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

Modelling allele dynamicsTABLE 12 Risk of expansion from PM to FM in affected families: results from four studiesStudy Mothers with PM Offspring with her mutation Excluding probandsNo. Repeat size No. No. with FM (%) No. No. with FM (%)USA,Texas 32 50–113 63 44 (70) – –Fu et al, 1991France 102 55–205 175 145 (83) 131 101 (77)Heitz et al, 1992Finland 66 60–130+ 122 92 (75) 79 49 (62)Väisänen et al, 1994USA, NY 110 50–130+ – – 184 119 (65)Fisch et al, 1995All 310 50–205 360 281 (78) 447 269 (60)40Risk of expansion accordingto PM sizeThe risk of expansion to the FM is correlated withthe size of the PM allele of the carrier mother. Thelarger the repeat size of PM, the greater the riskof expansion to an FM. There also appears to bea threshold PM size at which expansion to FMalways occurs. This is shown in Table 13, basedTABLE 13 Risk of expansion to FM according to PM size inaffected families: results from four studiesPM sizein motherStudyUSA, France Finland USA,Texas Heitz Väisänen NewFu et al, et al, et al, York1991 1992 1994 Fischet al,1995}50–550%20%55–6010%60–70 } 17% } } 46% } 17%70–80} 48% } 39%77% 56%80–90}} 92% } 76%90–100}}} 89%100–10590% } 91%100%}105–110100%110–115115–120 100% 100%120–130> 130}}}}on the four studies of expansion risks in affectedfamilies shown in Table 12.The studies report risks for groups of mothersand, since the groupings do not coincide betweenthe studies, it is difficult to combine the data.However, we have performed a meta-analysis andlogistic regression analysis of risk on size usingthe combined results, assuming that the risk forthe group applies at its mid-point. In addition, wewere able to compare the effect of ascertainmentbias by analysing data according to whether theproband was included or excluded. The valuespredicted from the regression equations are shownin Table 14 and appear to be close to the observedrisks. The equations are given in a footnote to thetable. The effect of excluding the proband fromthe analysis can be seen in Figure 7.Risk of expansion in thegeneral populationThe risk of expansion from PM to FM is likely tobe lower in the general population compared withthat observed in families with fragile X syndrome.There are two reasons for expecting this. First, inaffected families the distribution of PMs must, ofnecessity, be shifted towards greater repeat sizes:which is why the proband presented. Second, fora given size it is possible that in affected familiesthe risk of expansion from PM to FM is greaterthan in others due to some unknown factor. It isbelieved that, in the general population, silent PMsmay take several generations to expand to the FM(Richards et al, 1992; Chakravarti, 1992; Morton &Macpherson, 1992; Oudet et al, 1993a), and a PMthat took three generations to expand has actuallybeen observed (Brown et al, 1993). There are nopublished studies reporting the expansion risk in