Detailed molecular studies of chromosome rearrangements in man

Apparently balanced chromosome rearrangements (ABCRs), mainly reciprocal translocations and inversions, are common in our species and are present both in patients with clinical abnormalities and in phenotypically normal individuals. The four main features that are thought to explain clinical abnormalities in patients with ABCRs are: (i) breakpoint-mediated gene disruption, (ii) breakpoint-associated genomic imbalances, (iii) additional chromosomal complexity and (iv) genomic imbalances unrelated to the breakpoints. The work presented in this thesis represents one of the first systematic studies to ascertain the occurrence of the above four features in both phenotypically normal and abnormal carriers of ABCRs. Molecular cytogenetic analyses by FISH and/or array painting and by array CGH were applied in the characterisation of ABCRs in 31 phenotypically normal individuals (control cohort) and in 16 phenotypically abnormal patients (patient cohort). The occurrence of the above four features was assessed in both cohorts and the results were compared in an attempt to determine if the ABCRs in these two groups are molecularly distinct. Genomic imbalances both at the breakpoints and unrelated to the breakpoints and additional chromosomal complexity were present in 25% of the cases in the patient cohort, but in none of those in the control cohort. Surprisingly, breakpoint-mediated gene disruption was equally frequent in both cohorts. However, there was a difference in the type of genes involved, with those of the patient cohort being more commonly involved in development and function of the nervous system. These observations suggest that there are molecular differences in the two groups of carriers. Furthermore, among the four features analysed, genomic imbalances both at the breakpoints and elsewhere in the genome appear to be the main cause of phenotypic abnormalities in carriers of ABCRs; nevertheless disease candidate genes have also been identified and future studies will assess their contribution to the abnormal phenotypes. In summary, the application of molecular techniques is an invaluable approach to characterise genomic regions involved in chromosome rearrangements and other genomic regions unrelated to the breakpoints, thus aiding in the understanding of the contribution of these genomic regions to human disease and to human variation.