Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript |
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| Authors: | Lara Wahlster,Jeffrey M. Verboon,Leif S. Ludwig,Susan C. Black,Wendy Luo,Kopal Garg,Richard A. Voit,Ryan L. Collins,Kiran Garimella,Maura Costello,Katherine R. Chao,Julia K. Goodrich,Stephanie P. DiTroia,Anne O&#x Donnell-Luria,Michael E. Talkowski,Alan D. Michelson,Alan B. Cantor,Vijay G. Sankaran |
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| Affiliation: | 1. Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA ; 2. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA ; 3. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA ; 4. Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA |
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| Abstract: | Advances in genome sequencing have resulted in the identification of the causes for numerous rare diseases. However, many cases remain unsolved with standard molecular analyses. We describe a family presenting with a phenotype resembling inherited thrombocytopenia 2 (THC2). THC2 is generally caused by single nucleotide variants that prevent silencing of ANKRD26 expression during hematopoietic differentiation. Short-read whole-exome and genome sequencing approaches were unable to identify a causal variant in this family. Using long-read whole-genome sequencing, a large complex structural variant involving a paired-duplication inversion was identified. Through functional studies, we show that this structural variant results in a pathogenic gain-of-function WAC-ANKRD26 fusion transcript. Our findings illustrate how complex structural variants that may be missed by conventional genome sequencing approaches can cause human disease. |
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