Numerous linkage studies have indicated chromosome 18q21-22 as a locus of importance for blood pressure regulation. This locus harbors the neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) gene, which is instrumental for the regulation of the amiloride-sensitive epithelial sodium channel (ENaC). In a linkage study of 16 markers (including two single nucleotide polymorphism markers located within the NEDD4L gene) on chromosome 18 between 70-104 cM and ambulatory blood pressure (ABP), in 118 families, the strongest evidence of linkage was found for 24 h and day-time systolic ABP at the NEDD4L locus (82.25 cM) (P=0.0014). In a large population sample (n=4001), we subsequently showed that a NEDD4L gene variant (rs4149601), which by alternative splicing leads to varying expression of a functionally crucial C2 domain, was associated with diastolic blood pressure (DBP) (P=0.03) and DBP progression over time (P=0.04). A genotype combination of the rs4149601 and an intronic NEDD4L marker (rs2288774) was associated with systolic blood pressure (SBP) (P=0.01), DBP (P=0.04), and progression of both SBP (P=0.03) and DBP (P=0.05) over time. A quantitative transmission disequilibrium test in the family material of the rs4149601 supported this NEDD4L variant as being at least partially causative of the linkage result. In conclusion, our findings suggest that the chromosome 18 linkage peak at 82.25 cM is explained by genetic NEDD4L variation affecting cross-sectional and longitudinal blood pressure, possibly as a consequence of altered NEDD4L interaction with ENaC.
To assess the accuracy of the calculated risk for trisomy 18 assigned to individual women screened with the second-trimester triple test.
The study was based on 382598 women screened in the Ontario Maternal Serum Screening Programme between October 1993 and September 2000. Of the women screened, 111 cases of trisomy 18 were identified. Originally, 92874 women were screened using a risk cut-off level method. Estimated risks of trisomy 18 were calculated by applying published population parameters for the remaining women screened using a fixed analyte cut-off method. Women were ranked according to their individual risk for trisomy 18 syndrome in decreasing order and divided into 12 groups. The mean calculated risks of having an affected pregnancy at term for each group were compared with the birth prevalence of the corresponding group after allowing for spontaneous fetal losses.
Agreement between the mean calculated risks and the observed prevalence was seen across the entire risk range, although women identified as having high-risk pregnancies had an actual prevalence that was somewhat lower than that estimated by the screen.
The calculated risk for trisomy 18 syndrome assigned to the individual woman on the basis of the risk cut-off method accurately reflects their risk of having a term trisomy 18 syndrome pregnancy.
To examine the awareness and use of maternal serum screening (MSS) among women from the St. John's region of Newfoundland and Labrador.
We surveyed 300 women who had recently given birth. Our main outcomes were whether the woman had heard of MSS (prior to the study) and whether she had MSS during her pregnancy.
Among the 200 respondents (response rate 66.7%), 139 (69.5%) had heard of MSS and 53 (26.5%) had MSS (38.1% of those who had heard of it). A larger proportion of women over 35 years (59.0%) had heard of MSS than younger women (31.5%) (P = 0.001). Among those who had heard of MSS, a larger proportion of women who had MSS (96.2%) than those who did not have MSS (72.1%) discussed the test with their physician (P 0.001); 54.9% of the women who discussed MSS with their physicians decided not to have MSS. Most discussions regarding MSS (82.6%) lasted 10 minutes or less; discussion length was not related to use of MSS.
Almost two thirds of women surveyed were aware of MSS, and roughly one quarter had MSS. These findings confirm that most physicians offer MSS to their patients and suggest that patient preference accounts for the low use of MSS in the province. Understanding why women do not have MSS may lead to strategies to improve screening rates.
In studies concerning the interaction of B-CLL cells and Epstein-Barr virus (EBV), we encountered one patient whose cells had several unusual properties. In addition to the B-cell markers, the CLL cells expressed the exclusive T-cell markers CD3 and CD8 and carried a translocation t(18,22)(q21;q11), involving the bcl-2 and Ig lambda loci. The patient represents the 4th reported CLL case with this translocation. The CLL cells could be infected and immortalized by the indigenous and by the prototype B958 virus in vitro. The T-cell markers were not detectable on the established lines. In all experiments the immortalized lines originated from the CLL cells. Their preferential emergence over virus-infected normal B cells may be coupled to the high expression of the bcl-2 gene due to the translocation. In spite of the sensitivity of CLL cells to EBV infection in vitro, no EBNA-positive cells were detected in the ex vivo population. In vitro, we could generate cytotoxic function in T-lymphocyte cultures which acted on autologous EBV-infected CLL cells. Therefore we assume that if such cells emerged in vivo they were eliminated by the T-cell response.
Upper-limb defects with deficiencies of the radial ray have varying etiologies, with a low proportion of true Mendelian disorders. We carried out a population-based study to elucidate the birth prevalence and clinical spectrum of radial ray deficiencies in Finland. We identified all births with radial ray deficiency reported to the Finnish Register of Congenital Malformations in 1993-2005. Altogether 138 cases were identified (123 live births), with a birth prevalence of 1.83 per 10,000 births and a live birth prevalence of 1.64 per 10,000 live births. The proportion of infant deaths was as high as 35%. The majority of the cases were associated with known syndromes or multiple anomalies; only 13% were true isolated radial ray deficiencies. The most common syndrome was trisomy 18, and the most common in multiple anomalies was VACTERL association. In 8.7% of cases an association between radial ray deficiency and heart anomaly was observed. The high proportion of cases with associated major anomalies indicates that radial ray deficiency can be regarded isolated only after thorough assessment of the various organ systems in an affected infant.
Few studies of the frequency of chromosomal aberrations in an unselected material of mildly mentally retarded children have been published. The present paper summarizes the chromosomal abnormalities in children with mild mental retardation (MMR) in Västerbotten in the northernmost part of Sweden. Chromosome analyses were carried out by routine methods. In addition, children whose MMR had no clear diagnosis or cause were investigated as regarding X-chromosomes with a fragile site and selected cases with banding techniques. Every mentally retarded child born between 1959 and 1970 in the county of Västerbotten was traced. Out of a total number of 40,871 individuals, 171, i.e. 4.2 per 1,000, were found to be mildly mentally retarded. Chromosomal aberrations were seen in 11.9% of the children with MMR, compared with 39.1% of the 161 children with severe mental retardation (SMR) in the same population. The proportion of cases with mental retardation of unknown etiology is high, especially amongst those with MMR. The use of high resolution banding and other modern cytogenetic methods should reduce this figure.
The RET/PTC3 rearrangement is formed by fusion of the ELE1 and RET genes, and is highly prevalent in radiation-induced post-Chernobyl papillary thyroid carcinomas. We characterized the breakpoints in the ELE1 and RET genes in 12 post-Chernobyl pediatric papillary carcinomas with known RET/PTC3 rearrangement. We found that the breakpoints within each intron were distributed in a relatively random fashion, except for clustering in the Alu regions of ELE1. None of the breakpoints occurred at the same base or within a similar sequence. There was also no evidence of preferential cleavage in AT-rich regions or other target DNA sites implicated in illegitimate recombination in mammalian cells. Modification of sequences at the cleavage sites was minimal, typically involving a 1-3 nucleotide deletion and/or duplication. Surprisingly, the alignment of ELE1 and RET introns in opposite orientation revealed that in each tumor the position of the break in one gene corresponded to the position of the break in the other gene. This tendency suggests that the two genes may lie next to each other but point in opposite directions in the nucleus. Such a structure would facilitate formation of RET/PTC3 rearrangements because a single radiation track could produce concerted breaks in both genes, leading to inversion due to reciprocal exchange via end-joining.
To evaluate the performance of a new first trimester web-based software for the detection of chromosomal anomalies using a combination of ultrasound and biochemistry.
Registry-based cohort study.
Ultrasound units in the Stockholm region.
20 710 women with singleton pregnancies were examined at 11(+0) to 13(+6) weeks' gestational age during a three-year period 2006-2009.
The risks for trisomy 21, 13 and 18 were calculated using a combination of maternal age, serum markers and nuchal translucency. Individual risk estimates were calculated and then reported to a web-based system using a new algorithm based on likelihood ratios of each marker derived from Gaussian distributions in normal and affected pregnancies.
The impact on rates of invasive testing and the incidence of children born with Down's syndrome after implementing the method.
Approximately a third of all pregnant women in the region were examined with the combined test. The detection and test positive rates for Down's syndrome was 90 and 6.8%, respectively. Invasive testing among pregnant women decreased from 15 to 8% after introducing the method but the incidence of children born with Down's syndrome did not decrease during the study period.
The new web-based software is an effective method for the detection of trisomy 21 with similar performance compared to other programs. However, it needs to be offered to all pregnant women to have an impact on the incidence of Down's syndrome.
Juvenile polyposis (JP) is an autosomal dominant syndrome in which affected patients develop upper- and/or lower-gastrointestinal (GI) polyps. A subset of families with JP have germline mutations in the SMAD4 (MADH4) gene and are at increased risk of GI cancers. To date, six families with JP have been described as having the same SMAD4 deletion (1244-1247delAGAC). The objective of the present study is to determine whether this deletion is a common ancestral mutation or a mutational hotspot. DNA from members of four families with JP, from Iowa, Mississippi, Texas, and Finland, that had this 4-bp deletion was used to genotype 15 simple tandem repeat polymorphism (STRP) markers flanking the SMAD4 gene, including 2 new STRPs within 6.3 and 70.9 kb of the deletion. Haplotypes cosegregating with JP in each family were constructed, and the distances of the closest markers were determined from the draft sequence of the human genome. No common haplotype was observed in these four families with JP. A 14-bp region containing the deletion had four direct repeats and one inverted repeat. Because no common ancestor was suggested by haplotype analysis and the sequence flanking the deletion contains repeats frequently associated with microdeletions, this common SMAD4 deletion in JP most likely represents a mutational hotspot.
Cites: Nature. 2000 Dec 7;408(6813):708-1311130070
To provide a review of published studies on the use of cell-free fetal DNA in maternal plasma for the non-invasive diagnosis of Down syndrome, trisomy 18, and trisomy 13.
PubMed was searched for articles published between 2006 and October 2012, using appropriate key words (e.g., non-invasive prenatal diagnosis, Down syndrome, cell-free fetal DNA, aneuploidy screening). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and incorporated in the guideline to October 31, 2012. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.
The studies reviewed were classified according to criteria described by the Canadian Task Force on Preventive Health Care, and the recommendations for practice were ranked according to this classification (Table 1). Recommendations 1. Non-invasive prenatal testing using massive parallel sequencing of cell-free fetal DNA to test for trisomies 21, 18, and 13 should be an option available to women at increased risk in lieu of amniocentesis. Pretest counselling of these women should include a discussion of the limitations of non-invasive prenatal testing. (II-2A) 2. No irrevocable obstetrical decision should be made in pregnancies with a positive non-invasive prenatal testing result without confirmatory invasive diagnostic testing. (II-2A) 3. Although testing of cell-free fetal DNA in maternal plasma appears very promising as a screening test for Down syndrome and other trisomies, studies in average-risk pregnancies and a significant reduction in the cost of the technology are needed before this can replace the current maternal screening approach using biochemical serum markers with or without fetal nuchal translucency ultrasound. (III-A).