Genomic analysis of germline and somatic variants in familial myelodysplasia/acute myeloid leukemia

Jane E. Churpek, Khateriaa Pyrtel, Krishna-Latha Kanchi, Jin Shao, Daniel Koboldt, Christopher A. Miller, Dong Shen, Robert Fulton, Michelle O'Laughlin, Catrina Fronick, Iskra Pusic, Geoffrey L. Uy, Evan M. Braunstein, Mark Levis, Julie Ross, Kevin Elliott, Sharon Heath, Allan Jiang, Peter Westervelt, John F. DiPersio, Daniel C. Link, Matthew J. Walter, John Welch, Richard Wilson, Timothy J. Ley, Lucy A. Godley and Timothy A. Graubert

Key points

  • Known pathogenic germline variants in 12 genes can explain nearly 30% of families with inherited predisposition to MDS/AML.

  • Asymptomatic carriers of germline RUNX1 mutations develop detectable clonal hematopoiesis with a cumulative risk of greater than 80% by age 50.


Familial clustering of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) can be caused by inherited factors. We screened 59 individuals from 17 families with 2 or more biological relatives with MDS/AML for variants in 12 genes with established roles in predisposition to MDS/AML, and identified a pathogenic germline variant in 5 families (29%). Extending the screen with a panel of 264 genes that are recurrently mutated in de novo AML, we identified rare, non-synonymous germline variants in 4 genes segregating with MDS/AML in an additional 2 families each. Somatic mutations are required for progression to MDS/AML in these familial cases. Using a combination of targeted and exome sequencing of tumor and matched normal samples from 26 familial MDS/AML cases and asymptomatic carriers, we identified recurrent frameshift mutations in the cohesin-associated factor PDS5B, co-occurrence of somatic ASXL1 mutations with germline GATA2 mutations, and recurrent mutations in other known MDS/AML drivers. Mutations in genes that are recurrently mutated in de novo AML were under-represented in the familial MDS/AML cases, although the total number of somatic mutations per exome was the same. Finally, clonal skewing of hematopoiesis was detected in 67% of young, asymptomatic RUNX1 carriers, providing a potential biomarker that could be used for surveillance in these high-risk families.

  • Submitted April 16, 2015.
  • Accepted August 31, 2015.