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Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript

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Item Type:Article
Title:Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript
Creators Name:Wahlster, L. and Verboon, J.M. and Ludwig, L.S. and Black, S.C. and Luo, W. and Garg, K. and Voit, R.A. and Collins, R.L. and Garimella, K. and Costello, M. and Chao, K.R. and Goodrich, J.K. and DiTroia, S.P. and O’Donnell-Luria, A. and Talkowski, M.E. and Michelson, A.D. and Cantor, A.B. and Sankaran, V.G.
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.
Keywords:Cell Line, Chromosome Breakage, Chromosome Disorders, Exome, HEK293 Cells, HeLa Cells, Intercellular Signaling Peptides and Proteins, Mutation, Pedigree, Signal Transducing Adaptor Proteins, Single Nucleotide Polymorphism, Thrombocytopenia, Tumor Cell Line
Source:Journal of Experimental Medicine
Publisher:Rockefeller University Press
Page Range:e20210444
Date:7 June 2021
Official Publication:https://doi.org/10.1084/jem.20210444
PubMed:View item in PubMed

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