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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.    Electronic supplementary material  The online version of this article (doi:10.1186/s40246-017-0102-x) contains supplementary material, which is available to authorized users.

Whole-exome sequencing identifies novel candidate predisposition genes for familial polycythemia vera