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

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’Donnell-Luria, Michael E. Talkowski, Alan D. Michelson, Alan B. Cantor, Vijay G. Sankaran

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Article numbere20210444
JournalJournal of Experimental Medicine
Volume218
Issue number6
DOIs
StatePublished - Apr 15 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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