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. 2018 Feb 15;131(7):717-732.
doi: 10.1182/blood-2017-09-806489. Epub 2017 Nov 16.

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

Olivier Bluteau  1   2   3 , Marie Sebert  2   3 , Thierry Leblanc  4 , Régis Peffault de Latour  2   5   6   7 , Samuel Quentin  1 , Elodie Lainey  8 , Lucie Hernandez  2   3 , Jean-Hugues Dalle  2   4 , Flore Sicre de Fontbrune  6 , Etienne Lengline  9 , Raphael Itzykson  2   3   5   9 , Emmanuelle Clappier  1   2   3 , Nicolas Boissel  2   5   9 , Nadia Vasquez  1 , Mélanie Da Costa  1 , Julien Masliah-Planchon  3 , Wendy Cuccuini  1 , Anna Raimbault  1   2   3 , Louis De Jaegere  3 , Lionel Adès  2   9 , Pierre Fenaux  2   9 , Sébastien Maury  10 , Claudine Schmitt  11   12 , Marc Muller  11   12 , Carine Domenech  13 , Nicolas Blin  14 , Bénédicte Bruno  15 , Isabelle Pellier  16   17 , Mathilde Hunault  16   17 , Stéphane Blanche  18   19 , Arnaud Petit  20 , Guy Leverger  20 , Gérard Michel  21   22 , Yves Bertrand  13 , André Baruchel  2   4   5 , Gérard Socié  2   6   7 , Jean Soulier  1   2   3
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Free article

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

Olivier Bluteau et al. Blood. .
Free article

Abstract

Bone marrow (BM) 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% BM 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 germ line 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 inherited BMF (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, whereas 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.

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