A rare <i>CALR</i> exon 9 mutation p.E379Vfs*53 in AYA generation exhibits gain-of-function nature and can induce essential thrombocythemia; a case report

Current therapeutic strategies for essential thrombocythemia (ET) are mainly considered to prevent thrombo-hemorrhagic events, without increasing the rate of fibrotic progression or leukemic evolution. To treat the patients appropriately, the precise diagnosis of ET is essential. Although approximately 30% of ET cases are diagnosed as <i>CALR</i> mutation-positive; commercially available polymerase chain reaction-based methods for CALR mutation can detect only a limited variation of <i>CALR</i> mutations. We report the case of a 29-year-old woman admitted to our hospital because of thrombocytosis for 3 years. Leukocytosis, erythrocytosis, and <i>JAK2</i> V617F and <i>MPL</i> mutations were not detected. <i>CALR</i> mutation analysis for types 1–5 was negative, however Sanger sequencing identified a novel mutation, c.1136–1142 del7 insTCCTCTGTCCTT. <i>In vitro</i> assay revealed this mutation as a gain-of-function mutation where the C-terminus of calreticulin is altered. <i>In silico</i> analysis showed that the current mutation is considered as type-I CALR mutation like category, which is considered more likely to develop overt myelofibrosis. Our findings emphasize the importance of thorough genetic screening for patients with thrombocytosis, including those who standard CALR mutation assays produce negative results. In view of prognostic risk classification, identifying such novel mutations and determining their functional consequences can substantially improve the diagnostic accuracy and may provide future therapeutic opportunity.