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Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2021 Jun 07; Vol. 218 (6). - Publication Year :
- 2021
-
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.<br />Competing Interests: Disclosures: The authors declare no competing interests exist.<br /> (© 2021 Wahlster et al.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 218
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 33857290
- Full Text :
- https://doi.org/10.1084/jem.20210444