A Family with a Novel Mutation and Polycythemia Vera

Abstract Background. Chronic myeloproliferative neoplasms are derived from myeloproliferation of a single hematopoietic stem cell and result in either erythrocythemia or thrombocytosis. Polycythemia Vera (PV) is defined by persistent proliferation of red cell mass in the peripheral blood and bone marrow with hemoglobin more than or equal to 16.5 gr/dL (49% Hematocrit) in males and 16 gr/dL (48% Hematocrit) in females. Around 98% of patients with PV harbor an acquired Janus Kinase 2 mutation, namely JAK2V617F. Other well described mutations in PV patients include the EPOR gene, Hypoxia-inducible factor 2 alpha (HIF2A) gene, PHD2 gene mutations and the rare Hemoglobin Tarrant. These mutations and other identified predisposing gene variants have all accounted for familial cases of PV. Presence of specific mutations can be associated with increased risk of myelodysplastic syndrome, progression of disease, and neoplasms which causes a decreased overall survival. Methods: We reviewed the charts and collected clinical information of 3 generations of one family with erythrocythemia, including PV diagnostic testing. Results: The proband, a 3-year-old female, presented to our clinic at 6 months of age with a hemoglobin of 16 gr/dL (upper limit of normal for age is 12.5 gr/dL). Family consisted of 3 generations of related females (maternal grandmother, mother and daughter) with the clinical characteristics of PV as described above, requiring frequent phlebotomy. Genetic testing, for known PV mutations, on the proband revealed no identifiable mutations, similar to the mother's and grandmother's prior genetic testing. The proband had no other laboratory abnormalities, and a bone marrow biopsy and aspirate examination was normal. Now 3 years of age, she has been undergoing phlebotomy every 3 months since diagnosis; further testing with exome gene sequencing showed c.136G>A mutation on EPO gene, a variant of unknown significance. Discussion. Literature review showed 2 previous reports of c.136G>A mutation in the EPO gene. In 2015, Taylor et al described the mutation in two families with erythrocytosis. Their project was aimed at evaluating whole-genome sequencing for diagnosis of families with high suspicion of a genetic component to their clinical presentation with no previously identified pathogenic variants. They concluded that c.136G>A is of autosomal dominant inheritance. Later described in 2016 by Camps et al., the variant was also found in 4 different non-related patients after whole genome sequencing. None of the previous citations demonstrated causality. Determination of predisposing gene mutations, using exome gene sequencing specifically for families with an unknown mutation may help clinicians with prognosis, genetic counseling, and possibly specific treatments. Although an interesting result, a causality between the variant identified and the patient in this report has not yet been verified. Therefore, more testing and reports of this mutation are needed. Further steps in our case will include whole exome sequencing of the proband's family members with idiopathic erythrocytosis to assess the presence of this variant in the whole family. Identification of a specific familial inherited gene mutation resulting in PV can help classify patients based on the mutation. This will help predict disease course, improve quality of life and determine risk of disease transformation. Disclosures No relevant conflicts of interest to declare.