Clinical Utility of a Targeted Next-Generation Sequencing Panel for Inherited Platelet Disorders in Children

<b>Background/Objectives</b>: Inherited platelet disorders (IPDs) are diverse conditions characterized by abnormalities in platelet count and function. Next-Generation Sequencing (NGS) shows promise as a diagnostic tool in the diagnosis of IPDs. This study aims to assess the clinical value and limitations of using a targeted NGS panel in diagnosing children with suspected IPDs. <b>Methods</b>: We conducted a retrospective study of 93 children evaluated for suspected IPDs. A targeted NGS panel of 14 IPD-associated genes (<i>RUNX1</i>, <i>WAS</i>, <i>ADAMTS13</i>, <i>ANKRD26</i>, <i>CYCS</i>, <i>GATA1</i>, <i>GP1BA</i>, <i>GB1BB</i>, <i>GP9</i>, <i>ITGA2B</i>, <i>ITGB3</i>, <i>MASTL</i>, <i>MPL</i>, <i>MYH9</i>) was performed. <b>Results</b>: Genetic variants were identified in 30 patients (32.3% of the cohort). A total of 37 variants, of which 15 (40.5%) were novel, were found across 11 of the 14 genes on the panel (all except <i>MPL</i>, <i>CYCS</i>, and <i>RUNX1</i>). Variants were most frequently found in <i>ITGB3</i> (18.9% of variants), <i>GP1BA</i> (16.2%), and <i>ADAMTS13</i> (16.2%) genes. The majority of variants (64.9%) were classified as variants of uncertain significance (VUS), followed by likely pathogenic (LP) (27%) and pathogenic (8.1%) variants. Most variants were in a heterozygous state (73%). Specific cases highlighted complex genetic scenarios, such as co-occurring variants, and the identification of pathogenic and LP variants in patients initially presenting with immune thrombocytopenia. <b>Conclusions</b>: NGS helps to identify genetic causes, assess risk, manage, and provide genetic counseling in the management of IPDs. However, the prevalence of VUS underscores the need for a multidisciplinary approach to evaluate NGS results accurately.