CORRELATION BETWEEN THE ONSET AGE OF HUNTINGTONS-DISEASE AND LENGTH OF THE TRINUCLEOTIDE REPEAT IN IT-15

Huntington's disease (HD) is an autosomal dominant disorder with a variable age of onset that is influenced by the sex of the affected parent. The recent recognition that HD is caused by an expanded triplet repeat suggests the possibility that the onset age may be predicted by the length of the repeat. This hypothesis was tested by assaying the length of the repeat in 114 individuals who were clinically diagnosed with HD and had a known onset age. Every individual had an expanded allele. The range was from 36 to 82 repeats (mean = 48.4 +/- 9.51) and larger than the normal range (6 to 31). The size of the expanded allele was correlated with the age of onset (r = -0.65 p < .0001). Despite the highly significant correlation, the repeat size explains less than half of the variance in onset age. Furthermore, the age of onset cannot be predicted from the size of the triplet repeat, particularly if the number of repeats is in the smaller end of the expanded range. If the repeat is less-than-or-equal-to 50 triplets, the amount of variation in the age of onset explained by the length of the triplet repeat is less than 10%. As an illustration, the onset age of individuals with 39 repeats ranges from 30 to 65 years old. The sex of the affected parent had no effect in our sample beyond the effect of the length of the repeat. Affected offspring of affected fathers had longer repeats and a larger variance in allele size than offspring of affected mothers, perhaps reflecting greater instability in paternal transmission.