Page 272 - 2021_04-Haematologica-web

Letters to the Editor
A homozygous missense variant in UBE2T is associated with a mild Fanconi anemia phenotype
Fanconi anemia (FA) is a rare multi-system disorder characterized by bone marrow failure, congenital abnor- malities, and cancer predisposition.1 Pathogenic variants have been described in 22 known FA genes (FANCA- FANCW) that are required for the proper repair of DNA interstrand crosslinks.2,3 A key step in the repair of inter- strand crosslinks is FA pathway activation via monoubiq- uitination of FANCD2 and FANCI by FANCL, an E3 ubiq- uitin-ligase working with UBE2T/FANCT, an E2 ubiqui- tin-conjugating enzyme.4-7 Pathogenic germline variants in UBE2T have been described in three individuals with FA;6-8 thus, the knowledge of the phenotypic spectrum is limited for the FA-T complementation group. Here we describe a mild presentation of FA resulting from a hypo- morphic missense variant in UBE2T that partially dis- rupts the function of the encoded protein. This report highlights the importance of an algorithmic approach to bone marrow failure that combines genetic testing and functional cellular assays.9
Three patients have previously been reported with biallelic pathogenic variants in UBE2T consistent with an autosomal recessive disease. All three patients presented with the classic features of FA (Online Supplementary Table S1).6-8 Hira et al. reported two unrelated patients both
harboring a c.4C>G, p.Gln2Glu missense variant in trans with either a 23 kb whole gene deletion (patient 1) or a c.180+5G>A, p.Gln37Argfs*47 frameshift variant (patient 2). Both patients developed hematologic abnormalities and bone marrow failure. Patient 2 developed myelodys- plastic syndrome which evolved to acute myeloid leukemia. Both patients required hematopoietic stem cell transplantation.7 Rickman et al. and Virts et al. reported the findings of a maternally inherited Alu-mediated duplication, c.-64_468dup, producing an unstable tran- script and a paternally inherited Alu-mediated deletion, c.-64_468del, leading to loss of the majority of the gene. However, this patient did not develop bone marrow fail- ure as a result of somatic mosaicism identified in his peripheral blood.6,8
The patient reported here is a 22-year-old Hispanic female who was unaffected at birth, had a normal devel- opmental history, and a negative family history with no reported consanguinity. She originally presented to an another institution at 8 years of age and was reported to have mild neutropenia and thrombocytopenia; a bone marrow biopsy at that time was non-diagnostic. At 21 years, the patient presented with persistent neutropenia and macrocytosis, intermittent thrombocytopenia, episodic fevers, an urticarial erythematous rash, and metromenorrhagia (Online Supplementary Tables S1 and S2). No developmental anomalies or cutaneous hypo/hyperpigmentation were noted. Chromosomal
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haematologica | 2021; 106(4)