Molecular diagnosis of inherited platelet disorder via a targeted whole-exome virtual gene panel: a 5-year...

Inherited platelet disorders represent a prevalent but inadequately understood subset of bleeding diatheses, often with elusive causative genetics. The low rate of molecular diagnoses highlights the critical need for advanced genetic tools to enhance risk stratification and therapeutic personalization.

To address this, we retrospectively reviewed our institutional experience using a whole exome sequencing-based platelet virtual gene panel in patients with suspected inherited platelet disorders to determine the frequency of variant identification, rate of diagnosis assignment, and clinical phenotype associated with variants in the 67 evaluated genes.

Testing was performed clinically on 409 patients with genetically undefined platelet function abnormality and/or thrombocytopenia. Results of each gene panel underwent expert review by faculty in human genetics and hematology.

Of the 409 patients analyzed, 59 (14%) had variants that were deemed diagnostic for their clinical phenotypes: 37 associated primarily with thrombocytopenia, 4 with platelet function defects, and 18 impacting both platelet number and function. Notably, 22 diagnostic variants were identified in genes associated with familial myelodysplastic syndrome or leukemia, underscoring the far-reaching clinical implications of this testing.

The whole exome sequencing-based virtual panel approach thus provides molecular diagnoses that would otherwise remain elusive, offering patients and families both a diagnostic clarity and crucial information for genetic counseling and medical management. Moreover, the identification of variants associated with hematologic malignancies expands the scope of implications of risk stratification beyond that of platelet pathology, to include informed decision making about surveillance for malignant transformation.