Fragile-X carrier screening and the prevalence of premutation and full-mutation carriers in Israel

Fragile-X syndrome is caused by an unstable CGG trinucleotide repeat in the FMR1 gene at Xq27. Intermediate alleles (51-200 repeats) can undergo expan sion to the full mutation on transmission from mother to offspring. To eval uate the effectiveness of a fragile-X carrier-screening program, we tested 14,334 Israeli women of child-bearing age for fragile-X carrier status betw een 1992 and 2000. These women were either preconceptional or pregnant and had no family history of mental retardation. All those found to be carriers of premutation or full-mutation alleles were offered genetic counseling an d also prenatal diagnosis, if applicable. We identified 207 carriers of an allele with >50 repeats, representing a prevalence of 1:69. There were 127 carriers with >54 repeats, representing a prevalence of 1:113. Three asympt omatic women carried the fully mutated allele. Among the premutation and fu ll-mutation carriers, 177 prenatal diagnoses were performed. Expansion occu rred in 30 fetuses, 5 of which had an expansion to the full mutation. On th e basis of these results, the expected number of avoided patients born to w omen identified as carriers, the cost of the test in this study (U.S. $100) , and the cost of lifetime care for a mentally retarded person (>$350,000), screening was calculated to be cost-effective. Because of the high prevale nce of fragile-X premutation or full-mutation alleles, even in the general population, and because of the cost-effectiveness of the program, we recomm end that screening to identify female carriers should be carried out on a w ide scale.