Novel phenotypes observed in patients with<i>ETV6</i>-linked leukaemia/familial thrombocytopenia syndrome and a biallelic<i>ARID5B</i>risk allele as leukaemogenic cofactor

Abstract

<i>Background.</i> The phenotypes of patients with the recently discovered, dominant, <i>ETV6</i>-linked leukaemia predisposition and familial thrombocytopenia syndrome are variable, and the exact mechanism of leukaemogenesis remains unclear. <i>Patients and Methods.</i> Here, we present novel clinical and laboratory phenotypes of seven individuals from three families with <i>ETV6</i> 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. <i>Results.</i> Four individuals from two pedigrees harboured one novel or one previously described variant in the central domain of <i>ETV6</i> (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 <i>RUNX1</i> (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 <i>ETV6</i> (c.1136T>C, p.Leu379Pro) along with absence of heterozygosity of chromosome (10)(q21.2q21.3), yielding a biallelic leukaemia risk allele in <i>ARID5B</i> (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. <i>Conclusions.</i> Our clinical observations and results of high-resolution genetic analyses extend the spectrum of possible phenotypes cosegregating with <i>ETV6</i> germline mutations. Further, we propose <i>ARID5B</i> as potential leukaemogenic cofactor in patients with <i>ETV6</i>-linked leukaemia predisposition and familial thrombocytopenia syndrome.