PS1476 APPLICATION OF WHOLE EXOME SEQUENCING FOR PATIENTS WITH INHERITED PLATELET DISORDERS

Abstract

Background:Inherited platelet disorders (IPDs) are disorders consisting of thrombocytopenia, thromobocytopathy or a combination of these. Diagnosis is often hampered by the lack of specificity and correct validation of current hematological assays. In addition, these disorders exhibit a genetic heterogeneity with over 50 genes involved.Aims:This study evaluates an upfront diagnostic strategy using whole‐exome sequencing (WES) with a targeted analysis of a panel of 145 genes involved in thrombosis and hemostasis in patients suspected for an IPD.Methods:Sixty‐Six patients suspicious for an IPD were subjected to WES, followed by targeted analysis of 145 genes (besides platelet genes also genes involved in coagulation and venous thrombosis embolism are analyzed). Variants were classified according to the five‐tier (class 1 to class 5) scheme.Results:Fourteen patients (21%) harbored (likely) pathogenic variants that explained the clinical spectrum in these patients. Genes affected in these patients were GP9, MYH9 (2 cases), NBEAL2, P2RY12, RUNX1 (3 cases), SLFN14 and VWF (2 cases), all these genes are involved in thrombocytopenia or thromobocytopathy. In the disorders with an autosomal recessive mode of inheritance either the mutation was homozygous (GP9 and P2RY12), or compound heterozygous (NBEAL2). Additionally, 2 patients with a mutation in the THPO gene and 1 patient with a mutation in SEPRINC1 were observed, both genes are known to be involved in venous thrombosis.In 4 (6%) other patients only one heterozygous (likely) pathogenic variant of an autosomal recessive disease gene was observed. In 12 patients (18%) a variant of unknown significance (VUS/class 3) was observed. Further segregation studies within the family and functional studies are required to fully solve these cases.Summary/Conclusion:We found that WES is a powerful tool in genetically diagnosing patients with IPD.