The Fragile X Syndrome in Mentally Retarded Patients from Latvia. Doctoral Thesis

Abstract

Mental retardation (MR) is a complex phenotype, affecting 2 - 3% of the general population. A quarter of cases are caused by genetic disorders. Mental retardation is the most frequent cause of severe handicap in children. We focussed our study on fragile X syndrome, which is both well known and a common cause of X-linked mental retardation. One of principle tasks in our study was to estimate the prevalence of fragile X syndrome (FXS) in the entire Latvian male population. In the prevalence study we analysed retrospective data of the male individuals with mental retardation and developmental disabilities, diagnosed in ten years time. The prevalence of fragile X syndrome in the Latvian male population was estimated to be 1/6428 (95% CI 5538 – 7552) or 15.55/100 000 males (95% CI 13.24 – 18.05). Fragile X syndrome is caused by an expanded CGG repeat (> 200 units, full mutation) at the 5' end of the FMR1 gene. In our study we characterised the distribution and structure of CGG repeats among X chromosomes with normal CGG repeat alleles and chromosomes with full mutation. We analysed elsewhere described FMR1 gene linked STR based markers FRAXAC1, FRAXAC2 and DXS548, and one SNP based marker ATL1, found within 150 kb of the FMR1 CGG repeat. STR and SNP marker haplotypes were combined as follows: DXS548-FRAXAC1-ATL1-FRAXAC2. DNA studies of X chromosomes with normal CGG repeats revealed high incidences of allele 30 (29.95%), allele 31 (13.10%) and allele 29 (12.83%). A statistically significant association with ATL1 SNP was found in following cases: allele 29 and G (p = 0.001); allele 30 and A (p < 0.0001) and allele 31 with A (p = 0.0013). Polymorphism G was found to be associated with grey-zone CGG alleles (p = 0.0271) and exclusively associated with all FXS alleles. A structure analysis of grey-zone alleles suggest haplotype 7-4-A-5+ as a “protective” haplotype for CGG tract stability. The case-control study results also imply that in the Latvian population, haplotype 2-2-G-4 is a marker of CGG tract instability. Results of AMOVA for haplotypes revealed distinct genetic background for FXS chromosomes. This is the first study regarding FMR1 linked haplotypes in the Baltic States region. Our results provide evidence of different mutational pathways of CGG repeat expansion in North-Eastern Europe.