Structural chromosomal aberrations and neuropsychiatric disorders

Abstract: Infantile autism (IA) is a severe neurodevelopment disorder with a complex genetic predisposition. The underlying causes of autism are still not understood. Cytogenetic and molecular analysis of structural chromosomal aberrations found in patients with autism gives us information about possible candidate gene regions associated with these diseases and may increase understanding of brain function. Locations of chromosome regions responsible for diseases can be observed as breakpoints in various chromosomal abnormalities. In this thesis, I have studied structural chromosomal aberrations found in patients with neuropsychiatric disorders. Cytogenetic analysis of four patients with IA revealed an extra structurally abnormal chromosome (ESAC). Fluorescence in situ Hybridisation (FISH) demonstrated the extra chromosome to be an isodicentric chromosome 15 and the karyotype to be 47, XY, inv dup(15)(q13). I used Restriction Fragment Length Polymorphism (RFLP) for disclosing the size and origin of the isodicentric chromosome 15. The parental origin was shown to be maternal and the four IA patients were found to be tetrasomic for chromosome 15 Prader Willi/Angelman region. I performed cytogenetic and FISH studies on blood samples from a patient with a complex balanced translocation (1;6;4), involving the telomeres, associated with mental retardation. The aim of this study was to illustrate the importance of FISH in identifying cryptic translocations in the G-negative telomere regions. The issue of whether apparently balanced translocations related to abnormal phenotypes really are balanced is discussed and possible explanations of how balanced structural rearrangements in the genome can cause behavioural disorders are presented. Cytogenetic and FISH analysis revealed a de novo del(3)(p25.2) in a girl who fulfilled four of six criteria for RS. Polymerase Chain Reaction (PCR) with polymorph microsatellite markers covering the 3p deletion region confirmed this finding and identified the deletion breakpoint in the chromosome band p25.3 between the markers D3S3589 and D3S1263. The PCR analysis showed that the deleted chromosome 3 was of maternal origin.Two non-consanguineous patients diagnosed with Asperger syndrome (AS), a high-function autism-like disorder, had apparently balanced translocations involving chromosome 17p13. Balanced reciprocal translocations offer an opportunity to locate candidate genes. FISH experiments revealed that the two translocation breakpoints were separated by a 250-300 Kb region containing 14 identified genes. Additional analysis of one of the AS patients was performed, applying FISH methods with improved resolution in order to characterise the translocation region and identify any sub-microscopic imbalance. The fine characterisation of the breakpoint was performed by combining overlapping labelled PCR fragments and using them as FISH probes. The results demonstrated the translocation to split the KIAA1871 gene. FISH with small PCR fragments also showed the gene to be implicated in a paracentric inversion. We consider the possibility that KIAA 1871 is involved in the development of AS.