Genomic and functional overlap between somatic and germline chromosomal rearrangements. Genomic and functional overlap between somatic and germline chromosomal rearrangements

Genomic rearrangements are a common cause of human congenital abnormalities. However, their causes and consequences are poorly understood. Here, we performed in-depth molecular analysis of two patients with congenital disease who carried de novo genomic rearrangements. We found that the rearrangements in both patients hit cancer genes and drive formation of fusion genes similar to those described in cancer. Subsequent systematic analysis of a large set of 552 de novo germline genomic rearrangements underlying congenital disorders revealed significant enrichment for cancer genes and somatic cancer breakpoints. Breakpoints of common germline structural variations also strongly overlap with cancer breakpoints, but are depleted for cancer genes. We propose that the same genomic positions are prone to genomic rearrangements in germline and soma, but that timing and context of breakage determines whether developmental defects or cancer are promoted. These results are of relevance for explaining the co-occurrence of pediatric cancer and congenital morphological abnormalities in children and shed light on the molecular mechanisms that lead to congenital disease.