Advances in understanding the genetic basis for bone-marrow failure

Inherited marrow failure syndromes (IMFSs) are rare genetic diseases with varying degrees of cytopenia. Many of the syndromes are also characterized by nonhematological manifestations and a high risk of cancer. This review summarizes recent advances in understanding the genetic background of the common IMFSs.

Over recent years, numerous known and novel genes have been found to be associated with IMFSs. Although the functions of the proteins are largely unknown, they are postulated to play critical roles in fundamental cellular processes such as DNA repair, telomere maintenance, RNA metabolism, ribosomal biogenesis, growth-factor-signaling pathways and cell survival. For example, the telomere-related genes, DKC1 and TERC, have been identified as causes of dyskeratosis congenita. Also, homozygosity for the common cancer-associated gene, BRCA2, has been found to cause a rare subtype of Fanconi anemia.

The knowledge of the genetics of IMFSs has started to be translated into clinical practice. The identification of IMFS-related genes provided new diagnostic tools and better classification of the various disorders. Also, these advances enabled the design of clinical trials using gene therapy and preimplantation genetic diagnosis followed by in-vitro fertilization for selection of suitable embryos for hematopoietic stem-cell transplantation.