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


  • 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 of Experimental Medicine


  • J Exp Med 218 (6): e20210444


  • 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.