The role of genetic sequencing in the diagnostic workup for chronic immune thrombocytopenia

Immune thrombocytopenia (ITP) is a heterogenous autoimmune disorder diagnosed by excluding other conditions. Misdiagnosis of primary ITP occurs in patients with inherited thrombocytopenia and primary immunodeficiency syndromes. This study investigates whether genetic testing for inherited thrombocytopenia or primary immunodeficiency can enhance diagnostic accuracy in ITP, and guide treatment strategies. We performed whole genome sequencing or targeted panel sequencing on peripheral blood samples in a cohort of 80 participants with chronic ITP, utilizing the ThromboGenomics panel (n = 72) and the Genomics of Rare Immune Disorders panel (n = 50) consisting of genes known to cause bleeding and platelet disorders (BPDG) or primary immuodeficiency genes (PIDG) respectively. A replication cohort of 73 patients underwent clinical genomics testing with either the R90 (BPDG, n = 35) or R15 (PIDG, n = 50) National Health Service Genomics panels. Known pathogenic or likely pathogenic, disease-causing, variants were identified in 9 patients in the first cohort (11%, 95% confidence interval [CI]: 5-20); 7 patients (10%, 95% CI: 4-19) in BPDG and 2 patients (4% CI,1-14) in PIDG. In addition, 26 patients (32.5%) carried variants of uncertain significance. In the replication cohort, 8% (95% CI, 2-20) and 9% (95% CI, 2-23) of patients had a pathogenic variant identified on the R15 (PIDG) or R90 panel (BPDG), respectively. The findings impacted clinical management such as avoidance of immunosuppression (ANKRD26, GP1BB, ETV6, TUBB1, and ITGB3) and eligibility for allogeneic stem cell transplantation (UNC13D). Our findings demonstrate that genomic sequencing identifies diagnostically relevant variants in patients with chronic ITP. Identification of these variants can guide treatment decisions and improve patient outcomes.