Pericentric inversion of chromosome 19: prenatal diagnosis and genetic counselling

During prenatal diagnosis for advanced maternal age, a pericentric inversion of a chromosome 19 was detected in a male fetus. The inversion was familial, transmitted to the fetus by the phenotypically normal mother. The pregnancy resulted in a term birth of a phenotypically normal male infant. Inversion 19 appears to be a rare abnormality with only seven families reported thus far including ours. Infants with duplication deficiencies for chromosome 19 have not been reported in these families. This may suggest an apparent suppression of crossing over and recombination within the inverted segment of chromosome 19 during meiosis.     

Ethical problems in prenatal diagnosis: A cross-cultural survey of medical geneticists in 18 nations

In order to provide a basis for international discussion of ethics among geneticists, we surveyed the responses of medical geneticists to a questionnaire describing 14 hypothetical cases that posed ethical dilemmas. The cases were selected through discussions with leading geneticists in 12 nations, as representative of the most difficult problems of moral choice experienced in practice. Six cases involved indications for prenatal diagnosis or disclosure of information. All medical geneticists in each of 18 nations were included. Of 1053 asked to participate, 677 (64 per cent) responded. A large majority (83 per cent) would perform prenatal diagnosis for parents who oppose abortion but request the service. A smaller majority (63 per cent) would do so for maternal anxiety, and a minority (25 per cent) would perform for sex selection in the absence of X-linked disease. Most would disclose conflicting controversial, or ambiguous test results, and two-thirds would disclose colleagues' differences of opinion.     

Rapid detection of aneuploidy in uncultured chorionic villus cells using fluorescence in situ hybridization

Rapid detection of aneuploidy using chromosome-specific repetitive DNA probes and the potential diagnostic accuracy of fluorescence in situ hybridization (FISH) on interphase cells of chorionic villus samples (CVS) are presented. Analyses demonstrated the ability to correctly identify aneuploidy using FISH in uncultured CVS. Our preliminary investigation suggests that this technique offers a significant clinical potential to circumvent problems of culture, time, and cost in cytogenetic analysis.     

False-positive amniotic fluid acetylcholinesterase analysis in the third trimester

Thirty-two third-trimester amniotic fluid samples were studied according to the indication for amniocentesis, result of acetylcholinesterase (AChE) analysis, and outcome, in order to address the issue of the effectiveness of AChE testing late in gestation. The results indicate that third-trimester AChE analysis is less effective than second trimester in distinguishing open neural tube defects (ONTDs) and ventral wall defects (VWDs) from other abnormalities. False-positive results occurred in cases of isolated hydrocephaly (four of seven cases), polyhydramnios, and intrauterine growth retardation (IUGR). Caution is recommended in interpreting third-trimester AChE tests, particularly when neither an ONTD nor a VWD is observed by ultrasound.     

Sonographically determined anomalies and outcome in 170 chromosomally abnormal fetuses

Structural pathology and outcome were studied in 170 chromosomally abnormal fetuses. Numerical chromosomal abnormalities were established in 158 (93 per cent) cases, of which 110 (71 per cent) represented trisomies, 30 (18 per cent) Turner syndrome, and 18 (11 per cent) triploidy. Structural chromosomal abnormalities were diagnosed in 12 (7 per cent) cases. Gestational age at referral was significantly shorter for pregnancies with Turner syndrome than for the other chromosomal abnormalities. Referral before 20 weeks of gestation was mainly based on fetal structural pathology alone (92 per cent); after 20 weeks, patients were referred because of structural pathology combined with small for gestational age, oligohydramnios, or polyhydramnios. Referral as a result of suspected multiple organ pathology occurred in 73.5 per cent of pregnancies. An abnormal amniotic fluid volume was present in 59/170 (34.5 per cent) chromosomally affected pregnancies, i.e., oligohydramnios in 31 and polyhydramnios in 28 cases. Birth weight was below the tenth percentile in over half of the chromosomally abnormal fetuses, except for Turnersyndrome. Fetal outcome was poor, with a survival rate at 1 month of 30 per cent for trisomies which was mainly determined by trisomy 21 (14/18=77.5 per cent).     

Prenatal evaluation and outcome of fetal obstructive uropathies

Between January 1982 and January 1986, 76 pregnant women between 15 and 40 weeks of gestation were referred because of suspected fetal obstructive urinary tract pathology. A total of 14 high-level (ureter) and 17 low-level (urethral) obstructions were diagnosed. High-level obstructions were at the uretero-pelvic level in 11 and at the uretero-vesical level in 3 cases. Increased amniotic fluid volume was observed in 28 per cent. The survival rate was 86 per cent. In the 17 cases of urethral obstruction, oligohydramnios was present in 70 per cent, associated structural defects in 30 per cent, and an abnormal karyotype in 6 per cent. Pregnancy was terminated because of progressive massive hydronephrosis in 41 per cent; intrauterine or neonatal death occurred in 47 per cent, resulting in a survival rate of only 12 per cent.     

Prenatal diagnosis of chromosome mosaicism

The frequency of mosaicism and pseudomosaicism in the prenatal diagnosis of cytogenetic disorders is reported, based on 3000 pregnancies studied in our laboratory. Diagnosis of true mosaicism was only made when an abnomality was detected in two or more independent cultures established from an amniotic fluid sample. On this basis, 0.37 per cent of all cases were diagnosed as true mosaics. 1.07 per cent of all cases had pseudomosaicism involving more than one cell from the same culture with an identical abnormality. 4.13 per cent of cases had a single abnormal cell with an extra chromosome, loss of a sex chromosome (or part of a sex chromosome), or translocation. Details of the outcome and follow-up of cases is given. Particularly problematical were cases where multiple cells from one culture contained an abnormality which could have been clinically significant. A crude estimate of the extent to which true mosaicism might currently be misinterpreted as pseudomosaicism or entirely missed has been made, based on data from the U.S. survey (Hsu and Perlis, in press). It was concluded that even when two, and if necessary a third culture is extensively analysed with an average of 24 cells per culture counted, at least 4.5 per cent of cases of true mosaicism may be completely missed and at least 7 per cent could be misdiagnosed as pseudomosaicism. There is an urgent need for improved laboratory techniques which allow growth of a greater number of cell colonies and therefore a more broadly based analysis. Detailed long term follow-up of prenatally diagnosed mosaics is also essential for assessing the clinical significance of the laboratory findings.     

Rapid prenatal diagnosis of trisomy 18 and triploidy in interphase nuclei of uncultured amniocytes by non-radioactive in situ hybridization

Two biotinylated chromosome-specific DNA probes were used to quantify the number of chromosomes 18 and 1 in uncultured amniocytes. Thirty-three samples of uncultured amniocytes were hybridized with a chromosome 18-specific DNA probe. Uncultured cells from two of the 33 samples were also hybridized with a chromosome 1-specific probe. Thirty of the samples were disomic with respect to chromosome 18; two samples were trisomic with respect to chromosome 18, and one sample was trisomic with respect to chromosomes 1 and 18. The two cases of trisomy 18 and the single case of triploidy were identified on uncultured celis within 48-72 h after amniocentesis. They were found among five samples from pregnant women who had amniocentesis because of an ultrasonographically identified fetal malformation. A trisomic karyotype could be diagnosed with certainty in uncultured amniocytes because the majority of the responding nuclei exhibited three hybridization signals. In normal cells, the majority of nuclei exhibited two signals. In no cases was there discordance between the genotype as predicted by in situ hybridization and that determined by cytogenetic analysis.     

β-glucuronidase deficiency: Identification of an affected fetus with simultaneous sampling of chorionic villus and amniotic fluid

Four pregnancies at risk for mucopolysaccharidosis VII were monitored by chorionic villus sampling obtained in the first or second trimester of gestation. One fetus showed reduced β-glucuronidase activity following simultaneous sampling of chorionic villus and amniotic fluid at 17 weeks of gestation. The pregnancy was terminated. Subsequent assay of β-glucuronidase activity in the fetal tissues was consistent with a diagnosis of mucopolysaccharidosis VII, thus confirming that chorionic villus samples provide useful information for diagnosis of this condition.