DYNAMIC MUTATION IN DUTCH HUNTINGTONS-DISEASE PATIENTS - INCREASED PATERNAL REPEAT INSTABILITY EXTENDING TO WITHIN THE NORMAL SIZE RANGE

Analysis of the distribution of normal and expanded alleles of the pol ymorphic (CAG)n repeat in the IT15 gene in the Dutch population confir med the presence of an expanded repeat on all Huntington's disease (HD ) chromosomes. Our results show that the size distributions of normal and affected alleles overlap. Normal alleles range from 11 to 37 repea ts and HD alleles contain 37 to 84 repeats. A clear correlation is fou nd between age at onset and repeat length, but the spread of the age a t onset in the major repeat range producing characteristic HD is too w ide to be of diagnostic value. In the available parent-offspring pairs , maternal HD alleles show a moderate instability with a slight prepon derance of size increase over size decrease. Paternal alleles have a b imodal distribution: the majority (69%) behave similarly to the matern al alleles, while the remainder (31%) show a dramatic expansion, the d egree of which appears proportional to the initial size. This is shown in three out of four juvenile patients, who have repeats of 71, 74, a nd 84 copies, respectively, originating from expanded paternal HD alle les in the previous generation. Two sporadic cases are caused by expan sion of 'large' normal paternal alleles of 32 and 34 repeats, respecti vely, to 46 copies. This not only confirms the diagnosis of HD in two de novo cases, but it also underlines the increased paternal instabili ty. In addition paternal repeat instability was once detected within t he normal range in two sibs who inherited 21 and 22 repeats, respectiv ely, on the same paternal chromosome. In two Dutch HD families the seg regation of the expanded (CAG)n repeat was found. Analysis of the (CAG )n repeat in our previously reported recombinants confirmed their dise ase status.