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Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects

Lookup NU author(s): Dr Tina Biss, Dr Katherine Talks


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Inherited thrombocytopenias are a heterogeneous group of disorders characterized by abnormally low platelet counts which can be associated with abnormal bleeding. Next-generation sequencing has previously been employed in these disorders for the confirmation of suspected genetic abnormalities, and more recently in the discovery of novel disease-causing genes. However its full potential has not yet been exploited. Over the past 6 years we have sequenced the exomes from 55 patients, including 37 index cases and 18 additional family members, all of whom were recruited to the UK Genotyping and Phenotyping of Platelets study. All patients had inherited or sustained thrombocytopenia of unknown etiology with platelet counts varying from 11x10(9)/L to 186x10(9)/L. Of the 51 patients phenotypically tested, 37 (73%), had an additional secondary qualitative platelet defect. Using whole exome sequencing analysis we have identified "pathogenic" or "likely pathogenic" variants in 46% (17/37) of our index patients with thrombocytopenia. In addition, we report variants of uncertain significance in 12 index cases, including novel candidate genetic variants in previously unreported genes in four index cases. These results demonstrate that whole exome sequencing is an efficient method for elucidating potential pathogenic genetic variants in inherited thrombocytopenia. Whole exome sequencing also has the added benefit of discovering potentially pathogenic genetic variants for further study in novel genes not previously implicated in inherited thrombocytopenia.

Publication metadata

Author(s): Johnson B, Lowe GC, Futterer J, Lordkipanidze M, MacDonald D, Simpson MA, Sanchez-Guiu I, Drake S, Bem D, Leo V, Fletcher SJ, Dawood B, Rivera J, Allsup D, Biss T, Bolton-Maggs PHB, Collins P, Curry N, Grimley C, James B, Makris M, Motwani J, Pavord S, Talks K, Thachil J, Wilde J, Williams M, Harrison P, Gissen P, Mundell S, Mumford A, Daly ME, Watson SP, Morgan NV, UK GAPP Study Grp

Publication type: Article

Publication status: Published

Journal: Haematologica

Year: 2016

Volume: 101

Issue: 10

Pages: 1170-1179

Print publication date: 01/10/2016

Acceptance date: 10/06/2016

ISSN (print): 0390-6078

Publisher: Ferrata Storti Foundation


DOI: 10.3324/haematol.2016.146316


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Funder referenceFunder name
Department of Health via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Award to Guy's & St Thomas' NHS Foundation Trust
King's College Hospital NHS Foundation Trust
Platelet Charity
Healing Foundation
King's College London
Queen Elizabeth Hospital Charity
093994Wellcome Trust
RG/09/007British Heart Foundation
RG/PG/13/36/30275British Heart Foundation