The gene causing Huntington's disease, an autosomal dominantly inherited, neurodegenerative disorder, has been identified recently. The corresponding mutation is involving an expansion in the number of (CAG)n repeats in the coding region of the Huntington's disease gene on chromosome 4. In this report, we demonstrate the length variation of the repeat in 513 non-HD chromosomes from normal individuals and HD patients showing 23 alleles with 11 to 33 repeats. Analyzing the inheritance of the (CAG)n stretch we found meiotic instability for HD alleles ([CAG]40 to [CAG]75) with a mutation frequency of approximately 0.7, while in 431 meioses of normal alleles only two expansions were identified. The risk of expansion during spermatogenesis is enhanced compared to oogenesis explaining juvenile onset by transmission from affected fathers. Further, the number of (CAG)n copies in an affected individual in relation to the sex of the transmitting parent was evaluated and no significant differences were found. No mosaicism or differences in the repeat lengths were observed in the DNA from different tissues including brain and lymphocytes of two HD patients indicating mitotic stability of the mutation. Therefore, the determination of the repeat number in the DNA of blood lymphocytes is probably representative of all tissues in a patient.
Serum levels of alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), and unconjugated oestriol (uE3) were measured in serum samples of 4131 non-smoking and 1018 smoking women during the second trimester of pregnancy. The levels of all three analytes decreased with increasing body weight. The AFP median was significantly increased in smokers in a dose-response association; hCG decreased by 21 per cent and uE3 decreased by 3 per cent in smokers in a non-dose-related fashion. Regression functions for adjustment of serum levels for weight and smoking should be considered in risk estimation for Down syndrome in order to give a woman's individual risk more precisely.
A novel concept is described for the statistical analysis of multilocus DNA fingerprints. Utilizing this method, it is shown by simulation that the application of multilocus DNA fingerprints to paternity testing is robust against deviations from idealistic assumptions made about underlying models and parameters. Partial homozygosity, allelism and linkage at the DNA loci involved, as well as variations in estimates of band-sharing probabilities were studied for effects on the resulting paternity probabilities. None of the above-mentioned phenomena appear to change these values to an extent relevant for decision making in paternity cases.
Serum samples from 320 women with chromosomally normal fetuses and from 50 women with fetuses affected by Down's syndrome were assayed retrospectively for human chorionic gonadotropin (hCG), pregnancy-specific beta 1 glycoprotein (SP1), alpha fetoprotein (AFP), and unconjugated estriol (uE3) between 14 and 21 weeks of gestation. Nonparametric discriminant analysis was applied to calculate Down syndrome risks on the basis of various combinations of serum parameters. At a risk threshold that falsely identifies 5% of controls as being affected, 46 to 48% of Down syndrome pregnancies were detected by combinations of hCG/AFP, hCG/AFP/uE3, and hCG/AFP/uE3/SP1 respectively. HCG, AFP, and uE3 were assayed in 652 serum samples from women who underwent amniocentesis because of maternal age (> or equal to 35 years in this prospective study). 49% of women with euploid fetal karyotype, 8 of 10 pregnancies with Down's syndrome, and 3 pregnancies with sex chromosomal anomalies were identified as being at an increased risk (> 1:380).
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