DNA contains all the information for the development of a single fertilized egg cell into a complex organism containing billions of cells. Some changes in the DNA code can disturb the normal development of an embryo, which can lead to congenital disorders such as intellectual disability, skeletal defects or autism spectrum disorders. Despite impressive developments in DNA-sequencing technologies, which are used to detect variants in the DNA code, no genetic causes are identified in many of the patients with congenital disorders. Some of these DNA variants can be very large, affecting large parts of the DNA code. The causes and consequences of such large, complex structural DNA variants are studied in this thesis.
Most human fertilizations do not lead to a successful pregnancy. The DNA code of early human embryos is, for unknown reasons, very unstable, which frequently leads to the formation of new structural DNA variants during this early developmental phase. The research described in this thesis shows that part of this genetic instability in early embryos can be explained by DNA damage already occurring in sperm cells. Subsequently, various DNA-sequencing techniques are applied to study the molecular consequences of complex structural variation in cells derived from patients. New methods are described to determine the which specific genes are affected by the DNA variants, which can help to diagnose patients. Additionally, it was discovered that variants in the POLR3GL gene can cause specific bone and teeth abnormalities which have large consequences for the patients.