben Barak, Dalia Shtager, Jerry Stein, Amir Kuperman, Hagit Miskin, Orly Dgany, Neelam Giri, Blanche P Alter, Hannah Tamary
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 62 Issue 1 Pg. 103-8 (Jan 2015) ISSN: 1545-5017 [Electronic] United States
• PMID: 25284454 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• Adaptor Proteins, Signal Transducing
• DNA-Binding Proteins
• GFI1 protein, human
• HAX1 protein, human
• Transcription Factors
• WAS protein, human
• Wiskott-Aldrich Syndrome Protein
• Granulocyte Colony-Stimulating Factor
• Glucose-6-Phosphatase
• G6PC3 protein, human

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Adolescent
• Child
• Child, Preschool
• Combined Modality Therapy
• Congenital Bone Marrow Failure Syndromes
• DNA-Binding Proteins (genetics)
• Female
• Follow-Up Studies
• Genetic Testing
• Genotype
• Glucose-6-Phosphatase (genetics)
• Granulocyte Colony-Stimulating Factor (therapeutic use)
• Homozygote
• Humans
• Infant
• Infant, Newborn
• Israel (epidemiology)
• Leukemia, Myeloid, Acute (epidemiology, genetics, therapy)
• Male
• Mutation (genetics)
• Myelodysplastic Syndromes (epidemiology, genetics, therapy)
• Neutropenia (congenital, genetics, mortality, pathology)
• Prognosis
• Prospective Studies
• Stem Cell Transplantation
• Survival Rate
• Transcription Factors (genetics)
• Wiskott-Aldrich Syndrome Protein (genetics)