Huntington's disease: Molecular genetics, mutation and predictive testing

Predictive genetic testing offers the opportunity for persons at risk to obtain information about their carrier status concerning Huntington's disease (HD). HD is associated with the expansion of a (GAG) repeat in the gene IT15. HD chromosomes contain about 40-75 repeat units, whereas normal chromosomes show a range between 11 and 33 repeats. The HD repeat is highly unstable during transmission, involving both increases and decreases in size with the largest expansions occurring in male meioses. The number of (CAG) copies is inversely correlated with the onset age of the disorder. Investigation of sporadic cases revealed that new mutations for HD are more frequent than estimated. Analysis of the repeat length allows direct DNA diagnosis of affected individuals and asymptomatic persons at risk. From 1989 to March 1993 in our institute predictive testing by indirect DNA methods was requested by 108 persons at risk. After cloning of the HD gene in 1993, direct testing was requested by 113 persons at risk between April 1993 and April 1994 in Gottingen. In about 400 patients differential diagnosis was performed with the direct method. In approximately 82% of the patients the expanded (CAG) repeat was found, and the HD diagnosis could be confirmed.