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

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 (, ), telomeropathies (, ,), ribosome disorders (, ,), and DNA repair deficiency (). 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 and (N = 16 of the 86 patients, 18.6%), (N = 6, 7.0%), and (N = 7, 8.1%), each of which was associated with a distinct natural history; and patients often experienced transient aplasia and monosomy 7, whereas patients presented early-onset severe aplastic anemia, and 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.

MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia

“…On the basis of the phenotypic data from the patients in this and recent reports, 6,9,20,36,37 we conclude that heterozygous MECOM mutations or haploinsufficiency of MECOM resulting from microdeletions cause a syndromic disease with a variable phenotypic pattern, varying from severe BMF with multiple organ manifestations to isolated RUS without additional manifestations. Although RUS and BMF are the most common manifestations, none of these symptoms are mandatory for diagnosis of a MECOM-associated syndrome.…”

“…7,8 A study investigating germ line mutations in a group of 179 patients with IBMFS identified 6 more patients with MECOM mutations; interestingly, only 1 of them had RUS (supplemental Table 1). 9 In this study, we report on 12 patients with yet unclassified AT from different families caused by mutations in MECOM. We found a continuous spectrum of clinical manifestations in the patients and affected relatives.…”

“…In 2 patients (P5, P6) with severe congenital pancytopenia, we detected the mutation c.2248C.T (p.Arg750Trp) previously reported for 3 other patients with RUSAT2. 6,7,9 Both were platelet and erythrocyte transfusion dependent from birth and experienced severe recurrent bacterial and fungal infections. Radiographs for upper extremities revealed no anomalies; RUS could be excluded in P5 ( Figure 2C).…”

“…[6][7][8] However, most of our patients (as well as those in the IBMFS study by Bluteau et al 9 ) were not affected by RUS, including 2 patients bearing a mutation reported in the 3 patients with RUSAT2. 6,7,9 For a short time in embryonic development, the radius and ulna share a common perichondrium, and a perturbation of the process of segmentation by abnormal genetic or teratogenic factors can lead to a more or less distinct synostosis, 34 a fact which might explain the differences in the penetrance of this trait. MECOM is specifically expressed in the emerging limb buds in embryogenesis, but insufficient production seems to have no effect on bone development; skeletal abnormalities were not observed in any of the Evi1 knockout models.…”

“…Major phenotypic differences existed within families (eg, P1 and P2), and in 2 of our patients without RUS, we found a MECOM mutation identical to that previously described for 3 patients with RUSAT2. 6,7,9 Other genetic or epigenetic factors presumably influence the phenotypic characteristics.…”