MOLECULAR AND CYTOGENETIC INVESTIGATIONS OF THE FRAGILE-X REGION INCLUDING THE FRAX-A AND FRAX-E CGG TRINUCLEOTIDE REPEAT SEQUENCES IN FAMILIES MULTIPLEX FOR AUTISM AND RELATED PHENOTYPES

We undertook molecular and cytogenetic analyses in 25 families multipl ex for autism and related disorders, Three of the multiplex families e xhibited fragile X, and the affected offspring all exhibited CGG tripl et repeat insertion mutations in the FMR-1 gene, One of these families contained an affected pair of monozygotic female twins. Both had simi lar-sized CGG triplet repeat expansions, but different phenotypic mani festations, One suffered from autism and the other from mild mental re tardation and marked social anxiety, PCR and Southern hybridization an alysis of the CGG repeat sequences characterizing fragile X A (Frax A) and E and the methylation status of FMR-1 showed no evidence of abnor mal CGG repeat expansion or FMR-1 hypermethylation in the remaining 22 multiplex families, Moreover, there was no correlation between the Fr ax A or E (CGG)n repeat length with affected status, nor any associati on with the low-level (<3%) expression of cytogenetic fragility at Xq2 7 previously reported in these families, Our findings indicate that mo st instances of recurrence in families multiplex for autism and relate d disorders are not accounted for by Frax A and E, They also indicate that the phenotypic manifestations of Frax A may be influenced by stoc hastic, environmental and other biological factors.