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Biomedical subjects

M Bobrow

Publications and source records attributed to M Bobrow.

At least 55 records · Page 3Linked to original sources
PubMed1995

The natural history of Down syndrome conceptuses diagnosed prenatally that are not electively terminated.

The pregnancy outcomes on cases of Down syndrome diagnosed prenatally in which the mother did not elect termination were evaluated in data reported to a comprehensive Register of Down syndrome for England and Wales for 1989-94. In the 168 cases in which placental biopsy was not used, the overall rate of spontaneous loss was 35%, but this figure masks considerable heterogeneity by gestational stage at ascertainment. Data on ages at diagnostic procedure and on pregnancy termination enabled a more precise survival analysis. The loss rates were approximately 50% for those fetuses ascertained at 15-17 completed wk, 43% at 18 wk, 31% at 19 wk, 25% at 20 wk, and then a leveling off at approximately 20%-25% for fetuses ascertained at 21-28 completed wk. For fetuses ascertained prior to 18 wk, there was no evidence that maternal age was associated with fetal loss, consistent with earlier reports. At 18 wk and after, however, maternal age was on the average approximately 3 years greater in fetuses that were lost. Comparison of successive gestational birth cohorts provided no evidence in these 168 cases that the diagnostic procedure itself had any effect on loss or that selective ascertainment of mothers in risk of loss had any effect on the results. In contrast, in the 21 cases in which placental biopsy had been undertaken, the overall loss rates were not only higher when appropriate comparisons could be made, but there was some evidence for selective ascertainment and/or procedure-associated losses.(ABSTRACT TRUNCATED AT 250 WORDS)

Abortion, Spontaneous↗
PubMed1995

The identification of point mutations in Duchenne muscular dystrophy patients by using reverse-transcription PCR and the protein truncation test.

The protein truncation test (PTT) is a mutation-detection method that monitors the integrity of the open reading frame (ORF). More than 60% of cases of Duchenne muscular dystrophy (DMD) result from gross frame-shifting deletions in the dystrophin gene that are detectable by a multiplex PCR system. It has become apparent that virtually all of the remaining DMD mutations also disrupt the translational reading frame, making the PTT a logical next step toward a comprehensive strategy for the identification of all DMD mutations. We report here a pilot study involving 22 patients and describe the mutations characterized. These constitute 12 point mutations or small insertions/deletions and 4 gross rearrangements. We also have a remaining five patients in whom there does not appear to be a mutation in the ORF. We believe that reverse-transcription--PCR/PTT is an efficient method by which to screen for small mutations in DMD patients with no deletion.

Base Sequence↗
PubMed1994

A 6.5-Mb yeast artificial chromosome contig incorporating 33 DNA markers on the human X chromosome at Xq22.

The Xq22 region of the human X chromosome contains genes for a number of inherited disorders. Sixty-nine yeast artificial chromosome clones have been isolated and assembled into a 6.5-Mb contig that contains 33 DNA markers localized to this region. This contig extends distally from DXS366 to beyond DXS87 and includes the genes involved in X-linked agammaglobulinemia (btk), Fabry disease (GLA), and Pelizaeus-Merzbacher disease (PLP). The order of markers in this contig is consistent with the known genetic and physical mapping information of Xq22. This cloned material provides a source from which to isolate other genes located in this part of the X chromosome.

Adult↗
PubMed1994

Searching for the 1 in 2,400,000: a review of dystrophin gene point mutations.

The past few years have seen a rapid increase in our knowledge of naturally occurring mutations in the dystrophin gene. Although earlier studies were limited to gross rearrangement mutations, we are now in a position to draw lessons on the molecular etiology of the remaining one-third of cases of Duchenne and Becker muscular dystrophy (DMD, BMD) which are associated with small mutations. This paper reviews 70 published and unpublished small mutations in the dystrophin gene and asks what we can learn about their nature, their distribution, and approaches to their characterisation. Strikingly for such a well-conserved gene, missense mutations are extremely rare, and the vast majority of DMD point mutations, like the gross rearrangements, result in premature translational termination. It seems increasingly likely that almost all cases of DMD arise solely as a result of a reduction in the level of dystrophin transcripts, and we argue that > 95% of DMD mutations contribute nothing to the functional dissection of the dystrophin protein. Most of the few BMD point mutations presented here are missense mutations in the N-terminal or C-terminal domains or are splice-site mutations that probably act, like BMD deletions, via the production of in-frame, interstitially deleted transcripts.

DNA↗
PubMed1994

Techniques in current use in prenatal diagnosis.

Prenatal diagnosis is now offered to the majority of pregnant women in Europe and the United States. Advances in obstetric and laboratory techniques mean that increasing numbers of conditions can be diagnosed prenatally; indeed, gene carriers can be identified before pregnancy in some cases. Current obstetric and laboratory techniques for prenatal screening and diagnosis of genetic disorders are discussed.

Europe↗
PubMed1994

The cloning of FRAXF: trinucleotide repeat expansion and methylation at a third fragile site in distal Xqter.

Three fragile sites, FRAXA, FRAXE and FRAXF lie in the Xq27-28 region of the human X chromosome. The expression of FRAXA is associated with the fragile X syndrome, the most prevalent form of inherited mental retardation whilst the expression of FRAXE is associated with a rarer and comparatively milder form of mental handicap. Both the FRAXA and FRAXE sites have been cloned and the fragile site expression found to be due to the expansion of analogous CGG/GCC trinucleotide repeat arrays. We describe here the cloning of the third fragile site, FRAXF, and demonstrate that it involves the expansion of a (GCCGTC)n(GCC)n compound array. PCR analyses across the repeat of normal individuals show that the number of triplets in the array ranges from 12-26 and the most common allele consists of 14 triplet units. Sequencing analyses show that 95% of normal individuals have three copies of the GCCGTC motif and in these individuals, the size variation observed by PCR is due to copy number alterations in the GCC array. In a cytogenetically positive male with developmental delay, the array is expanded by > 900 triplets and the adjacent CpG-rich region is methylated. The array is also expanded in cytogenetically positive carrier females from the family originally used to define the FRAXF site. We conclude that the expanded array corresponds to the FRAXF fragile site.

Base Sequence↗
PubMed1994

Deletions in the 5' region of dystrophin and resulting phenotypes.

Deletions in the dystrophin gene give rise to both Duchenne and Becker muscular dystrophies. Good correlation is generally found between the severity of the phenotype and the effect of the deletion on the reading frame: deletions that disrupt the reading frame result in a severe phenotype, while in frame deletions are associated with a milder disease course. Rare exceptions to this rule, mainly owing to frameshift mutations in the 5' region of the gene (in particular deletions involving exons 3 to 7) which are associated with a milder than expected phenotype, have been reported previously. In order to characterise better the relationship between genotype and phenotype as a result of mutations arising in the 5' region of the gene, we have studied a large cohort of patients with small in frame and out of frame deletions in the first 13 exons of the dystrophin gene. Fifty-five patients with a deletion in this area were identified; approximately one third of them had a phenotype different from that theoretically expected. Patients were divided into two groups: (1) patients with a severe clinical phenotype despite the presence of a small, in frame deletion and (2) patients with a mild phenotype and an out of frame deletion. Noticeable examples observed in the first group were Duchenne boys with a deletion of exon 5, of exon 3, and of exons 3-13. In the second group we observed several patients with an intermediate or Becker phenotype and out of frame deletions involving not only the usual exons 3-7 but also 5-7 and 3-6. These data indicate that a high proportion of patients with a deletion in the 5' end of the gene have a phenotype that is not predictable on the basis of the effect of the deletion on the reading frame. The N-terminus of dystrophin has at least one actin binding domain that might be affected by the small, in frame deletions in this area. The effect of the in frame deletions of exon 3, 5, and 3-13 on this domain might account for the severe phenotype observed in these patients. Other mechanisms, such as unexpected effect of the deletion on splicing behaviour, might, however, also be implicated in determining the phenotype outcome.

Adolescent↗
PubMed1994

Counselling following diagnosis of a fetal abnormality: the differing approaches of obstetricians, clinical geneticists, and genetic nurses.

Women receiving a positive diagnosis of an abnormality during pregnancy may be counselled about a termination by one of several types of health professionals including obstetricians, geneticists, and genetic nurses. There is anecdotal evidence to suggest that these groups differ in both their approaches to counselling and their attitudes towards abnormality. The aim of the current study is to document how genetic nurses, geneticists, and obstetricians describe their own counselling of women following the diagnosis of specific fetal abnormalities. Obstetricians reported counselling in a significantly more directive fashion than did geneticists, who in turn reported counselling in a more directive way than did genetic nurses. The extent to which the groups differed in their reported approaches varied across conditions. The most marked difference was evident for Down's syndrome: 94% of genetic nurses, 57% of geneticists, and 32% of obstetricians reported counselling non-directively. Future research needs to focus on what these different groups see as the objectives of counselling in this situation, how they actually counsel, and with what effects.

Attitude of Health Personnel↗
PubMed1994

The impact of population based screening for carriers of cystic fibrosis.

The purpose of the study was to evaluate the short-term effects of population based screening for carriers of cystic fibrosis. The outcome measures included perceptions of health, anxiety, and understanding of test results. Those adults aged between 18 and 45, registered with a general practice in Inner London, who accepted the offer of carrier testing, completed questionnaires before testing, upon receipt of results, and three months later. Full data were obtained from 427 with negative test results and 14 carriers. Receipt of results had no effect upon perceptions of health or perceived risk of having an abnormal baby. Those receiving a positive test result were significantly more anxious upon receipt of this result. By three months, this anxiety had dissipated. While knowledge of the test improved from before to after testing, by three months there was some decay. Although the residual risk among those with a negative result of being a carrier was given as 1:135, at least 17% of those receiving a negative result incorrectly believed that they were at no risk of having a child with cystic fibrosis. Five of the 14 receiving a positive result erroneously believed that their results meant that they probably, but not definitely, carried the gene for cystic fibrosis. In the longer term the greatest problem of population screening would appear to be one of false reassurance rather than anxiety. Longer term studies are needed to determine how well carrier status information is retained, and how carriers and carrier couples plan and respond to pregnancy and how much understanding they retain of their test results.

Adolescent↗
PubMed1994

FISH detection of trisomy 21 in interphase by the simultaneous use of two differentially labelled cosmid contigs.

Techniques have been reported in which fluorescence in situ hybridisation (FISH) and cosmid probes are used to detect trisomy 21 (and other abnormalities involving chromosomes X, Y, 13, and 18) on uncultured amniocytes. However the detection rate of trisomy 21 is lower than for the other anomalies owing to a larger number of uninformative results and false negatives. We report the simultaneous use of two differentially labelled cosmid contigs to improve the detection rate of trisomy 21 on uncultured amniocyte samples thus allowing the prenatal diagnosis of Down's syndrome even if only few labelled nuclei are available.

Amniotic Fluid↗
PubMed1994

Counselling following diagnosis of fetal abnormality: a comparison between German, Portuguese and UK geneticists.

The principle of non-directiveness in genetic counselling is embraced by all relevant professional bodies. Little is known about the extent to which it is endorsed by geneticists, or incorporated into their clinical practice. The aim of the current study is to document how geneticists in three European countries, Germany, Portugal and the UK, report counselling women at risk for having children with a range of conditions. While geneticists in all three countries reported counselling in a largely non-directive style, this varied both across genetic conditions and between countries. German and Portuguese geneticists were significantly more directive than UK geneticists, although they differed in the way in which they were directive. German geneticists were more likely to encourage continuation of pregnancies, while Portuguese geneticists were more likely to encourage termination of affected pregnancies. There was no strong consensus on approaches to counselling for any of the genetic conditions, defined as agreement between 70% of all three groups of geneticists. Despite strong professional codes of non-directiveness, geneticists report being somewhat directive in some counselling situations. Future research needs to focus on what geneticists are trying to achieve in genetic counselling, how they actually counsel, and with what effects.

Abortion, Induced↗
PubMed1994

Monitoring trends in prenatal diagnosis of Down's syndrome in England and Wales, 1989-92.

The national register of chromosomal anomalies that lead to Down's syndrome has enabled the monitoring of change in prenatal diagnosis for this condition, and the factors which affect the change. The proportion of cases of cytogenetically diagnosed Down's syndrome in England and Wales detected prenatally rose to 46% in 1991-2 from 31% in 1988-9, a 1.5-fold increase (95% confidence interval 1.3 to 1.7). The increase was confined to mothers under 40 years and was due to the introduction of screening by maternal serum analysis and ultrasound. Over a quarter of affected pregnancies in women aged 25-29 were detected prenatally in 1991-2 compared with less than 10% in 1988-9. Analysis of the data showed regional differences in prenatal diagnosis rates, and in the length of time elapsing between the diagnostic test and termination of an affected pregnancy. An inexplicable finding was that this period varied with the sex of the fetus, being on average a day longer for females than for males.

Adult↗