Complications of whole-exome sequencing for causal gene discovery in primary platelet secretion defects

Haematologica
Marcin M GorskiFlora Peyvandi

Abstract

Primary platelet secretion defects constitute a heterogeneous group of functional defects characterized by reduced platelet granule secretion upon stimulation by different agonists. The clinical and laboratory heterogeneity of primary platelet secretion defects warrants a tailored approach. We performed a pilot study in order to develop DNA sequence analysis pipelines for gene discovery and to create a list of candidate causal genes for platelet secretion defects. Whole-exome sequencing analysis of 14 unrelated Italian patients with primary secretion defects and 16 controls was performed on Illumina HiSeq. Variant prioritization was carried out using two filtering approaches: identification of rare, potentially damaging variants in platelet candidate genes or by selecting singletons. To corroborate the results, exome sequencing was applied in a family in which platelet secretion defects and a bleeding diathesis were present. Platelet candidate gene analysis revealed gene defects in 10/14 patients, which included ADRA2A, ARHGAP1, DIAPH1, EXOC1, FCGR2A, ITPR1, LTBP1, PTPN7, PTPN12, PRKACG, PRKCD, RAP1GAP, STXBP5L, and VWF The analysis of singletons identified additional gene defects in PLG and PHACTR2 in two other patients. The f...Continue Reading

Methods Mentioned

BETA
genotyping
exome sequencing
chromosomal aberration

Software Mentioned

Genome Analysis Tool Kit
Short Oligonucleotide Analysis Package aligner soap2
Database for Annotation , Visualization and Integrated Discove...

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