Inherited thrombocytopenias (ITs) are genetic diseases characterized by low platelet count, possibly associated with congenital defects or predisposition to develop additional conditions. Next generation sequencing has consistently improved our knowledge of ITs, with >40 genes identified so far, but obtaining a molecular diagnosis remains a challenge especially for patients with non-syndromic forms, having no clinical or functional phenotypes that raise suspicion on specific genes. We performed exome sequencing (ES) in a cohort of 116 IT patients (89 families), still undiagnosed after a previously validated phenotype-driven diagnostic algorithm including a targeted analysis of suspected genes. ES achieved a diagnostic yield of 36%, with a gain of 16% over the diagnostic algorithm. This can be explained by genetic heterogeneity and unspecific genotype-phenotype relationships that make the simultaneous analysis of all the genes, enabled by ES, the most reasonable strategy. Furthermore, ES disentangled situations that had been puzzled by atypical inheritance, sex-related effects or false negative laboratory results. Finally, ES-based Copy Number Variant (CNV) analysis disclosed an unexpected high prevalence of RUNX1 deletions, predisposing to hematological malignancies. Our findings demonstrate that ES, including CNV analysis, can substantially contribute to the diagnosis of IT and can solve diagnostic problems that would otherwise remain a challenge.
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