Investigation of genetic causes in uncharacterized inherited bone marrow failures

Inherited Bone Marrow Failure Syndromes (IBMFSs) are a heterogeneous group of disorders that result from deficiency of in a single or more hemapoetic cell lineages. Fanconi Anemia, Dyskeratosis Congenita, Shwachman Diamond Syndrome are the classic examples, however there are a group of conditions termed as Uncharacterized Bone Marrow Failure Syndrome, which refer to a heterogeneous disease group of disorders, which cannot be classified as one of the common IBMFSs where one or more cell lineages are affected and may be accompanied by other systemic findings. In this thesis, 17 individuals with "uncharacterized bone marrow failure syndromes" sent from various regions of Turkey were first evaluated for genome-wide copy number variations, followed by whole exome sequencing (WES). A copy number variation of unknown significance was detected in 1 individual. WES analysis revealed the causative variants for 7 individuals. Disease-related variants were in genes involved in telomere maintenance, amino acid metabolism, ribosome maturation, vitamin metabolism and other cellular processes, which were previously associated with IBMFSs. In addition, one affected individual with bone marrow failure, who also had developmental delay, and dysmorphic features had a variant in a strong candidatre gene. This gene was also pointed out by homozygosity mapping involving the other affected sibling and nuclear family; has not been previously associated with any IBMFSs; and is critical in p53-related apoptotic pathways. In conclusion, with this study it has been demonstrated that the uncharacterized bone marrow failure syndromes are genetically and phenotypically a very heterogeneous group of disorders. The blended phenotypes and somatic mutations in a germline mutation background have been shown to complicate differential diagnosis in this group with high phenotype diversity.