Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript
Authors
- L. Wahlster
- J.M. Verboon
- L.S. Ludwig
- S.C. Black
- W. Luo
- K. Garg
- R.A. Voit
- R.L. Collins
- K. Garimella
- M. Costello
- K.R. Chao
- J.K. Goodrich
- S.P. DiTroia
- A. O’Donnell-Luria
- M.E. Talkowski
- A.D. Michelson
- A.B. Cantor
- V.G. Sankaran
Journal
- Journal of Experimental Medicine
Citation
- J Exp Med 218 (6): e20210444
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.