A comprehensive targeted next-generation sequencing panel for genetic diagnosis of patients with suspected inherited thrombocytopenia

Johnson, Ben; Doak, Rachel; Allsup, David; Astwood, Emma; Evans, Gillian; Grimley, Charlotte; James, Beki; Myers, Bethan; Stokley, Simone; Thachil, Jecko; Wilde, Jonathan; Williams, Mike; Makris, Mike; Lowe, Gillian C.; Wallis, Yvonne; Daly, Martina E.; Morgan, Neil V.; the UK GAPP Study Group

Abstract

Background: Inherited thrombocytopenias (ITs) are a heterogeneous group of disorders characterized by low platelet counts and often disproportionate bleeding with over 30 genes currently implicated. Previously the UK-GAPP study using whole exome sequencing (WES) identified a pathogenic variant in 19 of 47 (40%) patients of which 71% had variants in genes known to cause IT. Aims: To employ a targeted next-generation sequencing platform to improve efficiency of diagnostic testing and reduce overall costs. Methods: We have developed an IT-specific gene panel as a pre-screen for patients prior to WES using the Agilent SureSelectQXT transposon-based enrichment system. Results: Thirty-one patients were analyzed using the panel-based sequencing, of which; 10% (3/31) were identified with a classified pathogenic variant, 16% (5/31) were identified with a likely pathogenic variant, 51% (16/31) were identified with variants of unknown significance, and 23% (7/31) were identified with either no variant or a benign variant. Discussion and Conclusion: Although requiring further clarification of the impact of the genetic variations, the application of an IT-specific next generation sequencing panel is an viable method of pre-screening patients for variants in known IT-causing genes prior to WES. With an added benefit of distinguishing IT from idiopathic thrombocytopenic purpura (ITP) and the potential to identify variants in genes known to have a predisposition to hematological malignancies, it could become a critical step in improving patient clinical management.

Citation

Johnson, B., Doak, R., Allsup, D., Astwood, E., Evans, G., Grimley, C., …the UK GAPP Study Group. (2018). A comprehensive targeted next-generation sequencing panel for genetic diagnosis of patients with suspected inherited thrombocytopenia. Research and Practice in Thrombosis and Haemostasis, 2(4), 640-652. https://doi.org/10.1002/rth2.12151

• Journal Article Type: Article
• Acceptance Date: Aug 20, 2018
• Online Publication Date: Oct 8, 2018
• Publication Date: Oct 1, 2018
• Deposit Date: Oct 8, 2018
• Publicly Available Date: Oct 8, 2018
• Journal: Research and Practice in Thrombosis and Haemostasis
• Print ISSN: 2475-0379
• Electronic ISSN: 2475-0379
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 2
• Issue: 4
• Pages: 640-652
• DOI: https://doi.org/10.1002/rth2.12151
• Keywords: Bleeding; Gene mutations; Targeted panel sequencing; Thrombocytopenia
• Public URL: https://hull-repository.worktribe.com/output/1104710
• Publisher URL: https://onlinelibrary.wiley.com/doi/abs/10.1002/rth2.12151