Favourable mutation test outcomes for individuals at risk for Huntington disease change the perspectives of first-degree relatives

Abstract.

In mutation testing for Huntington disease, an autosomal dominant hereditary late-onset disorder, unfavourable test outcomes in at-risk individuals provide important information about other family members at risk. On the other hand, common counselling practice considers favourable outcomes as non-informative for at-risk relatives, except for the offspring of the tested individual. We shall show, however, that favourable outcomes also change the perspectives for the tested individual's first-degree relatives at risk. In the case of a (prospective) parent originally at 50% risk, and with n equalling the number of children or fetuses identified as non-carriers, the probability of being a non-carrier equals 2ⁿ/(2ⁿ+1) for the at-risk parent, providing that none of the offspring of this parent has been identified as a carrier. Likewise, the probability of being a non-carrier equals (2ⁿ⁺¹+1)/(2ⁿ⁺¹+2) for the (future) siblings of the tested individual. These changes in probabilities are important for individuals who are considering prenatal or presymptomatic DNA-testing for autosomal dominant hereditary late-onset disorders, such as Huntington disease and hereditary forms of cancer (BRCA1/2, FAP, HNPCC). Consequences can be far reaching in the case of pregnancies, where the risk of miscarriage after a prenatal test is 1%–2%. Parents initially at 50% risk may consider not having a prenatal test in successive pregnancies, knowing that favourable test results in previous pregnancies have considerably reduced their personal risk.