Diagnostic approach to inherited thrombocytopenias in a low-income setting

Abstract

Background: Inherited thrombocytopenias (IT) remain a diagnostic challenge due to clinical and genetic heterogeneity. Although more than 30 genes have been identified, the underlying abnormality is unknown in half of the patients. Advent of next-generation technologies represented significant advances although access is limited in low-income economies. Aims:To rationalize resources for IT diagnosis in Argentina. Methods:First, we applied a diagnostic algorithm (Balduini, 2003) based on phenotypic characterization followed by candidate gene sequencing and, second, whole exome sequencing (WES) was performed in an international center in undiagnosed patients after this algorithm. Results:We included 114 patients from 50 pedigrees, 25 (0-73) years old, 68 (4-172) x109/L platelets; 68%, 30% and 2% had large, normal-sized and small platelets; 21% had syndromic forms: 11% hearing loss, 6% nephropathy, 7% hematologic malignancy, 2% myelofibrosis. By applying the algorithm, a conclusive diagnosis was reached in 27/50 (54%) pedigrees, 38% MYH9-RD; 4% Bernard-Soulier syndrome (1 monoallelic, 1 classic); 4% Gray Platelet Syndrome; 4% ANKRD26-RT; 2% FPD/AML; 2% Wiskott-Aldrich Syndrome. WES was undertaken in 8/23 (35%) pedigrees without diagnosis following the algorithm and known disorders were identified in 4 (1 FPD/AML, 1 ANKRD26-RT, 2 BSS:1 monoallelic, 1 biallelic), whereas no pathogenic variants in either known or new genes were detected in 4. Undiagnosed patients after the algorithm in whom WES was not performed suffered from mild isolated macrothrombocytopenia without distinctive features. Altogether, by this combined approach (algorithm+WES), a definitive diagnosis was identified in 31/50 (62%) pedigrees, which does not differ from the yield of NGS panels. ConclusionsIn conclusion, careful clinical phenotyping allowed diagnosis in a substantial proportion of patients and MYH9-RD was the disorder most easily recognized by the algorithm. Restricting the application of NGS to patients with negative results after the algorithm allowed to optimize resources and improved the diagnostic yield, representing a feasible approach in low-income settings.