Germline Predisposition Variants Found Across Age Groups in Patients with MDS

While pathogenic or likely pathogenic germline variants are found in around a fifth of patients with myelodysplastic syndrome (MDS) who are diagnosed at or before the age of 40, a new study found nearly 10% of patients diagnosed with MDS at any age had pathogenic or likely pathogenic germline variants.

Simone Feurstein, MD, of the University of Chicago, and colleagues, conducted the study and published its results in Blood.

Dr. Feurstein and colleagues performed augmented whole exome sequencing on peripheral blood from 404 patients with MDS and their related donors before the patients underwent allogeneic hematopoietic stem cell transplantation. The researchers analyzed and interpreted single nucleotide and copy number variants in 233 genes. The germline status was established by the presence of a variant in the patient and their related donor, or by the presence of a variant seen previously only as germline allele.

Researchers identified pathogenic or likely pathogenic germline variants in 7% of patients within all age groups.

“If presumed germline variants were included, the yield of [pathogenic or likely pathogenic] variants would increase to 11% and by adding suspicious variants of unknown significance, it would rise further to 12%,” Dr. Feurstein and colleagues wrote.

Patients with pathogenic or likely pathogenic variants were more likely to develop higher grade MDS (43%) than patients who did not have variants (25%, P=.04). Pathogenic or likely pathogenic germline variants in bone marrow failure syndrome genes were reported in five patients under the age of 40. In patients over the age of 40, pathogenic or likely pathogenic variants in tumor predisposition genes were reported in 17 patients, variants in DD41 were reported in four patients, and variants in telomere biology disorder genes were reported in two patients.

“Deleterious germline predisposition variants are shared in patients [with MDS] and their related donors and occur at all ages,” the researchers wrote. “Based on the significant frequency of germline variants in [MDS], genetic testing is recommended for all patients.”

Feurstein SK, Trottier AM, Estrada-Merly N, et al. Germline predisposition variants occur in myelodysplastic syndrome patients of all ages. Blood. 2022. doi:10.1182/blood.2022015790