Whole-exome sequencing of a patient with severe and complex hemostatic abnormalities reveals a pathogenic frameshift mutation in C3AR1

The increasing availability of genome-wide analysis has made it possible to rapidly sequence the exome of patients with undiagnosed or unresolved medical conditions. Here, we present the case of a 64-year-old male patient with schistocytes in the peripheral blood smear and a complex and life-threatening coagulation disorder causing recurrent venous thromboembolic events, severe thrombocytopenia, and subdural hematomas. Whole-exome sequencing revealed a frameshift mutation (C3AR1 c.355-356dup, p.Asp119Alafs*19) resulting in a premature stop in C3AR1 (Complement Component 3a Receptor 1). Based on this finding, the patient was diagnosed with atypical hemolytic uremic syndrome due to a genetic predisposition and a targeted treatment regime with eculizumab was initiated. Life-threatening hemostatic abnormalities would most likely have persisted had it not been for the implementation of whole-exome sequencing in this particular clinical setting.