Testing For Carrier Status Research Articles

Prenatal diagnosis of Duchenne and Becker muscular dystrophies: Underestimated problem of the secondary prevention of monogenetic disorders.

The aim of this study was to analyze the influence of effective preconceptional testing for carrier status in women at risk for Duchenne and Becker muscular dystrophies (D/BMD) on the prenatal diagnosis. A retrospective analysis of 201 prenatal tests was performed in 169 Polish women at risk, in regard to time of testing for carrier status (prior to conception or during pregnancy) and carrier status of tested women, including confirmed D/BMD carriers (n = 78; 46.2%), D/BMD non-carriers - tested for germline mosaicism risk (n = 23; 13.6%), and women at risk with uncertain carrier status (n = 68; 40.2%). Only 52.7% of women were tested for D/BMD carrier status prior to conception and in these women prenatal diagnosis was carried out more frequently in the first trimester of pregnancy (64.7% vs 47.8%; P = 0.035). The results of prenatal testing in male fetuses in pregnancies of confirmed D/BMD carriers and D/BMD non-carriers - tested for germline mosaicism risk were conclusive in all cases, whereas in women with uncertain carrier status, only 60.0% of results were conclusive. Eighty-five of 103 female fetuses (82.5%) were tested prenatally and in 31.8% of them fetal carrier status was confirmed. Carrier status testing in women prior to conception has a positive impact on the frequency of first-trimester prenatal diagnosis and known D/BMD carrier status on the effectiveness of prenatal diagnosis. Due to the low percentage of women tested effectively prior to conception, carrier status testing in the families at risk should be propagated (including possibility of prenatal diagnosis of female fetuses).

Attitudes of cystic fibrosis patients and their parents towards direct-to-consumer genetic testing for carrier status.

An increasing number of direct-to-consumer (DTC) genetic testing companies have started offering tests for carrier status of autosomal recessive disorders. A written questionnaire was administered to 47 patients and 65 parents of children with Cystic Fibrosis (CF), a common severe autosomal recessive disorder, to assess their views about the offer of DTC carrier tests. All participants were recruited from a CF patient registry in Belgium. We found that very few patients and parents were aware of the offer of DTC genetic testing for carrier status, and were generally skeptical. A strong preference for the healthcare system over commercial companies as the provider of the test was observed. However, many participants believe people should have a right to access DTC genetic tests provided by commercial companies.

遺伝子解析による血友病保因者診断の意義

遺伝子解析による血友病保因者診断の意義

Genetic testing of children for adult-onset conditions: opinions of the British adult population and implications for clinical practice.

This study set out to explore the attitudes of a representative sample of the British public towards genetic testing in children to predict disease in the future. We sought opinions about genetic testing for adult-onset conditions for which no prevention/treatment is available during childhood, and about genetic ‘carrier' status to assess future reproductive risks. The study also examined participants' level of agreement with the reasons professional organisations give in favour of deferring such testing. Participants (n=2998) completed a specially designed questionnaire, distributed by email. Nearly half of the sample (47%) agreed that parents should be able to test their child for adult-onset conditions, even if there is no treatment or prevention at time of testing. This runs contrary to professional guidance about genetic testing in children. Testing for carrier status was supported by a larger proportion (60%). A child's future ability to decide for her/himself if and when to be tested was the least supported argument in favour of deferring testing.

First steps in exploring prospective exome sequencing of consanguineous couples

Consanguinity is one of the most frequent risk factors for congenital disorders. In theory, prospective exome sequencing of consanguineous couples could identify couples who both are carriers of autosomal recessive diseases, and empower such couples to make informed reproductive decisions. To investigate this, we sent blood samples to our laboratory of four pairs of consanguineous parents having one or more children affected by an autosomal recessive disorder, without revealing any diagnostic information. The study was restricted to find identical, previously described, or evidently pathogenic mutations in both parents of each couple, in over 400 genes known to result in severe autosomal recessive disorders. Out of the six autosomal recessive disorders known to the four couples studied, two were correctly identified. Carrier status of one not previously known autosomal recessive disorder was discovered. As expected, given the pipeline used, large deletions, mutations in genes not present in the gene list, mutations outside the exons and consensus splice sites, and mutations that were not evidently pathogenic and previously not reported, were not identified. The restriction to detecting only couples with identical mutations diminishes the risk of revealing unsolicited findings and shortens the time needed for analysis, but also results in missing couples with different mutations in the same gene. In addition to the proposed pipeline, couples should be offered testing for carrier status of frequent disorders that can present themselves by large deletions, non-exonic mutations or compound heterozygous mutations (e.g. thalassemia, spinal muscular atrophy, cystic fibrosis). Even though sensitivity is reduced, offering exome sequencing prospectively will increase reproductive options for consanguineous couples.

Screening for sickle cell disease and thalassaemia in primary care

General practice can be the first point of call in testing for carrier status in inherited blood conditions, as Claire Laurent explains

Adolescent Carrier Testing in Practice: The Impact of Legal Rulings and Problems with “Gillick Competence”

Testing for carrier status for various genetic conditions often takes place during adolescence or young adulthood. This paper aims to add to the discussion of when is the best time to test through an examination of how the law on medical treatment of children appears to be used in practice and how a careful examination of legal rulings might shed light upon best practice in this area. Our focus is on the Gillick ruling (Gillick v West Norfolk and Wisbech Area Health Authority 1986), which dealt with consent and confidentiality with respect to the provision of contraceptive advice to under 16-year-olds, but which has become a general benchmark for consent to medical treatment within UK law. In addition, we draw upon data from a qualitative research study which indicates potential problems with certain practices in respect of the influence of the Gillick ruling on carrier testing procedures. We present evidence that in at least some instances, adolescents have reduced capacity to grasp fully the implications of carrier test results. In the light of our findings we make recommendations for practice concerning the testing of children and young persons.

Attitudes Toward Fragile X Mutation Carrier Testing from Women Identified in a General Population Survey

Fragile X syndrome is primarily due to a CGG repeat expansion found in the FMR1 X-linked gene. In a previous study, we conducted focus groups with women to assess their attitudes towards fragile X carrier screening. In this follow-up study, we conducted in-depth interviews of general population reproductive-age women who were identified as carriers. We explored their attitudes toward testing for carrier status of the fragile X mutation. These women underwent screening primarily to participate in a research project rather than in search of a diagnosis for specific symptoms. As such, these women were wholly unprepared for positive carrier results. Their responses about their results and carrier screening, in many cases, were being worked out over the course of the interview itself. The most salient finding of this work is the apparent lack of relevance of carrier status to these women. Many expressed that although the information could be relevant in the future, it is not relevant at this stage of their lives in terms of family planning (either with respect to having unaffected offspring or to premature ovarian failure) and personal relationships. Although issues of abortion seemed prominent in the focus groups, we found that carrier status did not have an apparent effect on women's attitudes about termination. We hypothesize this may be related to the fact that women had not processed their new carrier status and had not related it to previously-formed personal opinions. The findings of this work have significant implications for genetic counseling and population screening. Genetic counselors should be mindful that general population women may not recognize the immediate importance of their carrier status even when literature is provided and discussed prior to providing a sample. As part of comprehensive genetic counseling, counselors should identify the reproductive life stage of the woman receiving the new information and help her identify when this information would be more meaningful in her life. Counselors can assist in setting up a personalized road map with specific types of services that will be more applicable to the woman as her carrier status becomes more relevant.

Genetic service providers' practices and attitudes regarding adolescent genetic testing for carrier status

PurposeTo characterize current practices and attitudes regarding testing adolescents for carrier status. MethodsElectronic survey of 294 genetic service providers from various professional organizations. Testing for predisposition and presymptomatic conditions was excluded from this study. ResultsEighty-three percent of providers had received requests to test adolescents for carrier status. Of these, 84% have performed testing. Providers cited adolescent desire, sexual activity/pregnancy, and adolescent competence as the main reasons for testing. Some providers who performed testing found the current guidelines unhelpful. ConclusionTesting adolescents for carrier status is common for at least some conditions. The guidelines regarding genetic testing of adolescents may need to be updated to reflect current concerns and practices.

Working Up Policy: The Use of Specific Disease Exemplars in Formulating General Principles Governing Childhood Genetic Testing

Non-therapeutic genetic testing in childhood presents a "myriad of ethical questions"; questions which are discussed and resolved in professional policy and position statements. In this paper we consider an underdiscussed but strongly influential feature of policy-making, the role of selective case and exemplar in the production of general recommendations. Our analysis, in the tradition of rhetoric and argumentation, examines the predominate use of three particular disease exemplar (Huntington's disease, Tay-Sachs disease and sickle cell disease) to argue for or against particular genetic tests (predictive testing and testing for carrier status). We discuss the influence these choices have on the type and strength of subsequent recommendations. We argue that there are lessons to be drawn about how genetic diseases are conceptualised and we caution against the geneticisation of medical policy making.

Women’s Attitudes Toward Testing for Fragile X Carrier Status: A Qualitative Analysis

Fragile X syndrome (FXS) is primarily due to a repeat expansion mutation found in the FMR1 X-linked gene. We have conducted a qualitative analysis of responses from women concerning their attitudes toward testing for carrier status of the fragile X mutation among reproductive-age women. We obtained responses from focus groups including women with and without FXS in their families. We found the following themes: (1) mothers of children with FXS have difficulty formulating their opinions on population screening because of their unique experiences surrounding their own carrier diagnosis and their relationship with their children with FXS, (2) the motivation for carrier testing and need for information differ by family history of FXS and parental status, and (3) the timing of carrier testing with respect to a woman's life stage dictates whether carrier information will be viewed as beneficial or detrimental. There was evidence that non-carrier women from the general population would be wholly unprepared for positive carrier results. These findings have significant implications for genetic counseling as well as for population screening.

Women's Attitudes Toward Testing for Fragile X Carrier Status: A Qualitative Analysis

Fragile X syndrome (FXS) is primarily due to a repeat expansion mutation found in the FMR1 X-linked gene. We have conducted a qualitative analysis of responses from women concerning their attitudes toward testing for carrier status of the fragile X mutation among reproductive-age women. We obtained responses from focus groups including women with and without FXS in their families. We found the following themes: (1) mothers of children with FXS have difficulty formulating their opinions on population screening because of their unique experiences surrounding their own carrier diagnosis and their relationship with their children with FXS, (2) the motivation for carrier testing and need for information differ by family history of FXS and parental status, and (3) the timing of carrier testing with respect to a woman's life stage dictates whether carrier information will be viewed as beneficial or detrimental. There was evidence that non-carrier women from the general population would be wholly unprepared for positive carrier results. These findings have significant implications for genetic counseling as well as for population screening.

Mutation carrier testing in Lesch-Nyhan syndrome families: HPRT mutant frequency and mutation analysis with peripheral blood T lymphocytes.

Mutations in the X chromosome hypoxanthine-guanine phosphoribosyl transferase (HPRT) gene are responsible for Lesch-Nyhan syndrome and related diseases in humans. Because the gene is on the X chromosome, males are affected and females in the families are at risk of being carriers of the mutation. Because there are so many different mutations that can cause the disease (218 different mutations in 271 families), genetic testing for carrier status of females requires detailed molecular analysis of the familial mutation. This analysis can be complicated by the unavailability of an affected male for study. In addition, when the mutation is a deletion (34 reported instances), molecular analysis in females is difficult because of the two X chromosomes. We have applied a peripheral blood T lymphocyte cloning assay that uses resistance to the purine analogue 6-thioguanine (TG) to measure the frequency of cells in females expressing a mutant HPRT allele to determine mutation carrier status in 123 females in 61 families. In families in which the HPRT mutation was determined and could be easily analyzed in samples from females, we found a mean (+/- SD) mutant frequency of 9.7 (+/- 8.7) x 10(-6) in noncarrier females and 2.9 (+/- 3.0) x 10(-2) in carrier females. The frequency in carrier females is less than the 0.5 expected for nonrandom X inactivation because of in vivo selection against HPRT mutation-expressing T lymphocytes or stem cells during prenatal development. The use of this cloning assay allows determination of the carrier status of females even when the HPRT mutation is not yet known or is difficult to determine in DNA samples from females. This approach provides a rapid assay that yields information on carrier status within 10 days of sample receipt.

Evaluation of a Tay-Sachs disease screening program.

Tay-Sachs Disease (TSD) is an autosomal recessive neurodegenerative disorder. TSD is prevalent in the Ashkenazi Jewish population, and carrier screening programs have been implemented worldwide in these communities. A screening program initiated in 1997 involving the Melbourne Jewish community (Australia) incorporated education, counselling and carrier testing of high-school students aged 15 to 18 years. This study aimed to assess the participation rates, level of knowledge obtained and predicted feelings and attitudes of the students involved. Seven hundred and ten students participated, there was a 67% uptake for testing with a carrier rate of 1 in 28 determined. The level of knowledge of the students following education was high and of relative importance in regard to decision making, as were their feelings and attitudes about genetic testing for carrier status. A significant impediment to test uptake was the need for blood sampling, resulting in a recommendation for the introduction of DNA analysis on cheek brush samples. The evaluation of this program has given a wider scope for further development as well as providing valuable information for the implementation of community screening programs.

Genetic testing in children.

In this article, the author focuses on the allocation of decision-making authority between parents and physicians. She argues that parents should have substantial room to decide whether genetic testing is good for their child and that they may appropriately consider interests in addition to those of their child in making such choices. A physician, however, may refuse to act pursuant to parental views about testing, when in the physician's view, the parents' choices would pose a risk of significant harm to the child. The balance of control between parents and physicians is illustrated by discussion of a series of case vignettes. Refusal to perform requested testing is most often warranted for testing for carrier status and for genetic predisposition to late onset disease. The author concludes her analysis by discussing why it is appropriate to give increasing deference to the views of the child as the child grows older.

Cystic fibrosis carrier screening in two New South Wales country towns

OBJECTIVE To assess the feasibility of offering community testing for carrier status of delta F508, a gene mutation associated with cystic fibrosis (CF). DESIGN Prospective pilot survey. SETTING General practice, the two main high schools and workplaces in the country towns of Young and Harden (combined population, 14,940; with 7707 people aged 16-55 years) in New South Wales (NSW). PARTICIPANTS Individuals aged 16 years and over. MAIN OUTCOME MEASURES Number of delta F508 carriers, test uptake rates, mode of learning about the testing, motivation for testing, retention of knowledge about CF, and test results and emotional effects of knowledge about carrier status. RESULTS We tested 610 people (8% of the population aged 16-55 years) and identified 47 carriers (20% of the expected number in the 7707 people aged 16-55 years). Testing in schools had the highest uptake. Retention of knowledge was high; all delta F508-positive individuals recalled their carrier status accurately. Anxiety was transient among carriers; over 90% of all respondents felt they had made the right decision to be tested. CONCLUSIONS We recommend community testing for carrier detection and suggest targeting those with a family history of CF and girls aged over 16 in high schools.

First experiences with genetic counselling based on predictive DNA diagnosis in hereditary glomus tumours (paragangliomas).

Hereditary glomus tumour (MIM 168,000) or paraganglioma (PGL) is a slowly progressive disorder causing benign tumour growth predominantly in the head and neck region. Though benign in nature the tumours can lead to severe morbidity. Inheritance of PGL is autosomal dominant and is strongly modified by genomic imprinting; only a paternally transmitted PGL gene leads to symptoms. A gene for PGL has recently been mapped to 11q22.3-q23. Genetic counselling on the basis of DNA linkage diagnosis was offered in an extended Dutch pedigree. Thirty-two subjects opted for further counselling, of whom 20 applied for DNA testing and participated in a standardised protocol. Sixteen cases had presymptomatic testing (paternal allele); four of these appeared to have the at risk haplotype and in two of them a glomus tumour was subsequently detected on MRI. In one case linkage results were inconclusive (recombination) and one person did not want to learn his test result. Four cases had testing for carrier status (maternal allele) of which one appeared to be a carrier. Our data show that genetic counselling gains significant accuracy when based on parent of origin, sex of the counsellee, and DNA linkage diagnosis. Moreover, a normal DNA result may prevent unnecessary worry and investigations, while an established presymptomatic diagnosis will guide adequate clinical management. The psychological impact of counselling and predictive DNA testing is unclear as yet. Further investigations into the natural history of PGL in gene carriers and into the psychological impact of DNA testing is desirable.

Cascade testing for carrier status in cystic fibrosis in a large family.

The offer to determine carrier status for cystic fibrosis (CF) was made to the 230 descendants of a couple who were presumed to carry the delta F508 mutation. "Cascade testing" was employed, in which the mutation is followed from the oldest generation down. Compliance was over 75% and family members were relieved of the anxiety engendered by uncertainty. In one couple considering having a family, both partners were found to be carriers.

Spectrum of phenylketonuria mutations in western Europe and north Africa, and their relation to polymorphic DNA haplotypes at the phenylalanine hydroxylase locus.

A total of 252 chromosomes from 126 patients with phenylalanine hydroxylase (PAH) deficiencies were analyzed for both mutant genotypes and restriction fragment length polymorphism (RFLP) haplotypes at the PAH locus. The mutant genes studied originated either from Western Europe (116 alleles) or from Mediterranean countries (136 alleles). Only 27% of all mutant alleles were found to carry identified mutations, particularly mutations at codon 252 (2.3%), 261 (7.5%), 280 (6.3%), 408 (3.5%) and at the splice donor site of intron 12 (6.3%). The mutant genotypes were associated with RFLP haplotypes 7, 1, 38, 2 and 3 at the PAH locus respectively. Except for the splice mutation of intron 12, these associations were preferential, but not exclusive, since the other four mutations were found on the background of at least two RFLP haplotypes. These results, together with the observation that 85% of PAH deficient patients are heterozygotes for their mutant genotypes, emphasize the great heterogeneity of PAH deficiencies in Mediterranean countries and hamper systematic DNA testing for carrier status in this population.