Complications of whole-exome sequencing for causal gene discovery in primary platelet secretion defects
| Autor: | Anna Lecchi, Flora Peyvandi, Silvia La Marca, Andrea Cairo, Andrea Artoni, Marcin M. Gorski, Luca A. Lotta, Emanuela Pappalardo, Eti A. Femia |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male Candidate gene Pilot Projects Hematology Computational biology Middle Aged FCGR2A Biology Phenotype Article Platelet Biology & its Disorders 03 medical and health sciences 0302 clinical medicine PRKCD Child Preschool Exome Sequencing Humans Missense mutation Female Blood Platelet Disorders Candidate Gene Analysis Gene Exome sequencing 030215 immunology |
| Zdroj: | Haematologica |
| ISSN: | 1592-8721 0390-6078 |
| DOI: | 10.3324/haematol.2018.204990 |
| Popis: | 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 family analysis confirmed a missense variant p.D1144N in the STXBP5L gene and p.P83H in the KCNMB3 gene as potentially causal. In summary, exome sequencing revealed potential causal variants in 12 of 14 patients with primary platelet secretion defects, highlighting the limitations of the genomic approaches for causal gene identification in this heterogeneous clinical and laboratory phenotype. |
| Databáze: | OpenAIRE |
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