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

Abstract

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.

Inherited thrombocytopenias: history, advances and perspectives

“…An early example is the ARID5B risk allele for leukemia in patients with ETV6-linked thrombocytopenias. 156 A future step for modern technologies is to identify variants and gene modulators able to influence phenotype and bleeding -either by protecting against or by exaggerating the primary disease. This will be key to improving prognosis and prevention.…”

Identification of clinical implications and potential prognostic models of chromatin regulator mutations in multiple myeloma

“…Loss of ARID1A expression was related to poor outcomes in ovarian clear cell carcinoma [ 25 ]. Mutations of ARID5B might be a potential cofactor in patients with ETV6-linked leukemia predisposition [ 26 ]. Frequent deletions of JARID2 promoted the transformation of chronic myeloid malignancies to leukemia [ 27 ].…”

Hyperdiploidy: the longest known, most prevalent, and most enigmatic form of acute lymphoblastic leukemia in children

“…Predisposing germline factors are unlikely to be directly responsible for the formation of HD precursor cells per se but rather alleviate the immediate survival of independently created cells by equipping them with essential elements that founder cells in non-predisposed individuals are forced to acquire as secondary changes [ 10 ]. The extent to which the occasional concurrence of two or even more such predisposition factors, for instance, ARID5B and ETV6 , will augment the respective risk remains to be determined [ 50 ].…”