Christine Gosden

A balanced chromosomal translocation partially co-segregating with psychotic illness in a family

Psychotic illness was associated with an apparently balanced 6;11 chromosomal translocation in a three-generation family. The mother and son carrying the translocation suffer from a chronic psychotic illness, a daughter who was a translocation carrier committed suicide, and her twin daughters who both carry the translocation have not yet reached the age of risk for developing this psychiatric illness, although one has attempted suicide. Two older members of the family have the translocation and have never suffered from a psychiatric disorder. The pattern of dominant inheritance of the psychotic illness only occurring in individuals carrying the translocation suggests that there may be a major genetic component in the etiology of the psychosis in this family. Genes at the chromosomal break points may be candidate genes implicated in this particular form of psychotic illness.

MICROVILLAR PEPTIDASE ACTIVITY IN AMNIOTIC FLUID: POSSIBLE USE IN THE PRENATAL DIAGNOSIS OF CYSTIC FIBROSIS

The activities of two microvillar peptidases, gamma-glutamyl transpeptidase (GGTP) and aminopeptidase M (APM), have been measured in 132 samples of mid-trimester amniotic fluid. These included samples from 16 pregnancies at risk for cystic fibrosis. The activities of both peptidases were significantly below the normal range in amniotic fluids from the 6 affected pregnancies. This points to early pathological changes in fetal tissues in which microvilli are prominent. In contrast, 4-methylumbelliferylguanidinobenzoate-reactive protease activity in amniotic fluid from the 6 affected pregnancies was normal. Correlation of individual values between GGTP and APM was close in all cases examined, so that when a further 7 samples from cases at risk became available they were tested for GGTP alone. Of these, the 3 affected pregnancies had significantly reduced GGTP activity, particularly in the early weeks of gestation. It is suggested that early amniocentesis and examination of gamma-glutamyl-transpeptidase isoenzyme constitution might make possible the reliable early diagnosis of cystic fibrosis.

The use of cloned Y chromosome-specific DNA probes for fetal sex determination in first trimester prenatal diagnosis.

SummaryPrenatal diagnosis by chorion biopsy in the first trimester of pregnancy has advantages over second trimester amniocentesis because diagnosis can be achieved at 9–12 weeks gestation, reducing prenatal anxiety and avoiding the trauma of late abortion. DNA can be prepared from chorionic villus biopsies in sufficient quantity and purity for use in prenatal diagnosis systems using specific DNA probes hybridised to restriction endonuclease digests.DNA probes derived from the Y chromosome have been used to determine fetal sex. The use of such probes means that the chromosomal sex of the fetus can be identified more quickly than by chromosome preparation and more accurately than by sex chromatin staining, and has the additional advantage that the same DNA preparation can be used for other diagnostic tests. A dot hybridisation method has been successfully used to provide even more rapid results than conventional hybridisation to Southern blots of restriction endonuclease digests.There is a risk that Y chromosome-specific DNA probes for sex determination may be subject to error if the parents have extreme Y chromosome variants such as a small or non-fluorescent Y or a Y autosome chromosome translocation. The precise extent to which such chromosome variants may lead to error has been investigated. Even extreme Y chromosome variants totally lacking fluorescence were identified as male by the cloned probes used. However, Y autosome translocations carried by females could cause error if not identified in the parents. The value of the probes has been confirmed provided that parental chromosomes and DNA are examined in parallel with the chorionic biopsy material

Fetal blood chromosome analysis: some new indications for prenatal karyotyping

Summary. Prenatal karyotyping using stimulated fetal blood lymphocytes was undertaken in 170 pregnancies between 16 and 36 weeks gestation for the following reasons‐(1) mosaicism or marker chromo somes found in amniotic fluid culture; (2) a family history of X‐linked mental retardation with fragile Xq28; (3) fetal abnormalities detected ultrasonographically; (4) late booking or amniotic fluid culture failure in patients with advanced age or balanced translocations; and (5) twin pregnancies discordant for a chromosomal anomaly. Forty‐one karyotypic abnormalities were detected (24%). These were: 45,X (7 cases). trisomy 13 (5 cases), trisomy 18 (6 cases), trisomy 21 (4 cases), twin pregnancy where one twin had trisomy 21 (1 case), supernumerary marker chromosome (3 cases, one of which occurred in a twin pregnancy). triploidy (3 cases), X‐linked mental retardation with fragile site at Xq28 in males (6 cases), fetal erythroleukaemia (3 cases including 2 cases with Turners), Fanconis anaemia (1 case), unbalanced chromosome translocation 47,XY+der22,t(l1;22) mat (1 case), mos 46,XXI8p‐/46,XX.‐18,+i(l8q) (1 case), 46,XXde1(2q) (1 case), and 46,XYt(5;17) de novo (1 case). In fetuses at high risk of a chromosome aberration. a rapidly obtaincd karyotype is helpful and fetoscopy and fetal blood sampling are justified in the second or third trimester.

INTRAUTERINE CONTRACEPTIVE DEVICES IN DIABETIC WOMEN

11 of 30 (36.6%) insulin-dependent diabetic women fitted with intrauterine contraceptive devices (IUCDs) became pregnant within 1 year, whereas the pregnancy rate for non-diabetic women fitted with the same types of IUCD by the same consultant gynaecologists over a similar time period was 4 per 100 women years (4%). As soon as the high risk was recognised, devices were removed (2 from diabetic women who were pregnant and 19 from non-pregnant diabetic women), and patients were advised about other methods of contraception. The IUCDs were examined in a scanning electron microscope with X-ray microprobe analysis to measure the amount of copper eroded from the wire, the extent of the encrustation (if any) deposited on the wire, and the composition of the deposit, and the data were compared with those for 111 devices removed from non-diabetic women, 40% of the IUCDs from diabetic women had sulphur and chloride in the deposit, compared with 15.3% of IUCDs from normal women, and fewer IUCDs from diabetic women had calcareous deposits. In devices from normal women, erosion and deposition seemed to occur independently, but in IUCDs from diabetic women, there was high erosion, there were also large deposits, and where there was little deposit, the erosion was slight. 7 of 14 IUCDs taken from normal women who had become pregnant with an IUCD in situ had a high sulphur plus chloride deposit; none of these IUCDs had a predominantly calcareous deposit compared with 19.8% of the IUCDs from non-pregnant normal women. The evidence militates against the insertion of IUCDs in diabetic patients and indicated that, even in non-diabetic women, there may be small groups for whom the risk of becoming pregnant is very high.

The fate of DNA statellites I, II, III and ribosomal DNA in a familial dicentric chromosome 13:14

SummaryIn a family with a stable dicentric 13:14 translocation chromosome, the distribution of DNA sequences complementary to satellite DNAs I, II and III and ribosomal RNA were studied. The translocation chromosome showed a loss of sequences complementary to all three satellite DNAs, located in the short arms of all the acrocentric chromosomes, but slightly more of the sequences complementary to satellite I were retained than of the other two satellite DNAs. The fact that material was lost from all three satellites indicates that they are not present as single discrete blocks in these chromosomes, when we would expect to find the distal sequences lost and the proximal ones retained, but consist of interspersed blocks with each sequence represented by more than one, and probably several blocks. There was a total loss of ribosomal DNA from the nucleolar organiser regions of the chromosomes involved in the 13:14 translocation, but an interesting finding was the presence of extra ribosomal DNA and satellite DNAs I, II and III in one chromosome 22 which was found in seven out of nine individuals of the family with the 13:14 translocation, and in only one of five individuals without the translocation. There may be a compensatory mechanism present when certain sequences are eliminated during chromosomal rearrangements. The relationship of such mechanisms to reproductive fitness is discussed.

Ten families with fragile X syndrome: linkage relationships with four DNA probes from distal Xq.

SummaryWe present clinical, cytogenetic, and linkage data of four DNA probes from the terminal long arm of the X chromosome in ten new families with fragile X syndrome. A prior/posterior method of multipoint linkage analysis is employed to combine these results with published data to refine the linkage map of terminal Xq. Ten possible probe/disease orderings were tested. The order with the greatest posterior probability (0.78) of the five loci is 52a-F9-fragile X gene-DX13-St14, although the order with reversal of the positions of 52a and F9 has a posterior probability 0.15. The mean estimates of the distances between the probes and the fragile X gene are 38cM and 33cM for the proximal probes 52a and F9, and 8 cM and 12 cM for the distal probes DX13 and St14. Although the current method of choice in the prenatal diagnosis and carrier detection of the fragile X syndrome remains detailed cytogenetic analysis, consideration is given to the potential role of these DNA probes, both singly and in pairs.

Linkage heterogeneity and fragile X

SummaryA multipoint test of heterogeneity on published data from 57 families with the fragile X syndrome has been undertaken. The hypothesis being tested was that there are two loci coding for fragile X expression, mutations at either of which can produce the phenotype. No predivision of the families was undertaken, as the test used an admixture parameter. Maximum likelihoods of the hypothesis have been calculated and compared with those produced on assuming a single locus for fragile X. The data do not suggest that there are two such loci within the interval between probes 52a and St14. In particular, the large kindred published by Camerino et al. (1983) does not supply convincing evidence of heterogeneity under this test. It is argued that the observed heterogeneity between factor IX and fragile X must have another explanation. There is some evidence for a second locus for fragile X outside the interval noted above; this locus being most probably proximal to these probes. The majority of the data suggesting this result comes from a family published by Davies et al. (1985).

Are second-trimester amniotic fluids being properly examined?

Amniocentesis is being carried out more and more because of a high serum-alpha-fetoprotein indication. For this reason it is important that laboratories revise their anmiotic fluid protocols which had previously been oriented toward anmiocentesis due to advanced maternal age or previous history of chromosome abnormality. The whole amniotic fluid not just the supernatant fraction should be examined through the following inexpensive and rapid tests: total cell-count viable-cell count RA-cell proportional count and RA-cell morphological examination. In this way antenatal diagnosis can be made a more discriminating procedure.

Immunoreactive trypsin and the prenatal diagnosis of cystic fibrosis

Immunoreactive trypsin (IRT) was measured by radio‐immunoassay in a series of amniotic fluids obtained at between 15 and 19 weeks from pregnancies with a 1‐in‐4 risk of fetal cystic fibrosis. IRT concentrations were significantly depressed in nine affected pregnancies, but the degree of overlap with the normal range was too great for this to be useful in early prenatal diagnosis. Furthermore, in one fetus, presumed to have cystic fibrosis, the fetal plasma IRT concentration was within the normal range.