A landscape of germline mutations in a cohort of inherited bone marrow failure patients

Olivier Bluteau, Marie Sebert, Thierry Leblanc, Régis Peffault de Latour, Samuel Quentin, Elodie Lainey, Lucie Hernandez, Jean-Hugues Dalle, Flore Sicre de Fontbrune, Etienne Lengline, Raphael Itzykson, Emmanuelle Clappier, Nicolas Boissel, Naddia Vasquez, Mélanie Da Costa, Julien Masliah-Planchon, Wendy Cuccuini, Anna Raimbault, Louis De Jaegere, Lionel Adès, Pierre Fenaux, Sébastien Maury, Claudine Schmitt, Marc Muller, Carine Domenech, Nicolas Blin, Bénédicte Bruno, Isabelle Pellier, Mathilde Hunault, Stéphane Blanche, Arnaud Petit, Guy Leverger, Gérard Michel, Yves Bertrand, André Baruchel, Gérard Socié and Jean Soulier

Key points

  • Next-generation sequencing broadens the spectrum of germline mutations in a cohort of patients with likely-inherited BMF.

  • Salient clinical features and distinct natural histories are consistently found in SAMD9L and SAMD9, MECOM/EVI1 and ERCC6L2 disorders.


Bone marrow failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% bone marrow blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germline mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in IBMF, such as SAMD9 and SAMD9L (N=16 of the 86 patients; 18.6%), MECOM/EVI1 (N=6, 7.0%), and ERCC6L2 (N=7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, while MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly-recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.

  • Submitted September 14, 2017.
  • Accepted October 28, 2017.