αIIbß3 variants defined by next-generation sequencing: predicting variants likely to cause Glanzmann thrombasthenia.
Proc Natl Acad Sci U S A
; 112(15): E1898-907, 2015 Apr 14.
Article
in En
| MEDLINE
| ID: mdl-25827233
ABSTRACT
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 αIIbß3 receptor subunit genes ITGA2B and ITGB3 identified by whole-exome or -genome sequencing in the ThromboGenomics project, comprising â¼32,000 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 â¼11% of the amino acids) and 68 novel missense variants in ITGB3 (affecting â¼9% 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 αIIbß3, we selected three novel variants that affect amino acids previously associated with GT for expression in HEK293 cells. αIIb P176H and ß3 C547G severely reduced αIIbß3 expression, whereas αIIb P943A partially reduced αIIbß3 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 αIIb or ß3 missense variants were predicted to be deleterious. Our data have implications for understanding the evolutionary pressure on αIIbß3 and highlight the challenges in predicting the clinical significance of novel missense variants.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thrombasthenia
/
Platelet Glycoprotein GPIIb-IIIa Complex
/
Mutation, Missense
/
High-Throughput Nucleotide Sequencing
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2015
Document type:
Article