EP406: Germline 16p13.1 microdeletion identified during routine hematologic testing

Abstract

Inversion 16 or translocation 16;16, resulting in CBFB::MYH11 fusion, accounts for approximately 5–8% of acute myeloid leukemia (AML) and is recognized by the World Health Organization (WHO) as a distinct entity within the category of AML with recurrent genetic abnormalities. It is critical to correctly characterize AML patients with CBFB::MYH11 fusion for appropriate diagnosis and the association with a favorable clinical prognosis (a high rate of complete remission and favorable overall survival). However, germline microdeletions spanning the MYH11 gene region are associated with a rare, but recurrent, 16p13.1microdeletion syndrome. We present this case series to highlight the risk of neoplastic versus germline mutational results involving the MYH11 locus and to initiate a discussion on standardization for reporting incidental germline findings in the setting of hematologic testing. We performed a retrospective review of the Mayo Clinic Cytogenetics Database and identified four cases that were tested using the Mayo homebrew CBFB::MYH11 dual-color, dual-fusion FISH (D-FISH) probe strategy and had a probable MYH11 germline microdeletion (Table 1). In 3 of 4 cases, loss of the MYH11 probe was observed in the absence of CBFB::MYH11 gene fusion. Since the MYH11 deletion was identified in 97-100% of nuclei in each of these cases, this result strongly suggested a germline 16p deletion. In addition, a MYH11 gene deletion is not associated with diagnostic or prognostic significance in the context of myeloid neoplasia. Germline 16p13.1 microdeletion syndrome is characterized by a broad spectrum of clinical phenotypes, with the most severely affected having intellectual disability, epilepsy and additional phenotypic features. However, the 16p13.1 microdeletion has also been identified in individuals with very mild clinical phenotypes and in apparently normal individuals, suggesting either incomplete penetrance and/or variable expressivity of the phenotype. In 3 of 4 patient cases identified in this study through an initial hematologic evaluation, additional studies were recommended to document the constitutional origin of the MYH11 gene deletion. To our knowledge, none of these cases pursued follow-up germline testing. However, in one patient (patient 2) FISH performed at diagnosis showed CBFB::MYH11 fusion in addition to the MYH11 deletion. A follow-up bone marrow specimen demonstrated no evidence of CBFB::MYH11 fusion, but the MYH11 deletion persisted, representing additional evidence for a constitutional deletion of the MYH11 gene region in this patient. These cases illustrate the possibility of discovering incidental constitutional abnormalities when performing testing on hematologic neoplasms. Currently there are no defined guidelines for the detection and reporting of possible germline alterations detected by conventional cytogenetic methods in hematologic disease. Consequently, patients may not be counselled appropriately, and testing consent forms in cancer settings often do not address the possibility of the discovery of germline abnormalities. These cases highlight a need of standardization for reporting incidental germline findings from hematologic testing by clinical laboratories as well as consenting and genetic counselling from the clinical perspective.Tabled 1Age (years)SexReason for referralSpecimennuc ish(MYH11x1,CBFBx2) %Additional clonal abnormalitiesPatient 122FemaleAcute myeloid leukemiaBone marrow100.0NoPatient 259FemaleInversion 16 at diagnosisBone marrow99.6UnknownPatient 339FemaleAcute myeloid leukemia relapseBlood97.4NoPatient 459FemalePancytopeniaBone marrow100.0No Open table in a new tab