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In 1986, a population study of school children in the city of Coventry gave an overall prevalence in males and females for fragile X syndrome of 1/952. The 29 children diagnosed as having fragile X syndrome in this study have been re-evaluated with molecular diagnostic techniques. Eighteen of the original 29 children have been found not to have the expansion of the FMR1 gene associated with fragile X syndrome. Revised prevalence figures have been calculated giving rise to an overall prevalence figure of 1/2720 (range 1/2198-1/3089). If the four children lost to follow up are also assumed not to have the fragile X syndrome, the revised prevalence figure was 1/5714 (range 1/4762-1/6349). Clinical review of boys with severe mental retardation from this and a subsidiary study show that the clinical features of head circumference greater than the 50th centile, testicular volume greater than the 50th centile, and IQ between 35 and 70 remain helpful in distinguishing boys with fragile X syndrome from those who have non-specific mental retardation.

Linkage analysis using the polymorphic loci DXS369, DXS296, DXS297 and DXS306 was carried out on a cohort of 17 families segregating for fragile X syndrome. The observed recombination fractions at: DXS369 (Zmax = 3.02; theta = 0.06), DXS297 (Zmax = 2.92; theta = 0.0), DXS296 (Zmax = 3.82; theta = 0.0), DXA306 (Zmax = 4.55; theta = 0.05) confirm that these loci are tightly linked to FRAXA. Our experience in the cytogenetic analysis of 58 at risk pregnancies by chorionic villus or fetal blood sample examination documents a false negative rate in obligate carrier male pregnancies for CVS of 11% and for FBS of 3%.

This paper describes a community based study of 156 boys with idiopathic, severe mental retardation. The boys were examined and a pedigree taken before the cytogenetic results were known. The prevalence of the fragile X chromosome among this group of boys was high: 9% in the whole group and 11% after 39 boys with specific features had been excluded. The fragile X syndrome is therefore an important cause of idiopathic, severe retardation. Its clinical features of large head, large testes, and IQ in the 35 to 70 range were often but not always present in the 14 boys identified in this study. In the whole group, the recurrence of severe mental subnormality was high: 1 in 8 for brothers and 1 in 25 for sisters. This high recurrence was partly due to the fragile X syndrome, partly to X linked mental retardation not accompanied by cytogenetic abnormalities, and partly due to autosomal recessive disease. Autosomal recessive disease was perhaps higher in the West Midlands than elsewhere (such as British Columbia, for example 1) because of the disproportionate contribution by Asian immigrants.

A clinical and cytogenetic study of children attending schools for the educationally handicapped has been carried out in the City of Coventry. As a result of this an estimate of the population incidence of the Martin-Bell syndrome among schoolchildren has been made. Among school-boys the incidence of mental retardation due to the fra (X) was found to be 0.73 per 1000 and among schoolgirls 0.48 per 1000. The overall prevalence is 0.61 per 1000. Genetic and cytogenetic analysis of 14 families ascertained in an unbiased manner showed that the expected 50% ratio of affected to unaffected relatives was disturbed, the possible result of a segregation distortion.

An account is given of a pregnancy in an obligatory carrier of the fragile-X syndrome, in whom examination of chorionic villus cells and fetal blood cells showed the presence of a male fetus who lacked the fragile-X chromosome. However, at 3 months of age he had 14 per cent of fragile-X cells in his blood. Reasons are suggested for this error in diagnosis. The empirical risk for an error of this sort is 3 per cent.

A population study has been carried out among schoolchildren in the City of Coventry in order to ascertain the frequency of mental retardation associated with the fragile X chromosome. The prevalence of the fragile X mental retardation syndrome in the 11 to 16 year age group (the age of greatest ascertainment) was about 1.0 per 1,000 and therefore indicates that the syndrome is a major cause of mental retardation.

Nineteen pregnancies at risk for the Martin-Bell syndrome have been monitored during the second trimester for the presence of the fragile Xq27. Of the 19 potential carrier mothers, 14 showed the presence of the fragile X in their lymphocytes at a level of 4 per cent or above. As one was a twin pregnancy, fetal blood was obtained at fetoscopy from 20 fetuses and amniotic fluid obtained simultaneously from 19 of them. Of the 20 fetuses, 18 were males (including both of the twins) and two were females. Of these 18 males, seven were found to carry the fragile Xq27 in lymphocytes and subsequently six of the seven were terminated. The diagnosis was confirmed in five of the six terminated fetuses (the sixth case was a patient whose pregnancy was terminated abroad) and also in a full-term male baby. Five of the seven males without the marker X who came to term had their karyotypes confirmed post natally. Of the two female fetuses one was found to be a carrier of the fragile X and the other was not. Both babies had full-term deliveries and both had their karyotypes confirmed post natally. In some cases the diagnosis made in fetal lymphocytes was confirmed later in amniocytes.

Co-cultivation studies in different combinations have been carried out between cells which have been found to be positive for the fragile (X) (q27) and control cells. As no increase or decrease was discernible in the level of Fra(X) detected in 'positive' cells, and no fragility was introduced into the 'negative' cells, it was concluded that there had been no intercellular co-operation, and a diffusible expression or suppression factor was not involved.

Second trimester ultrasound-guided fetal blood sampling and placental biopsy were performed on 10 pregnancies at risk for fra(X)-linked mental retardation (Martin-Bell syndrome). Three cases were diagnosed as affected after cytogenetic analysis of fetal blood and placental cultures. The fra(X)(q27.3) and common fragile sites were shown to be expressed at a lower level in placenta than in fetal blood. Induction methods included methotrexate, 5-fluoro-2-deoxyuridine, and excess thymidine. Excess thymidine may give the best expression of fra(X)(q27.3). Enhancement of fra(X)(q27.3) expression was not shown with caffeine or 5-methoxybenzamide.