Two leading European professional societies, the European Society of Human Genetics and the European Society for Human Reproduction and Embryology, have worked together since 2004 to evaluate the ...impact of fast research advances at the interface of assisted reproduction and genetics, including their application into clinical practice. In September 2016, the expert panel met for the third time. The topics discussed highlighted important issues covering the impacts of expanded carrier screening, direct-to-consumer genetic testing, voiding of the presumed anonymity of gamete donors by advanced genetic testing, advances in the research of genetic causes underlying male and female infertility, utilisation of massively parallel sequencing in preimplantation genetic testing and non-invasive prenatal screening, mitochondrial replacement in human oocytes, and additionally, issues related to cross-generational epigenetic inheritance following IVF and germline genome editing. The resulting paper represents a consensus of both professional societies involved.
An abbreviated tract of five thymidines (5T) in intron 8 of the
cystic fibrosis transmembrane conductance regulator (
CFTR) gene is found in ∼10% of individuals in the general population. When found ...in
trans with a severe
CFTR mutation, 5T can result in male infertility, nonclassic cystic fibrosis, or a normal phenotype. To test whether the number of TG repeats adjacent to 5T influences disease penetrance, we determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe
CFTR mutation on one
CFTR gene and 5T on the other. Of the unaffected individuals, 78% (21 of 27) had 5T adjacent to 11 TG repeats, compared with 9% (10 of 107) of affected individuals. Conversely, 91% (97 of 107) of affected individuals had 12 or 13 TG repeats, versus only 22% (6 of 27) of unaffected individuals (
P<.00001). Those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats (odds ratio 34.0, 95% CI 11.1–103.7,
P<.00001). Thus, determination of TG repeat number will allow for more accurate prediction of benign versus pathogenic 5T alleles.
Genetic modifiers of liver disease in cystic fibrosis Bartlett, Jaclyn R; Friedman, Kenneth J; Ling, Simon C ...
JAMA : the journal of the American Medical Association,
09/2009, Letnik:
302, Številka:
10
Journal Article
Recenzirano
Odprti dostop
A subset (approximately 3%-5%) of patients with cystic fibrosis (CF) develops severe liver disease with portal hypertension.
To assess whether any of 9 polymorphisms in 5 candidate genes ...(alpha(1)-antitrypsin or alpha(1)-antiprotease SERPINA1, angiotensin-converting enzyme ACE, glutathione S-transferase GSTP1, mannose-binding lectin 2 MBL2, and transforming growth factor beta1 TGFB1) are associated with severe liver disease in patients with CF.
Two-stage case-control study enrolling patients with CF and severe liver disease with portal hypertension (CFLD) from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America, with the University of North Carolina at Chapel Hill as the coordinating site. In the initial study, 124 patients with CFLD (enrolled January 1999-December 2004) and 843 control patients without CFLD were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 patients with CFLD (enrolled January 2005-February 2007) and 1088 with no CFLD.
Differences in distribution of genotypes in patients with CFLD vs patients without CFLD.
The initial study showed CFLD to be associated with the SERPINA1 Z allele (odds ratio OR, 4.72; 95% confidence interval CI, 2.31-9.61; P = 3.3 x 10(-6)) and with TGFB1 codon 10 CC genotype (OR, 1.53; 95% CI, 1.16-2.03; P = 2.8 x 10(-3)). In the replication study, CFLD was associated with the SERPINA1 Z allele (OR, 3.42; 95% CI, 1.54-7.59; P = 1.4 x 10(-3)) but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (OR, 5.04; 95% CI, 2.88-8.83; P = 1.5 x 10(-8)).
The SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (OR, approximately 5) of developing severe liver disease with portal hypertension.
Abstract There is wide agreement on the benefits of NBS for CF in terms of lowered disease severity, decreased burden of care, and reduced costs. Risks are mainly associated with disclosure of ...carrier status and diagnostic uncertainty. When starting a NBS programme for CF it is important to take precautions in order to minimise avoidable risks and maximise benefits. In Europe more than 25 screening programmes have been developed, with quite marked variation in protocol design. However, given the wide geographic, ethnic, and economic variations, complete harmonisation of protocols is not appropriate. There is little evidence to support the use of IRT alone as a second tier, without involving DNA mutation analysis. However, if IRT/DNA testing does not lead to the desired specificity/sensitivity ratio in a population, a screening programme based on IRT/IRT may be used. Sweat chloride concentration remains the gold standard for discriminating between NBS false and true positives, but age-related changes in sweat chloride should be taken into account. CF phenotypes associated with less severe disease often have intermediate or normal sweat chloride concentrations. Programmes should include arrangements for counselling and management of infants where the diagnosis is not clear-cut. All newborns identified by NBS should be managed according to internationally accepted guidelines. CF centre care and the availability of necessary medication are essential prerequisites before the introduction of NBS programmes. Clear explanation to families of the process of screening and of implications of normal and abnormal results is central to the success of CF NBS programmes. Effective communication is especially important when parents are told that their child is affected or is a carrier. When establishing a NBS programme for CF, attention should be given to ensuring timely and appropriate processing of results, to minimise potential stress for families.
How has the interface between genetics and assisted reproduction technology (ART) evolved since 2005?
The interface between ART and genetics has become more entwined as we increase our understanding ...about the genetics of infertility and we are able to perform more comprehensive genetic testing.
In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and ART and published an extended background paper, recommendations and two Editorials.
An interdisciplinary workshop was held, involving representatives of both professional societies and experts from the European Union Eurogentest2 Coordination Action Project.
In March 2012, a group of experts from the European Society of Human Genetics, the European Society of Human Reproduction and Embryology and the EuroGentest2 Coordination Action Project met to discuss developments at the interface between clinical genetics and ART.
As more genetic causes of reproductive failure are now recognized and an increasing number of patients undergo testing of their genome prior to conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and PGD may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from RCTs to substantiate that the technique is both effective and efficient. Whole genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo.
The legal landscape regarding assisted reproduction is evolving, but still remains very heterogeneous and often contradictory. The lack of legal harmonization and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe, and beyond.
This continually evolving field requires communication between the clinical genetics and IVF teams and patients to ensure that they are fully informed and can make well-considered choices.
Funding was received from ESHRE, ESHG and EuroGentest2 European Union Coordination Action project (FP7 - HEALTH-F4-2010-26146) to support attendance at this meeting.
No large-scale studies of the incidence or disease severity of cystic fibrosis (CF) in black patients have been reported to date. In this study, the CF Foundation National Patient Registry was used ...to establish new incidence figures and to compare the clinical status of U.S. black (
n = 601) and white patients (
n = 17,755) with CF. Results indicate that the incidence of CF is approximately 1 in 3,200 white and 1 in 15,000 black live births in the United States. Black patients with CF are currently, and were at diagnosis, younger and have poorer nutritional status and pulmonary function than white patients with CF. Fewer have meconium ileus, but more have distal intestinal obstruction syndrome. To control for genotype, each black ΔF508 homozygote (
n = 47) was compared with four age- and sex-matched white ΔF508 homozygotes. Only the difference in nutritional status remained. The ΔF508 mutation is associated with higher levels of meconium ileus than other genotypes, independent of race. In conclusion, the clinical manifestations of CF are similar in black and white patients except for poorer nutritional status in black patients, which appears to be independent of age and genotype. (J Pediatr 1998;132:255-9)
Two leading European professional societies, the European Society of Human Genetics and the European Society for Human Reproduction and Embryology, have worked together since 2004 to evaluate the ...impact of fast research advances at the interface of assisted reproduction and genetics, including their application into clinical practice. In September 2016, the expert panel met for the third time. The topics discussed highlighted important issues covering the impacts of expanded carrier screening, direct-to-consumer genetic testing, voiding of the presumed anonymity of gamete donors by advanced genetic testing, advances in the research of genetic causes underlying male and female infertility, utilisation of massively-parallel sequencing in preimplantation genetic testing and non-invasive prenatal screening, mitochondrial replacement in human oocytes, and additionally, issues related to cross-generational epigenetic inheritance following IVF and germline genome editing. The resulting paper represents a consensus of both professional societies involved.
Limited information is available on the effect of income level on whether people visit a dentist for preventive care, whereas more has been written regarding the effect of income on "any" dental ...visits--which may include emergencies. Also, little is known of the effects of "near-poor" income (101 to 200 percent of the U.S. federal poverty level) on dental visits and preventive dental visits. The authors examined the impact of income at the "poor" and "near-poor" poverty levels on preventive dental visits made by children and adolescents.
The authors used data from the 1996 Medical Expenditure Panel Survey for children and adolescents younger than 19 years of age to estimate the percentage of this group who had had preventive dental visits. They performed a multiple logistic regression analysis to adjust poverty levels by race and ethnicity, age and sex.
The distribution of preventive dental visits for those who were poor was similar to that for those who were near-poor, but the percentage distribution of preventive visits for children and adolescents with higher income was significantly different from that for those in the lower income groups. This was true across all the variables considered.
It is important to evaluate and monitor preventive care utilization trends for U.S. children and adolescents in the poor and near-poor categories separately, particularly in states that do not provide similar levels of access under the State Children's Health Insurance Program, or SCHIP. Enrollment of eligible children in Medicaid and SCHIP via oral health promotion outreach efforts, access to care and utilization of dental primary and secondary care services must be increased.
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