Frequent and clinically relevant germline DNA repair gene variants in young and familial myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) comprise a group of hematological disorders characterized by overproduction of blood cells caused by somatic driver mutations. While most MPN cases arise sporadically, familial clustering is increasingly recognized, occurring in around 7% of cases. Within affected families, different driver mutations ( JAK2, CALR, MPL ) and disease subtypes—including polycythemia vera, essential thrombocythemia, and myelofibrosis —can be observed [ 1 , 2 , 3 ]. Several germline variants increasing susceptibility to MPNs have been identified, including variants in JAK2 (‘46/1’ haplotype; 4-fold increased MPN risk) [ 4 ], TERT (2-fold), SH2B3, TET2, CHEK2, ATM, PINT , and GFI1B [ 3 , 5 , 6 , 7 ]. However, the underlying mechanisms by which these germline variants contribute to the acquisition of the somatic drivers remain unclear.