The genomics of inherited bone marrow failure: from mechanism to the clinic

Abstract

The inherited bone marrow failure syndromes (IBMFS) typically present with significant cytopenias in at least one haematopoietic cell lineage that may progress to pancytopenia, and are associated with increased risk of cancer. Although the clinical features of the IBMFS are often diagnostic, variable disease penetrance and expressivity may result in diagnostic dilemmas. The discovery of the genetic aetiology of the IBMFS has been greatly facilitated by next-generation sequencing methods. This has advanced understanding of the underlying biology of the IBMFS and been essential in improving clinical management and genetic counselling for affected patients. Herein we review the clinical features, underlying biology, and new genomic discoveries in the IBMFS, including Fanconi anaemia, dyskeratosis congenita, Diamond Blackfan anaemia, Shwachman Diamond syndrome and some disorders of the myeloid and megakaryocytic lineages.

Pregnancies in patients with inherited bone marrow failure syndromes in the NCI cohort

“…All diagnoses were confirmed with clinical and syndrome-specific laboratory findings, including genotyping in 78% of the 67. 2,3 Seven patients had undergone HCT: 1 with FA and 1 with DC; each of these had 2 pregnancies. The FA patient had 1 miscarriage and 1 elective abortion; the DC patient had donor egg and IVF for her first pregnancy, and IVF and preimplantation genetic diagnosis for the second, after the gene had been identified.…”

“…1 Patients with GCB have superior outcomes compared with ABC when classified using gene expression profiling (GEP). [1][2][3][4] NF-kB, a transcription factor involved in intracellular signaling, is activated from the downstream pathway of the B-cell receptor and is particularly important in the survival of ABC-DLBCL. [5][6][7] Ibrutinib is an oral covalent inhibitor of Bruton tyrosine kinase, which disrupts signaling from the B-cell receptor to NF-kB, thereby representing a rational therapeutic approach for the ABC subtype.…”

Long-Term Follow-Up of a Case with Dyskeratosis Congenita Caused by NHP2-V126M/X154R Mutation: Genotype-Phenotype Association

“…Dyskeratosis congenita (DC) is a rare inherited syndrome characterized by classical mucocutaneous features (nail dystrophy, lacy skin pigment abnormalities, and/or oral leukoplakia) and the presence of other clinical features including bone marrow failure, pulmonary fibrosis, liver cirrhosis, and a predisposition to cancer [1-3]. The symptoms develop at various ages and may manifest over time.…”

The importance of tying up loose (DNA) ends

“…Strikingly, the authors demonstrate that compound loss of Ssb1 and Ssb2 leads to rapid induction of interferons (IFNs) and HSC depletion, underwritten by severe replication stress and genomic instability in HSCs. As many bone marrow failure (BMF) syndromes arise from defects in DNA repair, 2 these findings provide new insights into the events and signals that initiate HSC depletion in this context.…”

“…Indeed, the inherited disorders Fanconi anemia (FA) and dyskeratosis congenita (DKC) are directly traced to mutations in key DNA repair and telomere maintenance genes, respectively. 2 In order to faithfully copy the genome, DNA replication machinery must resolve numerous obstacles, including conflicts with transcriptional machinery that can lead to stalled replication forks and accumulation of ssDNA:RNA hybrid "R-loops" that can lead to DNA doublestrand breaks (DSBs). 3 Ssb1 and Ssb2 interact with the Integrator complex, a multiprotein structure that binds to R-loop-prone DNA regions and facilitates their resolution.…”