Thrombocytopenia can be the first indication of an underlying condition in children and includes a wide range of differential diagnoses. Inherited thrombocytopenias are a heterogenous group of disorders with low platelet counts, with or without platelet dysfunction. With increasing access to genetic testing, the number of genes associated with this phenotype and number of patients diagnosed continue to grow. 1 Over 50 genes have been described to be associated with inherited thrombocytopenia and an estimated 2.7% are from disease-causing variants in ETS Variant Transcription Factor 6 (ETV6). 1,2 ETV6 is a transcription repressor in the ETS family of transcription factors, and it is implicated in normal hematopoiesis, thrombopoiesis, and platelet function. 3,4 Distinguishing ETV6-related thrombocytopenia (ETV6-RT) from other etiologies is important, given its associated risk of malignancy, 2-4 and requires genetic testing for diagnostic confirmation. This report describes the diagnostic approach and clinical challenges in a family with inherited thrombocytopenia that was found to carry a rare disease-causing ETV6 variant.

Pathogenic variants in the ETS Variant Transcription Factor 6 ( ETV6) are associated with inherited thrombocytopenia with predisposition to hematologic malignancy. We report two young sisters who presented with mild thrombocytopenia and mild bleeding symptoms. Further family history led to suspicion of inherited etiology, and genetic sequencing revealed a novel ETV6 variant (c.1085A>G) of paternal origin. Collaboration between clinical and laboratory teams allowed resolution of variant classification to likely pathogenic. Our report demonstrates genetic testing for inherited thrombocytopenia should be considered for children with mild, variable, and non-specific bleeding symptoms.