Further evidence for genetic heterogeneity in the fragile X syndrome

Abstract

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.

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.…”

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

“…Several studies have found tight linkage (0 = 0.05; Drayna and White, 1985;Brown WT et al 1987a;Arveiler et al 1988) whereas one large family shows loose linkage Veenema et al 1987; 8 recombinants in 32 meioses).…”