Point mutation analysis of the FMR-1 gene in autism

We have analysed all 17 exons of the human FMR-1 gene for mutations in autistic individuals using single-stranded conformational polymorphism (SSCP) analysis. We have identified three new polymorphisms. SSCP DNA fragment shifts were found for exons, 5, 10 and 11 in autistic individuals and in normal controls. Sequence analysis showed the exon 10 and 11 polymorphisms to result from base substitutions within introns, 14 and 73 bp downstream from the splice site respectively. In exon 5, a G to A base substitution at codon 138 has no effect on amino acid sequence. The intronic polymorphism adjacent to exon 10 was analysed amongst two groups of unrelated autistic individuals-one from the UK and one from Germany- and amongst a control population. Comparison of allele frequencies between Caucasian autism cases and Caucasian controls show a significant increase in the presence of the polymorphic intronic sequence 3' to exon 10 (Fisher's exact test, P = 0.01). The base change is at a position where it is unlikely to affect splicing of the FMR-1 transcript and is most likely a neutral variant that has only a spurious false positive association with autism. However further linkage disequilibrium analyses are justifiable. The positive association with autism should be explored in further samples to determine whether it has any validity as a genetic marker for autism.