Genomic and Cytogenetic Characterization of a Balanced Translocation Disrupting NUP98Thibodeau M.L.a · Steinraths M.d · Brown L.c · Zong Z.a · Shomer N.b · Taubert S.b · Mungall K.L.f · Ma Y.P.f · Mueller R.e · Birol I.a, f · Lehman A.a, g
aDepartment of Medical Genetics, bCenter for Molecular Medicine and Therapeutics, Rare Disease Group, BC Children's Hospital and cDepartment of Pathology, Cytogenetics Laboratory, University of British Columbia, Vancouver, BC, dDivision of Medical Genetics, Department of Pathology and eDepartment of Laboratory Medicine, Victoria General Hospital, Victoria, BC, fCanada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, and gChild and Family Research Institute, Vancouver, BC, Canada
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A 41-year-old Asian woman with bilateral renal angiomyolipomas (AML) was incidentally identified to have a balanced translocation, 46,XX,t(11;12)(p15.4;q15). She had no other features or family history to suggest a diagnosis of tuberous sclerosis. Her healthy daughter had the same translocation and no renal AML at the age of 3 years. Whole-genome sequencing was performed on genomic maternal DNA isolated from blood. A targeted de novo assembly was then conducted with ABySS for chromosomes 11 and 12. Sanger sequencing was used to validate the translocation breakpoints. As a result, genomic characterization of chromosomes 11 and 12 revealed that the 11p breakpoint disrupted the NUP98 gene in intron 1, causing a separation of the promoter and transcription start site from the rest of the gene. The translocation breakpoint on chromosome 12q was located in a gene desert. NUP98 has not yet been associated with renal AML pathogenesis, but somatic NUP98 alterations are recurrently implicated in hematological malignancies, most often following a gene fusion event. We also found evidence for complex structural events involving chromosome 12, which appear to disrupt the TDG gene. We identified a TDGP1 partially processed pseudogene at 12p12.1, which adds complexity to the de novo assembly. In conclusion, this is the first report of a germline constitutional structural chromosome rearrangement disrupting NUP98 that occurred in a generally healthy woman with bilateral renal AML.
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