Genetic backgrounds and clinical characteristics of congenital neutropenias in Israel

Lital Yeshareem, Joanne Yacobovich, Asaf Lebel, Sharon Noy-Lotan, Orly Dgany, Tanya Krasnov, Galit Berger Pinto, Nino Oniashvili, Jacques Mardoukh, Bella Bielorai, Ruth Laor, Noa Mandel-Shorer, Ayelet Ben Barak, Carina Levin, Mahdi Asleh, Hagit Miskin, Shoshana Revel-Vilk, Dror Levin, Marganit Benish, Tsila ZuckermanOfir Wolach, Idit Pazgal, Dafna Brik Simon, Oded Gilad, Asaf David Yanir, Tracie Alison Goldberg, Shai Izraeli, Hannah Tamary, Orna Steinberg-Shemer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background: Congenital neutropenias are characterized by severe infections and a high risk of myeloid transformation; the causative genes vary across ethnicities. The Israeli population is characterized by an ethnically diverse population with a high rate of consanguinity. Objective: To evaluate the clinical and genetic spectrum of congenital neutropenias in Israel. Methods: We included individuals with congenital neutropenias listed in the Israeli Inherited Bone Marrow Failure Registry. Sanger sequencing was performed for ELANE or G6PC3, and patients with wild-type ELANE/G6PC3 were referred for next-generation sequencing. Results: Sixty-five patients with neutropenia were included. Of 51 patients with severe congenital neutropenia, 34 were genetically diagnosed, most commonly with variants in ELANE (15 patients). Nine patients had biallelic variants in G6PC3, all of consanguineous Muslim Arab origin. Other genes involved were SRP54, JAGN1, TAZ, and SLC37A4. Seven patients had cyclic neutropenia, all with pathogenic variants in ELANE, and seven had Shwachman–Diamond syndrome caused by biallelic SBDS variants. Eight patients (12%) developed myeloid transformation, including six patients with an unknown underlying genetic cause. Nineteen (29%) patients underwent hematopoietic stem cell transplantation, mostly due to insufficient response to treatment with granulocyte-colony stimulating factor or due to myeloid transformation. Conclusions: The genetic spectrum of congenital neutropenias in Israel is characterized by a high prevalence of G6PC3 variants and an absence of HAX1 mutations. Similar to other registries, for 26% of the patients, a molecular diagnosis was not achieved. However, myeloid transformation was common in this group, emphasizing the need for close follow-up.

Original languageEnglish
Pages (from-to)146-162
Number of pages17
JournalEuropean Journal of Haematology
Issue number2
StateAccepted/In press - 2024


FundersFunder number
European Hematology Association
Israel Cancer Association20180029
Israel Cancer Association


    • SCN
    • Shwachman–Diamond syndrome
    • genetics
    • neutropenia
    • severe congenital neutropenia


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