Background. The phenotypes of patients with the recently discovered, dominant, ETV6-linked leukaemia predisposition and familial thrombocytopenia syndrome are variable, and the exact mechanism of leukaemogenesis remains unclear.
Patients and Methods. Here, we present novel clinical and laboratory phenotypes of seven individuals from three families with ETV6 germline mutations and a refined genetic analysis of one child with additional high-hyperdiploid acute lymphoblastic leukaemia (HD-ALL), aiming to elucidate second oncogenic hits.
Results. Four individuals from two pedigrees harboured one novel or one previously described variant in the central domain of ETV6 (c.592C>T, p.Gln198* or c.641C>T, p.Pro241Leu, respectively). Neutropenia was an accompanying feature in one of these families that also harboured a variant in RUNX1 (c.1098_1103dup, p.Ile366_Gly367dup), while in the other, an autism-spectrum disorder was observed. In the third family, the index patient suffered from HD-ALL and life-threatening pulmonary mucor mycosis, and had a positive family history of ‘immune’ thrombocytopenia. Genetic analyses revealed a novel heterozygous mutation in the ETS domain of ETV6 (c.1136T>C, p.Leu379Pro) along with absence of heterozygosity of chromosome (10)(q21.2q21.3), yielding a biallelic leukaemia risk allele in ARID5B (rs7090445-C). The neutrophil function was normal in all individuals tested, and the platelet immune histochemistry of all three pedigrees showed delta-storage-pool defect-like features and cytoskeletal defects.
Conclusions. Our clinical observations and results of high-resolution genetic analyses extend the spectrum of possible phenotypes cosegregating with ETV6 germline mutations. Further, we propose ARID5B as potential leukaemogenic cofactor in patients with ETV6-linked leukaemia predisposition and familial thrombocytopenia syndrome.
- Immune thrombocytopenia (ITP)
- cancer predisposition syndrome (CPS)
- high-hyperdiploid acute lymphoblastic leukemia (HD-ALL)
- genetic susceptibility to leukemia
- delta-storage pool defect, congenital thrombocytopenia / thrombocytopathy syndrome
Statistics from Altmetric.com
Contributors AK, MB, CU, IG and MGS cared for the patients; AK and MGS designed the study; AK drafted the manuscript; MGS wrote the final version of the manuscript and designed table 1 and the online supplementary figure; KN and OAH performed leukaemia genetics and designed online supplementary table 1; AS, MB, RP and AG performed platelet function tests and/or immune histochemistry and designed figure 1; KN, OAH, EH, HJ, GH and MRS performed genetic analyses.
Funding MGS was in part sponsored by the Styrian Children’s Cancer Aid (Steirische Kinderkrebshilfe). The authors OAH and KN acknowledge the networking support by the COST Action CA16223 ‘LEukaemia GENe Discovery by data sharing, mining and collaboration (LEGEND)’ and by the ‘IBFM Leukemia & Lymphoma Genetic Predisposition Committee’ as well as the ‘Österreichische Kinderkrebsforschung’ for funding their research.
Competing interests None declared.
Patient consent for publication Parental/guardian consent obtained.
Ethics approval The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The IRB approval 30-155 ex 17/18 of the Medical University Graz applies.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.