MOLECULAR ANALYSIS AND TEST OF LINKAGE BETWEEN THE FMR-I GENE AND INFANTILE-AUTISM IN MULTIPLEX FAMILIES

Approximately 2%-5% of autistic children show cytogenetic evidence of the fragile X syndrome. This report tests whether infantile autism in multiplex autism families arises from an unusual manifestion of the fr agile X syndrome. This could arise either by expansion of the (CGG)n t rinucleotide repeat in FMR-1 or from a mutation elsewhere in the gene. We studied 35 families that met stringent criteria for multiplex auti sm. Amplification of the trinucleotide repeat and analysis of methylat ion status were performed in 79 autistic children and in 31 of their u naffected siblings, by Southern blot analysis. No examples of amplifie d repeats were seen in the autistic or control children or in their pa rents or grandparents. We next examined the hypothesis that there was a mutation elsewhere in the FMR-1 gene, by linkage analysis in 32 of t hese families. We tested four different dominant models and a recessiv e model. Linkage to FMR-1 could be excluded (lod score between -24 and -62) in all models by using probes DXS548, FRAXAC1, and FRAXAC2 and t he CGG repeat itself. Tests for heterogeneity in this sample were nega tive, and the occurrence of positive lod scores in this data set could be attributed to chance. Analysis of the data by the affected-sib met hod also did not show evidence for linkage of any marker to autism. Th ese results enable us to reject the hypothesis that multiplex autism a rises from expansion of the (CGG)n trinucieotide repeat in FMR-1. Furt her, because the overall lod scores for all probes in all models teste d were highly negative, linkage to FMR-1 can also be ruled out in mult iplex autistic families.