ABSTRACT
BACKGROUND: Polycythemia vera (PV), characterized by massive production of erythrocytes, is one of the myeloproliferative neoplasms. Most patients carry a somatic gain-of-function mutation in JAK2, c.1849G > T (p.Val617Phe), leading to constitutive activation of JAK-STAT signaling pathway. Familial clustering is also observed occasionally, but high-penetrance predisposition genes to PV have remained unidentified. RESULTS: We studied the predisposition to PV by exome sequencing (three cases) in a Finnish PV family with four patients. The 12 shared variants (maximum allowed minor allele frequency <0.001 in Finnish population in ExAC database) predicted damaging in silico and absent in an additional control set of over 500 Finns were further validated by Sanger sequencing in a fourth affected family member. Three novel predisposition candidate variants were identified: c.1254C > G (p.Phe418Leu) in ZXDC, c.1931C > G (p.Pro644Arg) in ATN1, and c.701G > A (p.Arg234Gln) in LRRC3. We also observed a rare, predicted benign germline variant c.2912C > G (p.Ala971Gly) in BCORL1 in all four patients. Somatic mutations in BCORL1 have been reported in myeloid malignancies. We further screened the variants in eight PV patients in six other Finnish families, but no other carriers were found. CONCLUSIONS: Exome sequencing provides a powerful tool for the identification of novel variants, and understanding the familial predisposition of diseases. This is the first report on Finnish familial PV cases, and we identified three novel candidate variants that may predispose to the disease.
Subject(s)
Genetic Predisposition to Disease , Polycythemia Vera/genetics , Exome , Female , Finland , Humans , Male , Mutation , Polycythemia/congenital , Polycythemia/genetics , Polycythemia Vera/congenital , Sequence Analysis, RNAABSTRACT
A policitemia vera (PV) é um transtorno mieloproliferativo das células hematopoiéticas, caracterizada poruma produção anormal e acentuada de eritrócitos, leucócitos e plaquetas. É uma doença rara, com uma incidênciade 2,3/100.000 pessoas por ano. Apresentamos um relato de caso de uma paciente de 45 anos com sintomas,sinais e achados sugestivos de policitemia vera.
The polycythemia vera is a myeloproliferative disturb from haematopoietic cells characterized by abnormal and overstated production of erythrocytes, leukocytes and platelets. It is a rare disease with an incidenceof 2.3/100.000 people per year. We present a case report of a 45 years old patient with symptoms, signs andsuggestive results of polycythemia vera.
Subject(s)
Humans , Female , Middle Aged , Hemorrhage , Heredity , Hyperplasia , Leukemia , Polycythemia Vera , Thrombosis , Blood Platelets , Erythrocytes , Erythrocytes/metabolism , Erythrocytes/pathology , Hemorrhage/diagnosis , Hemorrhage/epidemiology , Hemorrhage/pathology , Heredity/genetics , Hyperplasia/epidemiology , Hyperplasia/metabolism , Hyperplasia/pathology , Leukocytes , Leukocytes/pathology , Blood Platelets/metabolism , Blood Platelets/pathology , Polycythemia Vera/congenital , Polycythemia Vera/metabolism , Thrombosis/diagnosis , Thrombosis/metabolism , Thrombosis/pathologySubject(s)
Erythropoiesis/physiology , Erythropoietin/physiology , Hypoxia/physiopathology , Oxygen/metabolism , Polycythemia/physiopathology , 2,3-Diphosphoglycerate/blood , Bisphosphoglycerate Mutase/deficiency , Gene Expression Regulation , Hemoglobinopathies/complications , Hemoglobinopathies/physiopathology , Homeostasis , Humans , Hypoxia/complications , Hypoxia/genetics , Kidney Diseases/complications , Kidney Diseases/physiopathology , Liver Diseases/complications , Liver Diseases/physiopathology , Neoplasms/complications , Neoplasms/physiopathology , Polycythemia/congenital , Polycythemia/etiology , Polycythemia/genetics , Polycythemia Vera/congenital , Polycythemia Vera/etiology , Polycythemia Vera/physiopathologyABSTRACT
Gestational diabetes mellitus is a relatively common medical condition that was described as early as the nineteenth century. This article discusses the maternal and fetal pathophysiology and the impact of the maternal condition on the neonate. Fetal macrosomia and infant respiratory distress syndrome, cardiomyopathy, hypoglycemia, hypocalcemia, hypomagnesemia, polycythemia, and hyperviscosity all can occur as a result of maternal hyperglycemia and are discussed in detail. Therapeutic approaches and treatment options for the mother, manifestations and diagnosis of the infant, and current research related to this condition are also included.
