An assessment of the use of flanking DNA markers for fra(X) syndrome carrier detection and prenatal diagnosis

One hundred and three individuals in 11 unrelated families with the fragile-X [fra(X)] syndrome were tested for polymorphisms identified by probes flanking the fra(X) site at Xq27.3. Two probes distal and 2 proximal to the fra(X) site were used. Thirteen known female carriers were analyzed retrospectively. DNA markers gave probabilities of carrying the mutation of 99% in 1 female, 89% in 8 females, and 10-55% in the other 4 females. We also estimated the probability of having inherited the mutation for 16 individuals of unknown fra(X) status using DNA markers and corrections for incomplete penetrance. The DNA marker test gave risks for females of 1-6% (7 females), 15% (1 female), and 97% (1 female). In males the risks were 1-3% (6 males) and 91% (1 male). In 3 families, DNA marker data were used to calculate probabilities of greater than or equal to 98.5% that transmission of the fra(X) mutation had occurred through normal males. In the retrospective studies, only 1 of 7 retarded males could have been diagnosed prenatally as having the fra(X) mutation with a probability of 99%. DNA marker analysis was uninformative in 5 of these males. When fra(X) carrier status cannot be established by chromosome analysis, DNA marker studies provide an alternative test that can be used to calculate individual risks more precisely. However, linkage analysis of the probe loci in these 11 families suggests that the recombination frequency between the fra(X) locus and the factor IX gene (F9) and DXS52 may be greater than previously suggested. Until the true recombination frequencies are established and the question of heterogeneity among families is fully analyzed, caution in using DNA markers as a predictive test is advised.