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.
Highlights
Recent progress in genome sequencing has enabled insights variants (SNVs) that de-repress ANKRD26 expression during into the cause of a range of rare diseases, including numerous megakaryocytic differentiation (Bluteau et al, 2014; Marconi congenital blood disorders (Hartley et al, 2020; Liggett and et al, 2017)
thrombocytopenia 2 (THC2) is generally characterized by thrombocySankaran, 2020; Thaventhiran et al, 2020; Turro et al, 2020). topenia accompanied by altered hematopoiesis and predisDespite these important technological and computational ad- position to myeloid malignancies
Here, we describe a multigenerational family affected with a phenotype resembling THC2 characterized by congenital thrombocytopenia (Pippucci et al, 2011)
Summary
Recent progress in genome sequencing has enabled insights variants (SNVs) that de-repress ANKRD26 expression during into the cause of a range of rare diseases, including numerous megakaryocytic differentiation (Bluteau et al, 2014; Marconi congenital blood disorders (Hartley et al, 2020; Liggett and et al, 2017). To directly assess the altered transcription occurring due to this SV, we performed RNA sequencing on peripheral blood mononuclear cells (PBMCs) from three affected probands (I-2, II-2, and II-3) and three unrelated healthy controls Alignment of these data demonstrated large numbers of both reads where a single read spanned WAC exon 1 and ANKRD26 exon 10 as well as paired reads wherein one read mapped to WAC and the other to ANKRD26 (Fig. 2 C). We noted significantly increased levels of ERK phosphorylation with either the overexpression of full-length or the exon 11+–truncated ANKRD26 in HSPCs, whereas this was not the case with the control empty vector (Fig. 3, E–H) This finding directly demonstrates that increased and deregulated expression of a truncated form of ANKRD26 is sufficient to result in increased MAPK activation downstream of the TPO receptor and in a larger fraction of HSPCs than is observed normally (Gibbs et al, 2011; Kaushansky, 2006)
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