Maria Vegter-van der Vlis

Experience in prenatal testing for Huntington's disease in The Netherlands: procedures, results and guidelines (1987–1997)

We have performed 31 exclusion tests (43 per cent) and 41 direct tests (57 per cent) in 43 couples at risk, in the period 1987 to 1997 in Leiden, The Netherlands. This resulted in termination of 28 pregnancies (39 per cent), with an increased risk. In 28 couples (65 per cent), the woman was at risk. Prenatal testing in consecutive pregnancies (mean number: 3) was performed in 15 couples (35 per cent), with a mean time interval of 15 months. Parents should make an independent choice for (every) pregnancy, although most (86 per cent) did not change their initial choice. It is important that the position of children in the same family, of whom some know their status as a result of prenatal testing, whereas others remain at risk, is taken into consideration in counselling. The relative number of exclusion tests when compared with direct tests has diminished since the mutation was identified. The prenatal exclusion–definitive test (Fig. 1) was rarely used (2/72, 3 per cent). Nowadays, direct mutation testing of the fetus only is simpler and faster and the risk of disclosure of the genetic status of the at‐risk parent is only 25 per cent. This test should therefore be offered as another option and included in the international guidelines. The uptake for prenatal testing is low: for 2 per cent of the at‐risk persons, 11 per cent of the tested carriers and a small group of at‐risk persons wishing not to be tested themselves, prenatal testing seems an acceptable choice regarding reproduction. Copyright

Predictability of age at onset in Huntington disease in the Dutch population

As previously described, the age at onset of Huntington disease (HD) ranges from 2 to 80 years, with a mean between 46.0 and 48.9 years. The number of repeats, in the causal CAG repeat expansion, is inversely related to the age at onset and accounts for 50%-77% of the variation in age at onset. We analyzed a Dutch cohort of 755 individuals retrospectively to assess the probability of onset for any given CAG repeat. The repeat size is the major determinant of age at onset, with a correlation of -0.74, stronger (-0.84) in paternal than in maternal inheritance (-0.64), consistent with increased repeat expansion and stronger anticipation in the paternal line. The age at onset within families was more similar than could be explained by the resemblance of the repeat size of persons in the same family. We hypothesized that if environmental factors were principally responsible for this familial aggregation, one would expect a greater correlation for sibs than for parents and children. This was not found to be the case. These observations suggest that genetic factors may play a greater role in the onset of HD than a shared environment. Finally, we discuss several explanations for the fact that the Dutch median age at onset for all expanded repeat sizes studied is significantly later, by about 10 years, than that found in a Canadian study.

Predictive testing of 25 percent at-risk individuals for Huntington disease (1987–1997)

Before the mutation causing Huntington disease was identified, predictive testing of 25% at-risk persons with a 50% at-risk parent who did not wish to know his/her genetic status, was only possible by exclusion testing. The exclusion test, using linked markers, ensures the parents wish not to know because the parents risk is not changed. When mutation analysis became available in 1993, new testing options for 25% at-risk persons emerged: viz., the exclusion-definitive test and direct mutation analysis. These new tests not only disclose the risk of the test candidate, but may also change the risk of the at-risk parent and siblings. The testing options for 25% at-risk test applicants and their consequences are discussed and the testing procedures and results of testing 64 25% at-risk persons in the period 1987 to 1997 are described. Relatives received unsought information in 56% of the test procedures before and 34% after the mutation was identified. A decision tree and guidelines for predictive testing of 25% at-risk test applicants are proposed. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:662-668, 1999.