Screening for Fragile X Syndrome (Murray et al.) - NIHR Journals ...

Health Technology Assessment 1997; Vol. 1: No. 4Chapter 10Modelling allele dynamicsThe published studies describing practicalexperience with screening do not providesufficient information in themselves to assess thepotential of the different screening strategies forfragile X syndrome. Instead, we found it necessaryto rely on theoretical calculations using the bestestimates available from the literature. Part of thisrequired the construction of a statistical modelwhich described the population dynamics of thePM and FM alleles between generations. Althoughseveral such models have been constructed theydo not meet the current needs. The earliest models(Winter, 1987; Sved & Laird, 1990) did not havethe benefit of knowledge of the molecular basis ofthe defect. Later models (Morton & Macpherson,1992; Kolehmainen, 1994; Ashley & Sherman,1995) were increasingly detailed, taking accountof the latest DNA studies, but are unnecessarilycomplicated for the purposes of screening.possible outcomes for their children, in terms ofallelic inheritance and the presence of fragile Xsyndrome. These possibilities are shown in Figure 5,using what is known about the molecular biologyof the PM and FM alleles. Some of the combinationsof couples have been left out (e.g. bothparents have a PM), as they would add complexitybut make little difference to the results. Bothmales and females with an FM are included,although the reproductive fitness of males isthought to be effectively zero and affected femalestend not to reproduce (Sherman et al, 1984).The critical components of the model are thefrequency of the alleles and the risk of expansionfrom PM to FM in one female generation. It islikely that different values will need to be assignedto these components according to whether thecouples are members of families affected by fragileX syndrome or of the general population.A simple modelA simple and understandable way of modellingthe screening process is to begin with a populationof 1 million couples and consider the variousPM frequencyThe results of nine studies in which the repeat sizehas been determined among unrelated individualswith no family history of fragile X syndrome areParentsFM FM PM NormalReproduceFoetalmutationFoetalFMFragile XFIGURE 5 Possible outcomes of pregnancy37