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Background Increasing germline gene mutations have been discovered in haematological malignancies with the development of next-generation sequencing (NGS), which is critical for proper clinical management and long-term follow-up of affected individuals. Tet methylcytosine dioxygenase 2 ( TET2 ) is one of the most common mutations in haematological neoplasms. We aimed to compare the clinical characteristics of patients with germline and somatic  TET2  mutations in haematological diseases and to analyse whether germline  TET2  mutations have a family aggregation and tumour predisposition. Methods Out of 612 patients who underwent NGS of 34 recurrently mutated genes in haematological diseases, 100 haematological patients with  TET2  mutations were selected for further study. Somatic mutations were detected by NGS in bone marrow/peripheral blood genomic DNA (gDNA). Germline  TET2  mutations were validated in nail/hair gDNA by Sanger sequencing. Digital data were extracted from the haematology department of the West China Hospital of Sichuan University.  TET2  mutation results were analysed by referencing online public databases (COSMIC and ClinVar). Results One hundred patients were studied, including 33 patients with germline and 67 patients with somatic  TET2  mutations. For germline  TET2  mutations, the variant allele frequency (VAF) was more stable (50.58% [40.5–55],  P  &lt; 0.0001), and mutation sites recurrently occurred in three sites, unlike somatic  TET2  mutations. Patients with germline  TET2  mutations were younger (median age 48, 16–82 years) ( P  = 0.0058) and mainly suffered from myelodysplastic syndromes (MDS) ( n  = 13, 39.4%), while patients with somatic  TET2  mutations were mainly affected by acute myeloid leukemia (AML) ( n  = 26, 38.8%) ( P  = 0.0004). Germline  TET2  mutation affected the distribution of cell counts in the peripheral blood and bone marrow ( P  &lt; 0.05); it was a poor prognostic factor for MDS patients via univariate analysis (HR = 5.3, 95% CI: 0.89–32.2,  P  = 0.0209) but not in multivariate analysis using the Cox regression model ( P  = 0.062). Conclusions Germline  TET2  mutation might have a family aggregation, and  TET2  may be a predisposition gene for haematological malignancy under the other gene mutations as the second hit. Germline  TET2  mutation may play a role in the proportion of blood and bone marrow cells and, most importantly, may be an adverse factor for MDS patients.

Pedigree investigation, clinical characteristics, and prognosis analysis of haematological disease patients with germline TET2 mutation