Genetic linkage heterogeneity in the fragile X syndrome

Abstract

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)

Report of the committee on the genetic constitution of the X and Y chromosomes

“…The pooled linkage data give for F9-FRAXA (Zmax = 23.42, 0 = 0.2) and for DXS52-FRAXA (Zmax = 41.05, 0 = 0.15). Evidence for linkage heterogeneity for the interval F9-FRAXA has been presented (Brown WT et al 1985;.and.appears confirmed by a large collaborative study involving the analysis of 147 families (Brown WT et al 1988). 30% of the families show very tight linkage between F9 and FRAXA ( less than or equal to 0.05) while remaining show loose linkage ( greater than or equal to 0.30).…”

“…F9 and DXS52 have initially been shown to be flanking markers (Camerino et al 1983;Oberl6 et al 1985a). Extensive linkage analyses have been carried out by several groups with DXS51 and F9 on the proximal side and DXS52 and DX15 on the distal side (Brown WT et al 1985;Oberl6 et al 1986b;1987;HGM9;Connor et al 1987;HGM9;Veenema et al 1987;Mulligan et al 1985;Warren et al 1985;Foster-Gibson et al 1986;Buchanan et al 1987;Mulley et al 1987;HGM9;Senior et al HGM9;Giannelli et al 1987). The pooled linkage data give for F9-FRAXA (Zmax = 23.42, 0 = 0.2) and for DXS52-FRAXA (Zmax = 41.05, 0 = 0.15).…”

Penetrance of Fra(X) gene: Influence of grandparental origin of the gene, mental status of the carrier mother, and presence of a normal transmitting male

“…It is well established that apparently unaffected males are able to transmit the fra(X) gene to their daughters [Martin and Bell, 1943;Webb et al, 1981;Fryns and Van den Berghe, 1982;Gardner et al, 1983;Froster-Iskenius et al, 1984;Pembrey et a1.,1984;Brown et al, 1985;1987;HowardPeebles and Friedman, 1985;Loesch et al, 1987;Holmgren et al, 19881. Most of these reports do not mention affected brothers and sisters of such NTM's.…”

Fragile X syndrome in an extended family with special reference to an affected male with Klinefelter Syndrome

“…Mattei, Centre de Genetique Medicale, HBpital d'Enfants de la Timone, 13385 Marseille Cedex 5, France. o 1991 Wiley-Liss, Inc. still unclear. Genetic heterogeneity has been suggested in several reports [Brown et al, 1985[Brown et al, ,1987Giannelli et al, 19871 and analysis of a large body of data has shown that the affection is transmitted through phenotypically normal males, termed transmitting males [Sherman et al, 1984[Sherman et al, ,1985Loeschet al, 19871. Genetic counseling in the fra(X) syndrome requires a complete family analysis including the clinically normal males.…”