Null alleles at the Huntington disease locus: Implications for diagnosticsand CAG repeat instability

PCR amplification of the CAG repeat in exon 1 of the IT15 gene is routinely undertaken to confirm a clinical diagnosis of Huntington disease (HD) and to provide predictive testing for at-risk relatives of affected individuals . Our studies have detected null alleles on the chromosome carrying the exp anded repeat in three of 91 apparently unrelated HD families. Sequence anal ysis of these alleles has revealed the same mutation event, leading to the juxtaposition of uninterrupted CAG and CCG repeats. These data suggest that a mutation-prone region exists in the IT15 gene bounded by the CAG and CCG repeats and that caution should be exercised in designing primers that ann eal to the region bounded by these repeats. Two of the HD families segregat ed null alleles with expanded uninterrupted CAG repeats at the lower end of the zone of reduced penetrance. The expanded repeats are meiotically unsta ble in these families, although this instability is within a small range of repeat lengths. The haplotypes of the disease-causing chromosomes in these two families differ, only one of which is similar to that reported previou sly as being specific for new HD mutations. Finally, no apparent mitotic in stability of the uninterrupted CAG repeat was observed in the brain of one of the HD individuals.