Cytogenetic and molecular analysis of chromosomal rearrangements associated with neuropsychiatric disorders

Detta är en avhandling från Uppsala : Acta Universitatis Upsaliensis

Sammanfattning: Genetic factors are important in the aetiology of neuropsychiatric disorders. Analysis of chromosomal abnormalities associated with these disorders may provide locus specific information for the identification of candidate genes and, subsequently, for our understanding of brain development and functioning. Cytogenetic and molecular analysis of two 46,XY sisters with mental retardation (MR), seizures and androgen insensitivity syndrome revealed that they carry a microdeletion on Xq11-q 12. With the fibre-FISH technique, we estimated the size of the deletion to 1.1 Mb, and we showed that the deleted region spans the androgen receptor gene and the oligophrenin-1 gene (OPHN1). The combined cytogenetic and clinical findings give further support for OPHN1 gene being involved in brain development and MR. A microdeletion on 19ql3.2 was identified in a patient with Diamond-Blackfan anaemia (DBA), skeletal abnormalities and MR. FISH to metaphase chromosomes and DNA fibres showed that the deletion spans 3.2 Mb of DNA including the RPS19 gene, known to be involved in DBA but not in MR. The results suggest a novel contiguous gene syndrome with a gene responsible for MR included in the deletion. We performed cytogenetic and molecular analysis of patients with autistic features associated with balanced translocations t(5;7), t(17;19) and t(13;17), respectively. FISH analysis of the balanced translocation t(5;7) showed that the chromosome 7 breakpoint coincides with an autism susceptibility locus identified in previous linkage studies. Mutation screening of the two genes closest to the breakpoint (T2R3 and SSBP) on DNA samples from a set of autistic patients did not reveal any alleles associated with the disease. The 7q methylation pattern in DNA from the t(5;7) patient was found normal. Two patients with t(17; 19) and t(13; 17) have been diagnosed with Asperger syndrome (AS), a mild form of autism. Mapping of the two chromosome 17 breakpoints revealed that they are separated by 250-300 kb, and this region contains 13 known genes. The expression of 9 of these genes was analysed on lymphoblastoid RNA obtained from the patients. The level of expression of the genes was found to be similar in the patients and normal controls. Further structural and functional analysis of the genes located around the two 17p breakpoints may reveal candidate sequences for the AS phenotype.

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