Abstract Number: OC 68.1
Meeting: ISTH 2022 Congress
Background: There is an increasing understanding of the relationship between rare coding pathogenic variants and their clinical sequelae. However, for bleeding, platelet, and thrombotic disorders (BPD) a large portion of heritable cases remain without a molecular diagnosis. We have shown that some of these unexplained cases are caused by non-coding variants in the gene-regulatory space (Turro et al., 2020).
Aims: This study aims to identify the regulatory regions of 93 diagnostic-grade BPD genes (Megy et al. 2019) in relevant cell types to increase the heritable-BPD diagnostic yield.
Methods: We differentiated human induced pluripotent stem cells into megakaryocytes, endothelial cells and hepatocytes. A capture Hi-C approach was used to identify regulatory regions of the 93 BPD genes (BPD-regulome hereafter) in these cells. The BPD-regulome was further constrained using statistical and experimental methods. We overlaid epigenetic features, RedPop and applied the BeviMed statistical approach (Greene et al., 2016; Turro et al., 2020). We searched the whole-genome-sequencing (WGS) data of 838 unexplained heritable BPD cases for putative pathogenic variants in the BPD-regulome, and measured their effects on transcription in reporter assays.
Results: We produced the highest resolution interaction maps to date for the 93 BPD genes, identifying 62,027 interactions to putative regulatory elements. This framework identified 31 possible associations between rare variants in the BPD-regulome of unexplained cases at a posterior probability >0.7. Moreover, a visual review of structural variants overlapping the BPD-regulome identified three possibly explanatory aberrations, including the recently described pathogenic deletion in the HDAC6-GATA1 locus (Turro et al. 2020). Finally, we showed that seven of these variants in the BPD-regulome alter gene expression in reporter assays.
Conclusion(s): We generated a high-resolution map of the BPD-regulome in the relevant cell types. The regulatory regions defined in this study lay the foundation to explore WGS-data from unexplained BPD cases for causal variants.
To cite this abstract in AMA style:Stefanucci L, Sims M, Lambourne J, Burden F, Grassi L, Seyres D, Stephens J, Tomaz R, Lugtu F, Greene D, Owens N, Megy K, Sivapalaratnam S, Freson K, Vallier L, Turro E, Ouwehand W, Frontini M. Identification of non-coding genomic regions involved in the aetiology of bleeding, platelet, and thrombotic disorders. [abstract]. https://abstracts.isth.org/abstract/identification-of-non-coding-genomic-regions-involved-in-the-aetiology-of-bleeding-platelet-and-thrombotic-disorders/. Accessed September 29, 2023.
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