Novel phenotypes observed in patients with ETV6-linked leukaemia/familial thrombocytopenia syndrome and a biallelic ARID5B risk allele as leukaemogenic cofactor.
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.
['Karastaneva|Anna|A|', 'Nebral|Karin|K|', 'Schlagenhauf|Axel|A|', 'Baschin|Marcel|M|', 'Palankar|Raghavendra|R|', 'Juch|Herbert|H|', 'Heitzer|Ellen|E|', 'Speicher|Michael R|MR|', 'Höfler|Gerald|G|', 'Grigorow|Irina|I|', 'Urban|Christian|C|', 'Benesch|Martin|M|', 'Greinacher|Andreas|A|', 'Haas|Oskar A|OA|', 'Seidel|Markus G|MG|0000-0003-0981-8661']
D000293:Adolescent D000328:Adult D000483:Alleles D002648:Child D002675:Child, Preschool D050676:Core Binding Factor Alpha 2 Subunit D004268:DNA-Binding Proteins D005260:Female D056726:Genetic Association Studies D020022:Genetic Predisposition to Disease D005820:Genetic Testing D018095:Germ-Line Mutation D006579:Heterozygote D006801:Humans D007223:Infant D007938:Leukemia D008297:Male D010375:Pedigree D010641:Phenotype D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma D050783:Proto-Oncogene Proteins c-ets D012097:Repressor Proteins D013921:Thrombocytopenia D014157:Transcription Factors D055815:Young Adult
Immune thrombocytopenia (ITP) cancer predisposition syndrome (CPS) delta-storage pool defect, congenital thrombocytopenia / thrombocytopathy syndrome genetic susceptibility to leukemia high-hyperdiploid acute lymphoblastic leukemia (HD-ALL)