A CCG REPEAT POLYMORPHISM ADJACENT TO THE CAG REPEAT IN THE HUNTINGTON DISEASE GENE - IMPLICATIONS FOR DIAGNOSTIC-ACCURACY AND PREDICTIVE TESTING

The polymorphic CAG repeat that is expanded on Huntington disease (HD) chromosomes is flanked by a CCG repeat. Here we show that this CCG tr act, previously assumed to be invariant at seven CCG repeats, is also polymorphic. We have identified five CCG alleles from 205 normal chrom osomes, with 137 (67%) having alleles of seven repeats, five (2%) with nine repeats, 61 (30%) with 10 repeats, one (0.5%) with 11 repeats an d one (0.5%) with 12 repeats. In contrast, analysis of 113 HD chromoso mes revealed that the majority (105 chromosomes, 93%) contained seven CCG repeats, while the remaining eight chromosomes (7%) had allele siz es of 10 CCG repeats. Despite evidence that both CAG and CCG are polym orphic on normal chromosomes, we have found that it is only the CAG le ngth that has a significant impact on age of onset. The discovery of l arger sized CCG alleles, however, has significant implications for the assessment of CAG repeat length, particularly for persons with estima ted CAG size of 36 - 42 repeats, since an overestimation of CAG length in this range could result in erroneous information being imparted to patients.