Germline predisposition variants occur in myelodysplastic syndrome patients of all ages.

The frequency of pathogenic/likely pathogenic (P/LP) germline variants in myelodysplastic syndrome (MDS) patients diagnosed at or younger than 40 years old is 15 to 20%. However, there are no comprehensive studies assessing the frequency of such variants across the age spectrum. We performed augmented whole exome sequencing from peripheral blood of 404 MDS patients and their related donors prior to allogeneic hematopoietic stem cell transplantation. Single nucleotide and copy number variants in 233 genes were analyzed and interpreted. Germline status was established by the presence of a variant in the patient and related donor or for those seen previously only as germline alleles. We identified P/LP germline variants in 28 out of 404 MDS patients (7%) within all age deciles. Patients with P/LP variants were more likely to develop higher-grade MDS than those without (43% vs. 25%, p=0.04). There was no statistical difference in outcome parameters between patients with and without a germline variant, but the analysis was underpowered. P/LP variants in bone marrow failure syndrome genes were found in five patients under age 40, whereas variants in DDX41 (n=4), telomere biology disorder genes (n=2), and tumor predisposition genes (n=17) were found in patients over 40. If presumed germline variants were included, the yield of P/LP variants would increase to 11% and by adding suspicious variants of unknown significance, it would rise further to 12%. The high frequency of P/LP germline variants in our study supports comprehensive germline genetic testing for all MDS patients regardless of their age at diagnosis.