Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders

Abstract

To study the prevalence of the Val617Phe JAK2 mutation in familial cases of myeloproliferative disorder (MPD) and its possible implication as a predisposing genetic factor, we analyzed 72 families including 174 patients (

Genetic complexity of myeloproliferative neoplasms

“…10,59 In all cases examined so far, JAK2-V617F and JAK2-ex12 mutations were acquired somatically in these families, never inherited through the germ line. 60,61 Thus, the unknown germline mutation inherited in these families predisposes carriers to somatically acquire JAK2 mutations and develop MPN. The penetrance of phenotype in familial MPN is incomplete because the germline mutation does not cause MPN on its own and the development of phenotype in familial MPN depends on the occurrence of somatic JAK2 mutation.…”

Clinical utility gene card for: Hereditary thrombocythemia

“…Neoplastic THCYT3/hereditary ET have a low but nevertheless elevated risk to develop myelofibrosis and/or acute leukemia. 20,21 THCYT3 can be positive for somatic JAK2 V617F 15 or germline JAK2 V617I (reported so far in one family). 16 Note that: MPL W515L/K mutations have been described in sporadic ET but as yet not in THCYT2.…”

“…Hereditary thrombocythemia cases with associated JAK2 alterations (THCYT3) have been described in a cohort of 66 European and 6 African families with somatic JAK2 V617F mutation 15 and germline JAK2 V617I was detected in a family from Great Britain. 16 Data from Sweden revealed that relatives of ET patients had elevated risk for any myeloproliferative neoplasm (MPN; RR ¼ 6.8; 95% CI, 3.4-13.5), ET (RR ¼ 8.8; 95% CI, 2.6-24.5), Polycythemia vera (RR ¼ 5.4; 95% CI, 2.2-13.1) and unclassifiable MPN (RR ¼ 16.1; 95% CI, 1.9-146.1) but no significantly increased risk for primary myelofibrosis (PMF; RR ¼ 4.0; 95% CI, 0.2-61.7).…”

“…No detectable JAK2 mutation does not exclude hereditary ET because B50% of cases can be JAK2 V617F-negative and JAK2 V617I has been reported so far in only one family. 15,16 Diagnosis of THCYT3/ hereditary ET in an index patient does not necessarily mean that other related patients must have an THCYT3/ET phenotype; it is known that different entities of MPN might present in individual patients of a family (hereditary MPN with individual ET manifestation). 13,15,20,21 Diagnosis of THCYTX requires exclusion of all other THCYT subtypes.…”

Familial polycythemia vera with non-germ line JAK2V617F mutation sparing the abnormal and clonal granulopoiesis

“…1 Although the distribution of Ph À CMPD phenotypes within families suggested autosomal-dominant inheritance with incomplete penetrance, the absence of the JAK2 V617F mutation both in purified B/T lymphocytes in 13 unrelated patients and variable ratios of the mutant allele in peripheral leukocytes indicated that JAK2 V617F was acquired and not transmitted by germ line. 1 We present a case of familial Ph À CMPD with JAK2 V617F mutation revealing different patterns of hematopoietic lineage involvement. The somatic nature of the mutation could be proven by comparison with non-hematopoietic tissues.…”