αIIbβ3 variants defined by next-generation sequencing: Predicting variants likely to cause Glanzmann thrombasthenia

• DOI: 10.1073/pnas.1422238112
• Publication Date: 2015-04-01T15:11:09Z
• Authors: Lorena Buitrago; Augusto Rendon; Yupu Liang; Ilenia Simeoni; Ana Negri; ; Marta Filizola; Willem H. Ouwehand; Barry S. Coller; Marie-Christine A...; Matthias Ballmaier; Tadbir Bariana; Daniel Bellissimo; Marta Bertoli; Paul Bray; Loredana Bury; Robin Carrell; Marco Cattaneo; Peter Collins; Deborah French; Remi Favier; Kathleen Freson; Bruce Furie; Manuela Germeshausen; Cedric Ghevaert; Keith Gomez; Anne Goodeve; Paolo Gresele; Jose Guerrero; Dan J. Hampshire; Charaka Hadinnapola; Johan Heemskerk; Yvonne Henskens; Marian Hill; Nancy Hogg; Jill Johnsen; Walter Kahr; Ron Kerr; Shinji Kunishima; Michael Laffan; Amit Natwani; Marguerite Neerma...; Paquita Nurden; Alan Nurden; Mark Ormiston; Maha Othman; Willem Ouwehand; David Perry; Shoshana Ravel Vilk; Pieter Reitsma; Matthew Rondina; Ilenia Simeoni; Peter Smethurst; Jonathan Stephens; William Stevenson; Artur Szkotak; Ernest Turro; Christel Van Geet; Minka Vries; June Ward; John Waye; Sarah Westbury; Sidney Whiteheart; David Wilcox; Bi Zhang
• Keywords: Exome/genetics; Models, Molecular; 0301 basic medicine; Protein Structure; Thrombasthenia/genetics/metabolism; integrin; Protein Conformation; Platelet Glycoprotein GPIIb-IIIa Complex/chemistry/genetics/metabolism; Immunoblotting; Mutation, Missense; Molecular modeling; 610; Integrin; Platelet Glycoprotein GPIIb-IIIa Complex; 576; Databases; 03 medical and health sciences; Gene Frequency; Models; Single-nucleotide variants; Glanzmann; integrin; molecular modeling; next-generation sequencing; single-nucleotide variants; Alleles; Databases, Nucleic Acid; Exome; Fibrinogen; Gene Frequency; HEK293 Cells; High-Throughput Nucleotide Sequencing; Humans; Immunoblotting; Models, Molecular; Platelet Glycoprotein GPIIb-IIIa Complex; Protein Binding; Protein Conformation; Protein Structure, Tertiary; Thrombasthenia; Mutation, Missense; Fibrinogen/chemistry/metabolism; Humans; ddc:576.5; Exome; single-nucleotide variants; Alleles; High-Throughput Nucleotide Sequencing/methods; Nucleic Acid; molecular modeling; info:eu-repo/classification/ddc/576.5; Molecular; Fibrinogen; High-Throughput Nucleotide Sequencing; Protein Structure, Tertiary; 3. Good health; HEK293 Cells; Mutation; Next-generation sequencing; next-generation sequencing; Missense; Glanzmann; Databases, Nucleic Acid; Tertiary; Protein Binding; Thrombasthenia

Significance

Next-generation sequencing is identifying millions of novel gene variants, presenting challenges to researchers and clinicians. Variations in the genes ITGA2B and ITGB3 affect integrin αIIbβ3, leading to the bleeding disorder Glanzmann thrombasthenia. We analyzed novel missense variants on ∼32,000 alleles of ITGA2B and ITGB3 and found missense variants affecting ∼10% of the amino acids in each protein in ∼1.3% of the population. Almost all variants are rare, indicating recent entry into the population. Two novel variants we predicted would be deleterious profoundly affected recombinant protein expression. At cut-off values that correctly predicted at least 69% of the known Glanzmann thrombasthenia mutations as deleterious, three variant prediction algorithms predicted that at least 27% of the novel variants are deleterious.