Reverse haplotyping: taking full advantage of 25% risk testing for the 50% at-risk parent in Huntington's disease

Presymptomatic testing (PT) for Huntington's disease (HD) has been available for over 40 years. Individuals who opt for PT are typically at a 50% risk, though in rare cases, '25% at-risk individuals' request to know their genetic status. Family planning is one of the main reasons why predictive testing is requested and with the availability of a direct test, new choices regarding reproduction emerged. In pregnancies, couples of whom the at-risk parent (ARP) does not want to know their own status may opt for direct testing in the 25% at-risk fetus. However, this option has a significant disadvantage: in 25% of cases, the gene expansion will be detected in the fetus, simultaneously revealing the ARP's status. Nevertheless, there is a benefit to this approach that has not yet been well exploited: adding haplotyping to a normal prenatal test outcome may find the ARP (the 'linking pin') no longer at risk of developing HD. We have coined the term reverse haplotyping for this approach. Data from three families in which we applied this method are presented. Our aim is to raise awareness of the full potential of DNA analysis in this context.