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Pathogenic Germline Variants Seen in Older Patients With MDS More Frequently Than Expected

October 27, 2022

November 2022

Patients of all ages with myelodysplastic syndromes (MDS) who underwent related allogeneic hematopoietic cell transplantation (alloHCT) have a greater frequency of pathogenic germline mutations than was previously known, according to recent findings reported in Blood. This study is the first time that pathogenic or likely pathogenic germ­line mutations have been examined in patients with MDS across the whole age spectrum who went through related alloHCT, offering a clearer picture of how common these mutations are.

Pathogenic or likely pathogenic germline variants are increasingly recognized as drivers of hematopoietic malignancies, and guidelines prioritize those age 40 or younger for screening. These new findings suggest, however, that screening should be conducted for all patients with MDS who are undergoing HCT and their donors, no matter the age, said study author Lucy Godley, MD, PhD, professor of medicine and human genetics at the University of Chicago. 

“You should test every patient with MDS going for allogeneic transplant,” Dr. Godley said. “This paper is the first one to show there is inherited risk across the entire age range, at every age decile, and that really challenges what people have thought is true about inherited risk. People have always assumed that if you have inherited risk, you will present young.”

Researchers pulled data from a cohort of 404 patients with MDS who had undergone alloHCT from their related donors from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Researchers performed augmented whole exome sequencing on peripheral blood samples from patients and donors.

Findings showed 7% of patients (n=28), with a median age of 59, had a pathogenic or likely pathogenic germline variant. The highest occurrence (33%) was seen in the 11- to 20-year-old group. That was followed by 8% for ages 21 to 30, 31 to 40, and 71 to 80; 7% in ages 51 to 60; and 6% in ages 41 to 50 and 61 to 70.

In every decade of life, at least 6% of patients had a pathogenic germline mutation.

Researchers found that 23 patients had a germline predisposition syndrome with autosomal dominant inheritance and that these variants were shared with their related donors in 20 cases. The findings make the case for standard-of-care germline screening for donors, Dr. Godley said.

“It’s a good idea not to re-introduce the causative mutation back into the person,” she said.

Although the percentage of pathogenic or likely pathogenic variants found was below 10% in adults, another 56 germline variants of unknown significance were found that were considered highly suspicious. If these highly suspicious variants had been considered pathogenic or likely pathogenic, the percentage would have risen to 12%.

Because of the rarity of each variant, the study wasn’t powered to assess clinical outcomes due to the presence of a germline pathogenic variant, Dr. Godley said; much larger studies are needed for that.

In hereditary breast, ovarian, and pancreatic cancer, the National Comprehensive Cancer Network recommends germline screening when the pre-test probability is more than 5%, she noted. These findings show that threshold is surpassed in MDS.

Because of the surprisingly high incidence of germline pathogenic and suspicious variants identified, Dr. Godley suggested screening patients eligible for allogeneic transplantation at diagnosis rather than in the short interval between remission and alloHCT. She hopes the findings spur fundamental changes in the field.

“It’s a wake-up call,” she said. “The transplant field needs to think hard about these results, and we need to ensure timely access to germline predisposition testing for all patients with MDS heading to transplant.”

Any conflicts of interest declared by the authors can be found in the original article.


Fuerstein SK, Trottier AM, Estrada-Merly N, et al. Germline predisposition variants occur in myelodysplastic syndrome patients of all ages [published online ahead of print, 2022 Aug 19]. Blood. doi: 10.1182/blood.2022015790.


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