Enter Note Done


Keywords: Hematopoietic system; Exome sequencing; Rare variants

A. Ferrer 1; L. Schultz-Rogers 1; A. Mangaonkar 2; N. Jacobi 3; M. Litzow 2; E. Klee 1,4; M. Patnaik 2

1) Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.; 2) Department of Hematology, Mayo Clinic, Rochester, Minnesota; 3) Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota; 4) Hennepin Healthcare, Minneapolis, Minnesota

Fanconi Anemia (FA) is characterized by genomic instability, bone marrow failure and skeletal abnormalities. Several subtypes of FA have been described and associated with variants in different genes. The FA complementation group T (FA-T) is caused by variants in UBE2T. Only 3 patients with (FA-T) have been reported to date, all carrying at least one loss-of-function (LoF) variant. Here we report a fourth FA-T case and the first one caused by a homozygous missense variant in UBE2T.

A 21-year-old Ecuadorian female presented to the Bone Marrow Failure Precision Medicine Clinic (Mayo Clinic, MN) for assessment. She reported periodic fevers, persistent macrocytosis and intermittent cytopenias since 8 years of age. Her last complete blood count (October 2018) indicated anemia, thrombocytopenia and increased MCV. Her bone marrow was moderately hypocellular (40% to 50%) without evidence of dysplasia or lymphoproliferation. Other phenotypes included urticaria, discoloration of hands with cold and intermittent ulcers on lips. Previous genetic testing including cytogenetics and a periodic fever gene panel were negative, as well as testings for autoimmunity and infectious diseases. No related family history or consanguinity was described.

The patient underwent a custom-designed XomeDSlice panel through GeneDX that uncovered a homozygous variant in UBE2T (c.196C>T; p.P66T) not reported in gnomAD or associated with disease (ClinVar and HGMD). The encoded proline is highly conserved across species and located in the UBC fold domain, critical for protein function. In silico tools (SIFT, MutationTaster, PolyPhen2, MCAP and PredictSNP2) agreed on a deleterious effect. To confirm this, a chromosomal breakage assay was performed and resulted positive (58% and 36% breakage positive cells with MMC and DEB, respectively) in line with previous FA-T reported. Complementation testing is currently underway. With these results we classified the variant as likely pathogenic by ACMG criteria.

This is the first FA-T patient reported with a homozygous missense likely pathogenic variant in UBE2T. This variant may cause a milder effect in the UBE2T function compared to the other three reported patients harboring one loss of function variant, possibly explaining the lack of skeletal finding in the proband. However, more research is needed to confirm this hypothesis. This case adds to our knowledge of FA-T causal variants and highlights the relevance of including UBE2T in FA evaluations.