TY - JOUR T1 - Novel phenotypes observed in patients with <em>ETV6</em>-linked leukaemia/familial thrombocytopenia syndrome and a biallelic <em>ARID5B</em> risk allele as leukaemogenic cofactor JF - Journal of Medical Genetics JO - J Med Genet SP - 427 LP - 433 DO - 10.1136/jmedgenet-2019-106339 VL - 57 IS - 6 AU - Anna Karastaneva AU - Karin Nebral AU - Axel Schlagenhauf AU - Marcel Baschin AU - Raghavendra Palankar AU - Herbert Juch AU - Ellen Heitzer AU - Michael R Speicher AU - Gerald Höfler AU - Irina Grigorow AU - Christian Urban AU - Martin Benesch AU - Andreas Greinacher AU - Oskar A Haas AU - Markus G Seidel Y1 - 2020/06/01 UR - http://jmg.bmj.com/content/57/6/427.abstract N2 - 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&gt;T, p.Gln198* or c.641C&gt;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&gt;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. ER -