1. Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript.
- Author
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Wahlster L, Verboon JM, Ludwig LS, Black SC, Luo W, Garg K, Voit RA, Collins RL, Garimella K, Costello M, Chao KR, Goodrich JK, DiTroia SP, O'Donnell-Luria A, Talkowski ME, Michelson AD, Cantor AB, and Sankaran VG
- Subjects
- Adolescent, Adult, Aged, Cell Line, Cell Line, Tumor, Child, Chromosome Breakage, Chromosome Disorders genetics, Exome genetics, Female, HEK293 Cells, HeLa Cells, Humans, Male, Middle Aged, Mutation genetics, Pedigree, Thrombocytopenia congenital, Adaptor Proteins, Signal Transducing genetics, Intercellular Signaling Peptides and Proteins genetics, Polymorphism, Single Nucleotide genetics, Thrombocytopenia genetics
- 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., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 Wahlster et al.)
- Published
- 2021
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