European journal of haematology · 2024
Genetic backgrounds and clinical characteristics of congenital neutropenias in Israel.
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Yeshareem Lital, Yacobovich Joanne, Lebel Asaf, Noy-Lotan Sharon, Dgany Orly, Krasnov Tanya, Berger Pinto Galit, Oniashvili Nino, Mardoukh Jacques, Bielorai Bella, Laor Ruth, Mandel-Shorer Noa, Ben Barak Ayelet, Levin Carina, Asleh Mahdi, Miskin Hagit, Revel-Vilk Shoshana, Levin Dror, Benish Marganit, Zuckerman Tsila, Wolach Ofir, Pazgal Idit, Brik Simon Dafna, Gilad Oded, Yanir Asaf David, Goldberg Tracie Alison, Izraeli Shai, Tamary Hannah, Steinberg-Shemer Orna
Аннотация
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.
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.
Предметные рубрики MeSH
HumansNeutropeniaMaleIsraelFemaleChildMutationCongenital Bone Marrow Failure SyndromesChild, PreschoolAdolescentGenetic Predisposition to DiseaseAdultHematopoietic Stem Cell TransplantationInfantConsanguinityGlucose-6-PhosphataseAllelesRegistriesHigh-Throughput Nucleotide SequencingYoung AdultPhenotypeGenetic Association Studies