title: Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects.
abstract: 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 11×109/L to 186×109/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.
authors.affiliation: Institute for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Johnson
authors.affiliation: Institute for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, UK.
authors.forename: Gillian C
authors.initials: GC
authors.lastname: Lowe
authors.affiliation: Institute for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Futterer
authors.affiliation: Institute for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, UK.
authors.forename: Marie
authors.initials: M
authors.lastname: Lordkipanidzé
authors.affiliation: Institute for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, UK.
authors.forename: David
authors.initials: D
authors.lastname: MacDonald
authors.affiliation: Division of Genetics and Molecular Medicine, King's College, London, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.affiliation: Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Sanchez-Guiú
authors.affiliation: Institute for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Drake
authors.affiliation: Institute for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, UK.
authors.forename: Danai
authors.initials: D
authors.lastname: Bem
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, University of Sheffield, UK.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Leo
authors.affiliation: Institute for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Fletcher
authors.affiliation: Institute for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, UK.
authors.forename: Ban
authors.initials: B
authors.lastname: Dawood
authors.affiliation: Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Rivera
authors.affiliation: Hull Haemophilia Treatment Centre, Hull and East Yorkshire Hospitals NHS Trust, Castle Hill Hospital, Hull, UK.
authors.forename: David
authors.initials: D
authors.lastname: Allsup
authors.affiliation: Department of Haematology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK.
authors.forename: Tina
authors.initials: T
authors.lastname: Biss
authors.affiliation: Department of Haematology, Manchester Royal Infirmary, Manchester, UK.
authors.forename: Paula Hb
authors.initials: PH
authors.lastname: Bolton-Maggs
authors.affiliation: Arthur Bloom Haemophilia Centre, School of Medicine, Cardiff University, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Collins
authors.affiliation: Oxford Haemophilia & Thrombosis Centre, Churchill Hospital, Oxford, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Curry
authors.affiliation: Nottingham Haemophilia Centre, Nottingham University Hospital, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Grimley
authors.affiliation: Regional Centre for Paediatric Haematology, Leeds Children's Hospital, UK.
authors.forename: Beki
authors.initials: B
authors.lastname: James
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, University of Sheffield, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Makris
authors.affiliation: Department of Haematology, Birmingham Children's Hospital, UK.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Motwani
authors.affiliation: Department of Haematology, Oxford University Hospitals NHS Foundation Trust, UK.
authors.forename: Sue
authors.initials: S
authors.lastname: Pavord
authors.affiliation: Department of Haematology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Talks
authors.affiliation: Department of Haematology, Manchester Royal Infirmary, Manchester, UK.
authors.forename: Jecko
authors.initials: J
authors.lastname: Thachil
authors.affiliation: Adult Haemophilia Centre, Queen Elizabeth Hospital, Birmingham, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wilde
authors.affiliation: Department of Haematology, Birmingham Children's Hospital, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Williams
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Harrison
authors.affiliation: Medical Research Council, Laboratory for Molecular Cell Biology, University College London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.affiliation: School of Physiology, Pharmacology and Neuroscience, University of Bristol, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Mundell
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mumford
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, University of Sheffield, UK.
authors.forename: Martina E
authors.initials: ME
authors.lastname: Daly
authors.affiliation: Institute for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, UK.
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
authors.affiliation: Institute for Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, UK n.v.morgan@bham.ac.uk.
authors.forename: Neil V
authors.initials: NV
authors.lastname: Morgan
mesh_terms: D001792:Blood Platelets / Q000473:pathology; D059472:Exome / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020125:Mutation, Missense; D010976:Platelet Count; D013921:Thrombocytopenia / Q000235:genetics*