Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 15, Pages E1898-E1907Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1422238112
Keywords
Glanzmann; integrin; single-nucleotide variants; next-generation sequencing; molecular modeling
Categories
Funding
- National Heart, Lung and Blood Institute [HL19278]
- National Center for Advancing Translational Sciences, National Institutes of Health Clinical and Translational Science Award program [UL1 TR000043]
- Stony Brook University
- British Heart Foundation [RG/09/012/28096] Funding Source: researchfish
- Medical Research Council [MR/K023489/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10214, RP-PG-0310-1002, NF-SI-0513-10151] Funding Source: researchfish
- MRC [MR/K023489/1] Funding Source: UKRI
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Next-generation sequencing is transforming our understanding of human genetic variation but assessing the functional impact of novel variants presents challenges. We analyzed missense variants in the integrin alpha IIb beta 3 receptor subunit genes ITGA2B and ITGB3 identified by whole-exome or -genome sequencing in the Thrombo-Genomics project, comprising similar to 32,000 alleles from 16,108 individuals. We analyzed the results in comparison with 111 missense variants in these genes previously reported as being associated with Glanzmann thrombasthenia (GT), 20 associated with alloimmune thrombocytopenia, and 5 associated with aniso/macrothrombocytopenia. We identified 114 novel missense variants in ITGA2B (affecting similar to 11% of the amino acids) and 68 novel missense variants in ITGB3 (affecting similar to 9% of the amino acids). Of the variants, 96% had minor allele frequencies (MAF) < 0.1%, indicating their rarity. Based on sequence conservation, MAF, and location on a complete model of alpha IIb beta 3, we selected three novel variants that affect amino acids previously associated with GT for expression in HEK293 cells. alpha IIb P176H and beta 3 C547G severely reduced alpha IIb beta 3 expression, whereas aIIb P943A partially reduced alpha IIb beta 3 expression and had no effect on fibrinogen binding. We used receiver operating characteristic curves of combined annotation-dependent depletion, Polyphen 2-HDIV, and sorting intolerant from tolerant to estimate the percentage of novel variants likely to be deleterious. At optimal cut-off values, which had 69-98% sensitivity in detecting GT mutations, between 27% and 71% of the novel aIIb or beta 3 missense variants were predicted to be deleterious. Our data have implications for understanding the evolutionary pressure on alpha IIb beta 3 and highlight the challenges in predicting the clinical significance of novel missense variants.
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