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

Author:

Wahlster Lara123ORCID,Verboon Jeffrey M.123ORCID,Ludwig Leif S.123ORCID,Black Susan C.123ORCID,Luo Wendy123ORCID,Garg Kopal123ORCID,Voit Richard A.123ORCID,Collins Ryan L.34ORCID,Garimella Kiran3ORCID,Costello Maura3ORCID,Chao Katherine R.3ORCID,Goodrich Julia K.3ORCID,DiTroia Stephanie P.3ORCID,O’Donnell-Luria Anne3ORCID,Talkowski Michael E.34ORCID,Michelson Alan D.12ORCID,Cantor Alan B.12ORCID,Sankaran Vijay G.123ORCID

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

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.

Funder

Lodish Family

National Institutes of Health

Broad Institute

National Eye Institute

National Heart, Lung, and Blood Institute

National Human Genome Research Institute

Seventh Framework Programme

New York Stem Cell Foundation

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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