Genomic rearrangements at the cause of three genetic disorders in man

Sammanfattning: Genomic rearrangements are a common cause of genetic disorders in man. This thesis describes the analysis of genomic rearrangements observed in patients with the Hunter syndrome (MPS II), incontinentia pigmenti (IP) and the Blepharophimosis, ptosis and epicanthus inversus syndrome (BPES). MPS II is an X-linked recessive lysosomal storage disorder. In MPS II, structural rearrangements in the IDS locus are observed in 20 % of affected individuals. In order to analyze and characterize these aberrations, rearrangement junctions were isolated and analyzed from eight unrelated individuals suffering from inversions or deletions in the IDS region. The results showed that rearrangements had occurred either by means of nonhomologous end joining (NHEJ) or homologous recombination (HR). Some of the deletions in the IDS gene were the result of NHEJ while inversions were the result of HR between the IDS gene and a locus of high sequence identity, IDS-2, located telomeric of the IDS gene. We also propose that the HR was initiated by a double-strand break in the IDS locus. A novel rearrangement in the IDS locus was also identified in a family with XY, XX and XXY males. IP is a rare multisystem ectodermal disorder with X-linked dominant inheritance. A large set of Swedish patients with IP was screened for mutations in the NEMO gene. In 70 % of the probands, including both familial and sporadic cases, a 12 kb deletion spanning exons 4-10 of the NEMO gene was observed. The deletion is caused by a homologous recombination event between two identical repeats located in intron 3 of the NEMO gene and 3´ of the gene. The clinical manifestations were quite variable, even within IP patients carrying the same mutation. BPES is a disorder affecting cranofacial development. A transcription factor, FOXL2, has been found to be defective in patients with the disorder. A boy with BPES and associated anomalies, suggestive of a contiguous gene deletion syndrome, was investigated using polymorphic markers and fluorescent in situ hybridization (FISH). A deletion of approximately 40 kb was identified within a novel gene, C3orf5. The deletion is located approximately 250 kb upstream of FOXL2. It was suggested that the extragenic deletion in C3orf5 may exert a position effect of FOXL2, and possibly also of other genes in the BPES region.