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

J Exp Med. 2021 Jun 7;218(6):e20210444. doi: 10.1084/jem.20210444.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adolescent
  • Adult
  • Aged
  • Cell Line
  • Cell Line, Tumor
  • Child
  • Chromosome Breakage
  • Chromosome Disorders / genetics
  • Exome / genetics
  • Female
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Male
  • Middle Aged
  • Mutation / genetics
  • Pedigree
  • Polymorphism, Single Nucleotide / genetics*
  • Thrombocytopenia / congenital
  • Thrombocytopenia / genetics*

Substances

  • ANKRD26 protein, human
  • Adaptor Proteins, Signal Transducing
  • Intercellular Signaling Peptides and Proteins
  • WAC protein, human

Supplementary concepts

  • Thrombocytopenia chromosome breakage