Unstable triplets and their mutational mechanism: size reduction of the CGG repeat vs. germline mosaicism in the fragile X syndrome.

The mechanism responsible for the characteristic expansion of the trinucleotide repeat involved in the pathogenesis of the fragile X syndrome is still largely unclear. Slipped strand mispairing (SSM) and similar DNA replication errors could determine both increases and decreases of the unit number in simple repetitive sequences. Actually, there have been a few reports of size reduction of the (CGG)n in parent-to-child transmission of the fragile X syndrome, which may help in understanding the mutational mechanism and may have practical implications for genetic counseling. We describe here 5 such cases from our series of fragile X patients and emphasize the possible role of SSM-like events in causing (CGG)n expansions and reductions. The possibility that some of these reductions are only apparent, resulting from parental germinal mosaicism is also considered.