Genome wide whole blood transcriptome profiling across inherited bone marrow failure subtypes.

Abstract

Gene expression profiling has long been used in understanding the contribution of genes and related pathways in disease pathogenesis and susceptibility. We have performed whole blood transcriptomic profiling in a subset of inherited bone marrow failure (IBMF) cases that are clinically and genetically characterised as Fanconi anemia (FA), dyskeratosis congenita (DC) and Shwachman Diamond syndrome (SDS). We hypothesized that annotating whole blood transcripts genome wide will aid in understanding the complexity of gene regulation across these IBMF subtypes. Initial analysis of these blood derived transcriptomes revealed significant skewing towards upregulated genes in FA cases when compared to controls. Both DC and SDS cases also showed similar skewing profiles in their transcriptional status revealing a common pattern across these different IBMF subtypes. Gene set enrichment analysis revealed shared pathways involved in protein translation and elongation (ribosome constituents), RNA metabolism (nonsense mediated decay) and mitochondrial function (electron transport chain). We further identified a discovery set of 26 upregulated genes at stringent cut-off (FDR<0.05) that appeared as a unified signature across the IBMF subtypes. Subsequent transcriptomic analysis on genetically uncharacterised BMF cases revealed a striking overlap of genes, including 22 from the discovery set indicating a unified transcriptional drive across the classic (FA, DC and SDS) and uncharacterised BMF subtypes. This study has relevance in disease pathogenesis, for example in explaining the features (including the BMF) common to all IBMF cases and suggests harnessing this "transcriptional signature" for patient benefit.