Anticipation (genetics)

In medicine, anticipation is a phenomenon whereby the symptoms of a genetic disorder become apparent at an earlier age as it is passed on to the next generation. In most cases, an increase of severity of symptoms is also noted. It is common in trinucleotide repeat disorders like Huntington's disease, myotonic dystrophy and fragile X syndrome, where triplet repeat mutations in DNA are implicated. Rather strangely, all of these diseases produce neurological symptoms.

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Trinucleotide Repeats and Expansion

Trinucleotide repeats are apparent in a number of loci on the human genome, including introns, exons and 5' or 3' UTR's. They consist of a pattern of three nucleotides (e.g. CGG) which is repeated a number of times. During meiosis, they undergo triplet expansion (see later section); thus, the germ cells produced have a greater number of these repeats. For many of the loci, this expansion is harmless, but in some areas expansion can eventually affect the expression of a gene, causing symptomatology. To cause this effect, the number of repeats needs to cross a certain threshold; for example, normal individuals have between 5 and 30 CTG repeats at the disease loci for myotonic dystrophy. If the number of repeats becomes greater than 50, the person is only mildly affected - perhaps having only cataracts; also, the locus is meiotically unstable, meaning the number of repeats will grow (dynamic mutations). Once the number of copies reaches over 100, the disease will manifest earlier in life (although the individual will still reach adulthood before the symptoms are evident) and the symptoms will be more severe - including electrical myotonia. As the number progresses upwards past 400, the symptoms show themselves during childhood.

Triplet Expansion

The mechanism behind the expansion of the triplet repeats is not well understood. One theory is that the increasing number of repeats influence the overall shape of the DNA, which can have an effect on its interaction with DNA polymerase and thus the expression of the gene.