Syndromes predisposing to leukemia are a major cause of inherited cytopenias in children

Oded Gilad, Orly Dgany, Sharon Noy-Lotan, Tanya Krasnov, Joanne Yacobovich, Ron Rabinowicz, Tracie Goldberg, Amir A. Kuperman, Abed Abu-Quider, Hagit Miskin, Noa Kapelushnik, Noa Mandel-Shorer, Shai Shimony, Dan Harlev, Tal Ben-Ami, Etai Adam, Carina Levin, Shraga Aviner, Ronit Elhasid, Sivan Berger-AchituvLilach Chaitman-Yerushalmi, Yona Kodman, Nino Oniashvilli, Michal Hameiri-Grosman, Shai Izraeli, Hannah Tamary*, Orna Steinberg-Shemer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Prolonged cytopenias are a non-specific sign with a wide differential diagnosis. Among inherited disorders, cytopenias predisposing to leukemia require a timely and accurate diagnosis to ensure appropriate medical management, including adequate monitoring and stem cell transplantation prior to the development of leukemia. We aimed to define the types and prevalences of the genetic causes leading to persistent cytopenias in children. The study comprises children with persistent cytopenias, myelodysplastic syndrome, aplastic anemia, or suspected inherited bone marrow failure syndromes, who were referred for genetic evaluation from all pediatric hematology centers in Israel during 2016-2019. For variant detection, we used Sanger sequencing of commonly mutated genes and a custom-made targeted next-generation sequencing panel covering 226 genes known to be mutated in inherited cytopenias; the minority subsequently underwent whole exome sequencing. In total, 189 children with persistent cytopenias underwent a genetic evaluation. Pathogenic and likely pathogenic variants were identified in 59 patients (31.2%), including 47 with leukemia predisposing syndromes. Most of the latter (32, 68.1%) had inherited bone marrow failure syndromes, nine (19.1%) had inherited thrombocytopenia predisposing to leukemia, and three each (6.4%) had predisposition to myelodysplastic syndrome or congenital neutropenia. Twelve patients had cytopenias with no known leukemia predisposition, including nine children with inherited thrombocytopenia and three with congenital neutropenia. In summary, almost one third of 189 children referred with persistent cytopenias had an underlying inherited disorder; 79.7% of whom had a germline predisposition to leukemia. Precise diagnosis of children with cytopenias should direct follow-up and management programs and may positively impact disease outcome.

Original languageEnglish
Pages (from-to)2081-2095
Number of pages15
Issue number9
StatePublished - Sep 2022


FundersFunder number
Israeli Center for Better Childhood
Israeli Ministry of Science14940-3, 3-14354
Israel Cancer Association
Ministry of Health, State of Israel3-15001


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