Familial thrombocytopenia: The long and short of it

Abstract

In this issue, Wahlster, Verboon, and colleagues (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210444) describe a multigenerational family with inherited thrombocytopenia where the causal variant was not identified using conventional genome sequencing approaches. Long-read sequencing and RNA sequencing revealed a complex structural variant, causing overexpression of a pathogenic gain-of-function WAC-ANKRD26 fusion transcript.

Insights from Murphy and Mead.

Schematic demonstrating normal and aberrant ANKRD26 expression in healthy individuals and those with TCH2. (A) The binding of transcription factors (TF) RUNX1 and FLI1 to the promotor region of ANKRD26 results in silencing of ANKRD26 and reduced MAPK–ERK signaling leading to normal megakaryocyte maturation, proplatelet formation, and platelet release. (B) A mutation in the 5′ untranslated region (UTR) of ANKRD26 prevents binding of RUNX1 and FLI1 and the repression of the gene. This leads to hyperactivation of the MAPK–ERK pathway, resulting in impaired proplatelet formation in THC2 individuals. (C) A complex structural variant results in a WAC-ANKRD26 fusion transcript encoding a functional truncated form of ANKRD26. Overexpression of this gene, driven by the active WAC promoter, likely leads to increased MAPK activation mirroring the phenotype seen in conventional THC2. Adapted from Bluteau et al., 2014 and created with BioRender.com (2021).