In about 50% of first trimester spontaneous abortion the cause remains undetermined after standard cytogenetic investigation. We evaluated the usefulness of array-CGH in diagnosing chromosome abnormalities in products of conception from first trimester spontaneous abortions. Cell culture was carried out in short- and long-term cultures of 54 specimens and cytogenetic analysis was successful in 49 of them. Cytogenetic abnormalities (numerical and structural) were detected in 22 (44.89%) specimens. Subsequent, array-CGH based on large insert clones spaced at ~1 Mb intervals over the whole genome was used in 17 cases with normal G-banding karyotype. This revealed chromosome aneuplodies in three additional cases, giving a final total of 51% cases in which an abnormal karyotype was detected. In keeping with other recently published works, this study shows that array-CGH detects abnormalities in a further ~10% of spontaneous abortion specimens considered to be normal using standard cytogenetic methods. As such, array-CGH technique may present a suitable complementary test to cytogenetic analysis in cases with a normal karyotype.

Fragile X syndrome is the most frequent cause of inherited mental retardation. The phenotype in this syndrome is quite variable and less conspicuous in younger patients, making clinical diagnosis difficult and thus making molecular diagnosis necessary. The use of clinical checklists in mentally retarded individuals can help selecting patients to be given priority in the molecular investigation for the fragile-X mutation in the FMR1 gene. We evaluated two clinical checklists in a sample of 200 Brazilian male patients with mental retardation. The highest scores in the two checklists concentrated among the 19 males (9.5%) found to carry full mutations. Our results confirm the importance of fragile-X checklists as a clinical tool in the study of mentally retarded patients.

The loss-of-function mutation of the FMR1 gene due to expansion of the 5' UTR CGG repeat causes the fragile X syndrome, the most frequent form of inherited mental retardation. On the other hand, the FMR1 premutation, which is transcriptionally active and produces the protein, confers an increased risk for premature ovarian failure (POF) to carrier females. Among 41 unrelated Brazilian women with idiopathic POF, we found three carriers of premutations (CGG expansionse > 59 repeats) and two carriers of high-intermediate alleles (50-55 repeats). Two premutations and two intermediate alleles were detected among the 16 familial POF cases, and one premutated woman, among the 25 sporadic cases. The premutation frequency among the familial cases (12.5%) differed significantly from that found in a control group of 96 unrelated Brazilian women aged > 47 years, who had not experience POF and in which no premutations or high-intermediate alleles were detected. In the search for factors influencing the probability of a premutation carrier presenting POF, another 20 unrelated premutated women with POF, from fragile X families, were included in the study. The analysis of the FMR1-linked loci DXS548 and FRAXAC1 did not indicate any association of a particular haplotype with the occurrence of POF. An effect of X-inactivation skewing was not apparent in blood cells, and POF-associated premutations showed a wide range of repeat sizes, from 59, the smallest known to expand to full mutations upon transmission to offspring, to approximately 200.

Entrevistamos 193 mulheres de famílias com afetados pela síndrome do cromossomo X frágil, quanto a sua história ginecológica e reprodutiva. Entre as 101 portadoras da pré-mutação, 14 tiveram menopausa precoce, mas nenhuma das 37 portadoras da mutação completa ou das 55 não portadoras apresentaram esta anomalia. Observamos uma tendência para a concentração da menopausa precoce em certas famílias, o que poderia significar uma peculiariedade de certas pré-mutações. Entretanto, o fato de as mulheres pré-mutadas tenderem a entrar em menopausa mais cedo do que as não portadoras sugere que a menopausa precoce seja o extremo do espectro de efeitos ovarianos da pré-mutação.

The gynecological and reproductive histories of 193 women from fragile X families were surveyed. Among the 101 carriers of the premutation, 14 experienced premature menopause, contrarily to their 37 fully mutated and 55 noncarrier female relatives. Although premature menopause showed a tendency to cluster in certain fragile X families, as a group, the premutated women experienced menopause earlier than noncarriers. This suggests that premature menopause may be the extreme effect of a spectrum of ovarian anomalies associated with the fragile X premutation.