Abstract
Chromosomal rearrangements can lead to various serious clinical manifestations, including mental retardation and congenital malformation syndromes. Chromosomal rearrangements larger than 5-10 Mb in size can be detected by conventional karyotyping. A considerable number of clinical disorders, however, is caused by submicroscopic chromosomal rearrangements smaller than 5-10 Mb in size. To routinely detect these rearrangements, an efficient and robust genome-wide technology is needed. One such technology is array-based comparative genomic hybridization (array CGH), an approach which is also referred to as molecular karyotyping. In analogy to the application of array CGH in cancer research, we reasoned that this technology might also be suited for the detection of submicroscopic chromosomal rearrangements in patients with unexplained mental retardation and/or congenital malformation syndromes. The specific aim of this thesis was to explore the feasibility of the array CGH technology for the delineation of DNA copy number alterations for applied clinical genetic and basic genome research purposes. During the course of the project, the concept of molecular karyotyping rapidly changed the field of clinical genetics and genome research and, without any doubt, will continue to do so in the years to come. In case of clinical genetics, we conclude that molecular karyotyping has led to a significant increase in the diagnostic yield in patients with unexplained mental retardation and/or malformation syndromes; the identification of a gene underlying CHARGE syndrome, and the identification of a novel microdeletion syndrome involving chromosome 17q21.31. In case of genome research, we conclude that molecular karyotyping has led to novel insight into the occurrence of copy number variation within the human genome, and into the recombination mechanisms and genomic architectural features underlying the occurrence of copy number variation. Based on the above, we conclude that molecular karyotyping serves as a powerful tool for linking gene dosage alterations to (disease) phenotypes
