Accurate Sizing of (CAG)n Repeats Causing Huntington Disease by Fluorescent PCR

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Abstract
Huntington disease (HD) is an autosomal dominant progressive neurodegenerative disorder characterized by motor disturbance, cognitive loss, and psychiatric manifestations. Mapping of the putative HD gene to chromosome 4 in 1983 [1] facilitated presymptomatic testing of people at risk for HD by using linked polymorphic DNA markers. This method required DNA from related individuals to track the putative HD allele within a family. The situation changed after the gene responsible for HD was identified in 1993 [2], and a new method, based on PCR, became available for the detection of the disorder. This new method also enabled direct mutation analysis and genetic counseling for new mutation HD families. The mutation mechanism was found to be the expansion of a CAG repeat in the 5′-translated region of the HD gene. The mechanism by which the increased trinucleotide repeat length leads to the characteristic clinical symptoms and neuropathology of HD is, as yet, unknown. The CAG repeat of the HD gene is polymorphic in the population, varying between 8 and 36 repeats on normal chromosomes and is expanded with >37 repeats in chromosomes of HD-affected individuals [3].