The Hematologist

May-June 2018, Volume 15, Issue 3

Germline Mutations in a Cohort of Inherited Marrow Failure Patients: A Varied Landscape

Sioban Keel, MD Associate Professor of Medicine
University of Washington School of Medicine, Seattle, WA

Published on: April 12, 2018

Bluteau O, Sebert M, Leblanc T, et al. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood. 2018;131:717-732.

With increasing frequency, molecular profiling and panel-based testing are used to detect germline syndromes that predispose to bone marrow failure (BMF) and/or hematopoietic malignancies. The result is an expanding number of patients and families who are recognized as having an inherited predisposition. These include inherited myelodysplastic syndrome (MDS) and leukemia predisposition syndromes with (e.g., GATA2 haploinsufficiency) and without (e.g., CEBPA, DDX41) nonhematopoietic findings, classical inherited bone marrow failure syndromes (e.g., Fanconi anemia, telomere biology disorders), familial myeloproliferative disorders, traditional “solid tumor” cancer predisposition syndromes (e.g., Li Fraumeni), and other genetic disorders (e.g., familial platelet disorder with associated myeloid malignancy). To inform appropriate clinical management, the identification of these underlying inherited causes is critical. Patients may require surveillance for disease-specific extrahematopoietic complications and clonal hematopoiesis, often respond poorly to immune suppressive therapies,1 and need specialized consideration of a familial donor and potentially a reduced intensity conditioning regimen for hematopoietic stem cell transplantation.2 The recognition of a familial genetic disorder also allows for appropriate genetic counseling and follow-up of affected family members.

Prior work has studied the causative mutations in and incidences of these inherited syndromes, typically by testing large panels of genes.3,4 In this study, Dr. Olivier Bluteau and colleagues broaden the molecular and clinical portraits of these syndromes using a whole-exome sequencing (WES) approach and DNA obtained from skin fibroblasts available in a centralized biorepository and obtained between February 2002 and June 2006 from patients clinically evaluated at 31 French centers.5 The researchers retrospectively included 179 patients with marrow failure of suspected inherited origin who remained genetically undefined after initial clinical evaluation (from 172 distinct families). Marrow failure was defined as having at least one cytopenia (absolute neutrophil count < 1.5 × 109/L; platelets < 150 × 109/L; and/or hemoglobin < 2 SD below the age-adjusted mean) of central origin confirmed by bone marrow examination. The inclusion criterion of suspected inherited origin was defined by the presence or at least one physical abnormality (growth, skeletal, neurological, genitourinary, cardiac, lung, liver, skin, nail, or hair) and/or a suggestive family history (defined as consanguinity determined by WES or family history of a hematologic disorder), and/or young age (≤ 2 years). Patients with Fanconi anemia were excluded from the study based on chromosome fragility testing of all banked samples. Patients who carried an upfront diagnosis of a known inherited marrow failure syndrome based on syndromic presentation, paroxysmal nocturnal hemoglobinurea, acquired aplastic anemia, or “Bloom syndrome, Seckle syndrome, or other cancer predispositions” were excluded from the study. Results of blood tests and marrow examinations were reviewed. Notably this study did not include a centralized pathology review, and the authors did not provide details on how clinical data (sex, age, family history, physical abnormalities, age of first hematological symptoms, cytopenias, and follow-up information) were ascertained. Whole-exome sequencing was performed, and data were analyzed by a homemade bioinformatics pipeline that notably restricted the reported variants to 156 known or candidate-inherited bone marrow failure genes. Variants were classified based on clinical and molecular evidence reviewed by a panel of experts as “causal or likely causal” or “suspected but not regarded as causal.”

The median age at genetic evaluation was 11 years, with 63 percent of patients younger than 18 years; the remainder were adults. The median age of first hematologic symptoms was eight years. Patients with MDS and acute myeloid leukemia were included in the study. An increased marrow blast percentage (≥ 5 %) was observed in 12 percent (21/175) of patients, and 28 percent (45/161) of patients were characterized as having an abnormal karyotype.

The authors assigned causal or likely causal germline mutation(s) in 48.0 percent of patients (86/179) involving a total of 28 genes causing both autosomal dominant and recessive disorders. This high percentage may reflect the study inclusion criteria. The most commonly implicated genes were SAMD9L (10/179; 5.6%), TERC (9/179; 5.0%), GATA2 (7/179; 3.9%), TINF2 (7/179; 3.9%), ERCC6L2 (7/179; 3.9%), MECOM/EVI1 (6/179; 3.4%), SAMD9 (6/179; 3.4%), and RUNX1 (5/179; 2.8%). The causal or likely causal genes clustered in biological pathways involved in telomere maintenance (TERT, TERC, DKC1, and RTEL) in 29 (33.7%) of 86 patients, and a second cluster emerged in hematopoietic genes, mostly transcription factors (GATA2, RUNX1, MECOM/EVI1), in 21 (24.4%) of 86 patients. A third cluster included genes primarily involved in ribosome assembly (SBDS, SRP72, DNAJC21, and RPL5) in 12 (14.0%) of 86 patients. DNA damage response genes (ERCC6L2, LIG4, and ATR) were mutated in 11 patients (12.8%).

The authors also correlated the genetic findings with available clinical data and compared this to reports described in the literature associated with the corresponding gene. Many patients found to have causal or likely causal germline mutations in known inherited bone marrow failure syndrome genes lacked prototypical clinical findings of the disorders. Additionally, 23.3 percent of patients found to have causal or likely causal germline mutations initially presented with hematologic signs as adults (20/86 were ≥ 18 years of age). These findings underscore that predicting genotype based on clinical information alone is unreliable. Germline mutations in the SAMD9 and SAMD9L genes, located in tandem on chromosome 7, are associated with a clinical spectrum of autosomal-dominant disorders including the MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy),6 ataxia-pancytopenia syndrome, and myelodysplasia and leukemia syndrome with monosomy 7.7,8 In the current study, patients with mutations in SAMD9 and SAMD9L typically experienced early onset severe bone marrow failure with frequent dysplastic features characterized by a monosomy 7 karyotype. Strikingly, in many of these individuals, the cytopenias improved and the monosomy 7 karyotype resolved over time in patients who acquired a somatic mutation leading to replacement of the mutated allele by the wild-type allele, confirming earlier reports of this important finding.8

This work extends our understanding of the inherited genetic underpinnings of marrow failure and hematologic malignancy predisposition. The findings affirm that these disorders are indeed heterogeneous, involve mutations in a broad number of genes, and can present in both pediatric and adult patients without classical syndromic findings. Importantly, the data provide clinical rationale to screen broadly for these disorders. The work extends the list of genes more commonly implicated in these inherited disorders to include SAMD9, SAMD9L, MECOM, and ERCC6L2, which were not sequenced in a number of earlier large studies.3,4,9 In this study, variants classified by the American College of Medical Genetics and Genomics criteria as of uncertain significance could be reclassified as “causal or likely causal” based on clinical acumen (roundtable sessions involving bioinformatics specialists, scientists, biologists, and physicians trained in germline syndromes that predispose to hematopoietic malignancies), raising a concern for the reproducibility of variant classification and providing strong support for ongoing efforts in the field to more systematically collate inherited variants conferring risk to myeloid malignancies. An additional clinical pearl to take away from this meaningful work is the importance of a constitutional DNA source for testing or parental testing in these disorders to exclude the possibility of hematopoietic reversion (observed in patients with mutations in SAMD9L and SAMD9) or somatic mutations.


  1. Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev. 2010;24:101-122.
  2. Gadalla SM, Sales-Bonfim C, Carreras J, et al. Outcomes of allogeneic hematopoietic cell transplantation in patients with dyskeratosis congenita. Biol Blood Marrow Transplant. 2013;19:1238-1243.
  3. Zhang MY, Keel SB, Walsh T, et al. Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity. Haematologica. 2015;100:42-48.
  4. Ghemlas I, Li H, Zlateska B, et al. Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes. J Med Genet. 2015;52:575-584.
  5. Bluteau O, Sebert M, Leblanc T, et al. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood. 2018;131:717-732.
  6. Narumi S, Amano N, Ishii T, et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet. 2016;48:792-797.
  7. Chen DH, Below JE, Shimamura A, et al. Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L. Am J Hum Genet. 2016;98:1146-1158.
  8. Tesi B, Davidsson J, Voss M, et al. Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms. Blood. 2017;129:2266-2279.
  9. Keel SB, Scott A, Sanchez-Bonilla M, et al. Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients. Haematologica. 2016;101:1343-1350.

Conflict of Interests

Dr. Keel indicated no relevant conflicts of interest. back to top