No abstract

We screened 183 autistic males for the fra(X) and found 24 (13.1%) to be positive. Adding the subjects of this study to those of 11 other surveys, of which 6 were positive and 5 were negative, a total of 614 autistic males have been screened. Overall 47 (7.7%) were positive. Based on this estimate and the prevalence of autism and fra(X), we estimate that 12.3% of fra(X) males are autistic. We have found that 17.3% of our fra(X) males were autistic and overall a 21.2% frequency has been reported, these higher figures are most likely due to biases in age and ascertainment. With an overall 7.7% frequency of fra(X) among autistic males and an estimated 12.3% of autism among fra(X) males, we conclude there is likely to be a significant association of fra(X) with autism. Because fra(X) appears to be the single most common cause of the condition, chromosomal testing is recommended for any autistic person with undiagnosed etiology.

Genetic linkage between a factor IX DNA restriction fragment length polymorphism (RFLP) and the fragile X chromosome marker was analyzed in eight fragile X pedigrees and compared to eight previously reported pedigrees. A large pedigree with apparently full penetrance in all male members showed a high frequency of recombination. A lod score of -7.39 at theta = 0 and a maximum score of 0.26 at theta = 0.32 were calculated. A second large pedigree with a nonpenetrant male showed tight linkage with a maximum lod score of 3.13 at theta = 0, a result similar to one large pedigree with a nonpenetrant male previously reported. The differences in lod scores seen in these large pedigrees suggested there was genetic heterogeneity in linkage between families which appeared to relate to the presence of nonpenetrant males. The combined lod score for the three pedigrees with nonpenetrant males was 6.84 at theta = 0. For the 13 other pedigrees without nonpenetrant males the combined lod score was -21.81 at theta = 0, with a peak of 0.98 at theta = 0.28. When lod scores from all 16 families were combined, the value was -15.14 at theta = 0 and the overall maximum was 5.13 at theta = 0.17. To determine whether genetic heterogeneity was present, three statistical tests for heterogeneity were employed. First, a "predivided-sample" test was used. The 16 pedigrees were divided into two classes, NP and P, based upon whether or not any nonpenetrant males were detected in the pedigree. This test gave evidence for significant genetic heterogeneity whether the three large pedigrees with seven or more informative males (P less than 0.005), the eight pedigrees with three informative males (P less than 0.001), or all 16 pedigrees (P less than 0.001) were included in the analysis. Second, Morton's large sample test was employed. Significant heterogeneity was present when the analysis was restricted to the three large pedigrees (P less than 0.025), or to the eight pedigrees with informative males (P less than 0.05) but not when smaller, less informative pedigrees were also included. Third, an "admixture" test for heterogeneity was employed which tests for linkage versus no linkage. A trend toward significance was seen (0.05 less than P less than 0.10) which increased when the analysis was restricted to the larger, more informative pedigrees.(ABSTRACT TRUNCATED AT 400 WORDS)

A multilocus analysis of the fragile X (fra(X] syndrome was conducted with 147 families. Two proximal loci, DXS51 and F9, and two distal loci, DXS52 and DXS15, were studied. Overall, the best multipoint distances were found to be DXS51-F9, 6.9%, F9-fra(X), 22.4%; fra(X)-DXS52, 12.7%; DXS52-DXS15, 2.2%. These distances can be used for multipoint mapping of new probes, carrier testing and counseling of fra(X) families. Consistent with several previous studies, the families as a whole showed genetic heterogeneity for linkage between F9 and fra(X).

The X-linked fragile X [fra(X)] syndrome, associated with a fragile site at Xq27.3, is the most common Mendelian inherited form of mental deficiency. Approximately 1 in 1060 males and 1 in 677 females carry the fra(X) chromosome. However, diagnosis of carrier status can be difficult since about 20% of males and 44% of females are nonpenetrant for mental impairment and/or expression of fra(X). We analyzed DNA from 327 individuals in 23 families segregating fra(X) for linkage to three flanking polymorphic probes: 52A, F9, and ST14. This allowed probable nonpenetrant, transmitting males and carrier females to be identified. A combined linkage analysis was conducted using these families and published probe information on F9 in 27 other families, 52A in six families, and ST14 in five families. The two-point recombination fraction for 52A-F9 was 0.13 (90% confidence interval, 0.10-0.16), for F9-fra(X) was 0.21 (0.17-0.24), and for fra(X)-ST14 was 0.12 (0.07-0.17). Tight linkage between F9 and fra(X) was observed in some families; in others loose linkage was seen suggesting genetic linkage heterogeneity. Risk analysis of carrier status using flanking DNA probes showed that probable nonpenetrant transmitting males were included in families showing both tight and loose linkage. Thus, in contrast to our previous conclusions, it appears that the presence or absence of nonpenetrant, transmitting males in a family is not an indicator of heterogeneity. To determine if heterogeneity was present, we employed the admixture test. Evidence for linkage heterogeneity between F9 and fra(X) was found, significant at P less than 0.0005. Nonsignificant heterogeneity was seen for 52A-F9 linkage. No heterogeneity was found for fra(X)-ST14. The frequency of fra(X) expression was significantly lower in families with tight F9-fra(X) linkage than in families with loose linkage. Cognition appeared to relate to linkage type: affected males in tight linkage families had higher IQs than those in loose linkage families. These findings of genetic heterogeneity can account in part for the high prevalence and apparent high new mutation rate of fra(X). They will affect genetic counseling using RFLPs. An understanding of the basis for genetic heterogeneity in fra(X) will help to clarify the nature of the unusual pattern of inheritance seen in this syndrome.