TY - JOUR
T1 - Genetic analysis and clinical picture of severe congenital neutropenia in Israel
AU - Lebel, Asaf
AU - Yacobovich, Joanne
AU - Krasnov, Tanya
AU - Koren, Ariel
AU - Levin, Carina
AU - Kaplinsky, Chaim
AU - Ravel-Vilk, Shoshana
AU - Laor, Ruth
AU - Attias, Dina
AU - Barak, Ayelet Ben
AU - Shtager, Dalia
AU - Stein, Jerry
AU - Kuperman, Amir
AU - Miskin, Hagit
AU - Dgany, Orly
AU - Giri, Neelam
AU - Alter, Blanche P.
AU - Tamary, Hannah
N1 - Publisher Copyright:
© 2014 Wiley Periodicals, Inc.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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. Pediatr Blood Cancer 2015;62:103-108.
AB - 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. Pediatr Blood Cancer 2015;62:103-108.
KW - Bone marrow failure
KW - Molecular genetics
KW - Neutropenia
UR - http://www.scopus.com/inward/record.url?scp=84922823799&partnerID=8YFLogxK
U2 - 10.1002/pbc.25251
DO - 10.1002/pbc.25251
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C2 - 25284454
AN - SCOPUS:84922823799
SN - 1545-5009
VL - 62
SP - 103
EP - 108
JO - Pediatric Blood and Cancer
JF - Pediatric Blood and Cancer
IS - 1
ER -