Fragile-X syndrome is caused by an unstable CGG trinucleotide repeat in the FMR1 gene at Xq27. Intermediate alleles (51-200 repeats) can undergo expansion to the full mutation on transmission from mother to offspring. To evaluate the effectiveness of a fragile-X carrier-screening program, we tested 14,334 Israeli women of child-bearing age for fragile-X carrier status between 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 and 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 asymptomatic women carried the fully mutated allele. Among the premutation and full-mutation carriers, 177 prenatal diagnoses were performed. Expansion occurred in 30 fetuses, 5 of which had an expansion to the full mutation. On the basis of these results, the expected number of avoided patients born to women 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 prevalence of fragile-X premutation or full-mutation alleles, even in the general population, and because of the cost-effectiveness of the program, we recommend that screening to identify female carriers should be carried out on a wide scale.

A previously unknown signal transduction pathway is important in human cognitive development.

Objective: The objective of this study was to identify the gene causing autosomal recessive infantile bilateral striatal necrosis. Methods: We have mapped the disease gene in the candidate region to approximately 230kb on 19q13.33 in 8 interrelated families including a total of 12 patients and 39 unaffected individuals. Results: Sequencing of the nup62 gene showed a missense mutation causing a change from glutamine to proline (Q391P) in all the patients, producing a substitution from a polar, hydrophilic residue to a nonpolar, neutral residue. All the other 12 candidate genes were sequenced, and no pathogenic sequence changes were found. Comparisons of p62 protein sequences from diverse species indicate that glutamine at position 391 is highly conserved. Five prenatal diagnoses were performed in three at-risk families. Interpretation: This is the second example of a nuclear pore complex protein causing mendelian disease in humans (the first one is triple A syndrome). Our findings suggest that p62 has a cell type-specific role and is important in the degeneration of the basal ganglia in humans.

Our results suggest that prenatal aCGH should be offered particularly in cases with abnormal U/S. We found the rate of detecting an abnormality by aCGH in low-risk pregnancies was 1:84, but larger studies will be needed to expand our knowledge and validate our conclusions.