DECREASE IN THE CGG(N) TRINUCLEOTIDE REPEAT MUTATION OF THE FRAGILE-XSYNDROME TO NORMAL SIZE RANGE DURING PATERNAL TRANSMISSION

The fragile X syndrome, the most common inherited form of mental retar dation, is caused by the expansion of a CGG(n) trinucleotide repeat in the FMR-1 gene. Although the repeat number usually increases during t ransmission, few cases with reduction of an expanded CGG(n) repeat bac k to the normal size range have been reported. We describe for the fir st time a family in which such reduction has occurred in the paternal transmission. The paternal premutation (Delta = 300 bp) was not detect ed in one of the five daughters or in the son of this daughter, althou gh he had the grandpaternal RFLP haplotype. Instead, fragments indicat ing the normal CGG(n) repeat size were seen on a Southern blot probed with StB12.3. PCR analysis of the CGG(n) repeat confirmed this; in add ition to a maternal allele of 30 repeats, an allele of 34 repeats was detected in the daughter and, further, in her son. Sequencing of this new allele revealed a pure CGG(n) repeat configuration without AGG int erruptions. No evidence for a somatic mosaicism of a premutation allel e in the daughter or a normal allele in her father was detected when i nvestigating DNA derived from blood lymphocytes and skin fibroblasts. Another unusual finding in this family was lack of the PCR product of the microsatellite marker RS46 (DXS548) in one of the grandmaternal X chromosomes, detected as incompatible inheritance of RS46 alleles. The results suggest an intergenerational reduction in the CGG(n) repeat f rom premutation size to the normal size range and stable transmission of the contracted repeat to the next generation. However, paternal ger m-line mosaicism could not be excluded as an alternative explanation f or the reverse mutation.