Onco-developmental breakpoints are novel sites of recurrent genome rearrangement marked by late replication timing

Genomic rearrangements are a common cause of human congenital abnormalities and mental retardation. However, in the majority of cases a molecular mechanism linking rearranged chromosomes to disease phenotype is lacking. Here, we systematically investigated genome-wide patterns of structural variation breakpoints underlying congenital disease. We observed that breakpoints are non-randomly distributed throughout the genome and frequently target cancer genes or overlap with somatic breakpoints from cancer rearrangements. The overlapping breakpoints do not involve known sites of genome fragility, but specifically associate with late replicating regions, which are prone to replication stress. Molecular profiling of the effects of recurrent rearrangements in congenital patients revealed expression of gene fusions involving the cancer genes ETV1, FOXP1 and the oncogenic miRNA cluster C19MC. We show that expression of C19MC miRNAs results in severe defects in brain morphogenesis during embryonic development. Altogether, these findings define novel sites of recurrent genome breakage, that we term onco-developmental breakpoints, which lead to structural changes that can drive both cancer and defects in embryonic development.