Population Carrier Screening Research Articles

Cystic fibrosis: to screen or not to screen? Involving a Citizens' jury in decisions on screening carrier.

ContextIn recent years, the continuous improvements in molecular biology techniques have made it possible to detect carriers for several genetic conditions, including cystic fibrosis (CF). In some countries, CF carrier screening is offered to increasing subset of the general population.Offering of carrier screening at a population level should not be decided by local health authorities only, without consulting citizens' preferences. One way to involve citizens in the decision process might be to a Citizens' jury, a method of deliberative democracy.ObjectiveThe object of the study is to produce a recommendation statement about CF carrier screening using a Citizens' jury. As this is a new method in the field, the study also provided the opportunity to evaluate its effectiveness.DesignThe project is designed and managed by an executive committee. The whole process is superintended by a multidisciplinary scientific committee. The 16 members of the jury attend a 1 day meeting, assisted by a non‐medical and unbiased facilitator. Informative material was prepared and distributed 15 days before the jury meeting; during the meeting, experts and witnesses interact directly with all the jurors through questions and answers.ResultsAll except one member of the jury felt positively about the Health Service actively providing population carrier screening for CF. The final statement was available to public, clinicians, researchers and decision‐makers.DiscussionIn general, a Citizens' jury is a feasible method for involving citizens in public health decision‐making process and in particular for obtaining a community view about CF carrier screening.

A mixed methods exploration of families' experiences of the diagnosis of childhood spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease with a carrier frequency of 1 in 41 in Australia. Childhood SMA is classified into three types based on the age at which children present with symptoms and the clinical severity. Families' experiences leading up to the diagnosis have not been described, but are important when considering the potential for a diagnostic odyssey. Using a mixed methods approach, data were collected from interviews and a national survey of families of children with SMA to explore their experiences of this journey. The combined findings (n=28) revealed that the journey to receiving a diagnosis was protracted. The time from first noticing symptoms to finally receiving a diagnosis was emotional and frustrating. Once parents or other family members became aware of symptoms, almost all had consulted with multiple different health professionals before the diagnosis was ultimately made. Not surprisingly, receiving the diagnosis was devastating to the families. The nature of the information and the way it was given to them was not always optimal, particularly because of the difficulties predicting clinical severity. Most felt that their child could have been diagnosed earlier and, although there were mixed views around the benefit of this for their child, they felt it may have reduced the emotional impact on families. Overall, families were more in favour of population carrier screening for SMA when compared with newborn screening of the population. Despite an increasing awareness of SMA, the diagnostic delay continues to have negative impacts on families.

Community genetics approaches in the prevention of beta-thalassemia: towards achieving 'Zero beta-thalassemia' status in India.

The estimates of prevalence of b-thalassemia in India are grossly underestimated, as it is based on 0-5% carrier frequency, while population surveys indicated communities with as high frequency as 24%. The overall carrier frequency distribution of b-thalassemia, is highly heterogeneous with wide geographical foci of high risk communities with 8% and above carrier frequency all over the country. As of now, there is no mechanism to evaluate whether the frequencies are increasing or decreasing in the populations. Prenatal diagnosis and prevention of births of b-thalassemia homozygotes is the most preferred approach adopted in India. However, the extent of distribution and the occurrence across various stratification in the society with large component of rural masses, it is difficult to assume that prenatal diagnosis alone can bring in ‘Zero’ b-thalassemia status in India. Countries like Cyprus could achieve such status where large scale population carrier screening programs involving education and premarital counselling were also effectively employed besides prenatal diagnosis. In India, there is urgent need to initiate large scale population carrier screening of high risk communities along with education and awareness. The extent of b-thalassemia distribution, identifying high risk communities and geographical regions presenting a population design for carrier screening program in India, will be presented.

ACMG Position Statement on Prenatal/Preconception Expanded Carrier Screening

The American College of Medical Genetics and Genomics (ACMG) believes that advances in genetic technology should be considered carefully before they become part of routine clinical care. The organization has defined a standard of care for prenatal/preconception population carrier screening for common single-gene autosomal recessive disorders. With advances in genetic sequencing and microarray hybridization analysis, large quantities of disease-specific genetic variants can be determined in a time frame suited to prenatal/preconception screening and diagnosis. Commercial laboratories offer expanded carrier screening panels, but no professional guidance has been forthcoming on which disease genes and mutations to include. The proper selection of appropriate disease-causing targets for general population-based carrier screening should be developed using clear criteria rather than including as many disorders as possible. Disorders should be of a nature that most at-risk patients and their partners identified would consider having a prenatal diagnosis to facilitate making decisions about reproduction. The inclusion of disorders characterized by variable expressivity or incomplete penetrance and those associated with a mild phenotype should be optional and made transparent when these technologies are used for screening (ethical principle of nonmaleficence). When adult-onset disorders are included, patients must provide consent to screening for these conditions, especially if they have implications for the health of the individual being screened or other family members (ethical principles of autonomy and nonmaleficence). For each disorder, the causative genes, mutations, and mutation frequencies should be known in the population being tested to allow meaningful assessment of residual risk in individuals who test negative. Laboratories should specify how residual risk is calculated using pan-ethnic population data or a specific race/ethnic group. This calculation requires knowledge of the carrier frequency within a population and the proportion of disease-causing alleles detected using the specific testing platform. Laboratories offering expanded carrier screening should keep data and regularly report findings that allow calculation of residual risk estimates for all disorders being offered. There must be validated clinical association between the mutation(s) detected and the severity of the disorder. Materials must include specific citations that support inclusion of the mutations for which screening is being performed. Quality control and proficiency testing must comply with the ACMG Standards and Guidelines for Clinical Genetics Laboratories and should include the entire process of preanalytic, analytic, and postanalytic phases. A multifactorial approach will require a more generic consent process than is generally used for single-disease screening because it may not be practical for clinicians to discuss each disease included in a multidisease carrier screening panel. A pamphlet or Web site containing a brief description of each disorder included in a test panel should be available to patients. Genetic counseling before and after testing should be available, especially for those who have positive results. This counseling should include disclosure of the mutation(s) detected, description of the clinical nature of the disorder, facilitation of testing of the reproductive partner, calculation of the revised fetal risk when the partner is not available or declines testing, identification of other at-risk family members, and discussion of options for fetal testing and reproductive decision making.

Expanded carrier screening panels-does bigger mean better?

Prenatal carrier screening is offered for some inherited conditions based on recommendations of the American Congress of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG). Currently, ACOG and ACMG recommend that cystic fibrosis carrier screening be offered to all women of reproductive age and that fragile X syndrome (FXS) carrier screening be offered to women with a family history suggestive of FXS or who ask to have testing following genetic counseling (Committee Opinion 469 2010; Committee Opinion 486 2011). For individuals of Eastern European Jewish descent, ACOG recommends carrier screening for Tay-Sachs disease, Canavan disease, cystic fibrosis, and familial dysautonomia (Committee Opinion 442 2009) stating that further testing should be permitted with appropriate counseling if the patient inquires about other conditions that occur more commonly in their ethnic group. ACMG recommends general population screening for spinal muscular atrophy, though this is unsupported by ACOG (Committee Opinion 432 2009; Prior 2008). All of these conditions are inherited in an autosomal recessive fashion except for fragile X syndrome, which is X-linked. People have two copies of each autosomal gene, one inherited from each parent. Recessive conditions manifest when both copies of the same gene have a mutation or do not function normally. Carriers have one abnormal gene copy, as well as one normal copy and are asymptomatic individuals. A 25 % risk for an affected child exists when both parents are carriers, as that poses a one in four risk for a child to receive a gene mutation from both parents. It is estimated that each individual is a carrier of between zero and seven severe childhood recessive conditions, with an average of 2.8 found in one study (Bell et al. 2011). As the first condition for which ethnicity based carrier screening was offered, cystic fibrosis (CF) is the most common lifelimiting autosomal recessive condition in non-Hispanic Caucasians. The debate over general population carrier screening began in 1990 following the discovery of the gene associated with cystic fibrosis (Karem et al. 1989; Beaudet 1990; Caskey et al. 1990; Tatsugawa et al. 1994). The discovery of the gene and the subsequent development of a genetic test were considered breakthroughs in science that would presumably lead to a cure. Questions of when and to who to offer the test presented a new ethical quandary at that time. The first report regarding routine CF carrier screening recommended against offering it to pregnant women stating that it should not yet be considered standard of care (Caskey et al. 1990). With the main benefit being to provide information for reproductive decision making, the potential limitations include anxiety over residual risk, anxiety associated with carrier status, and the cost of testing a large volume of people with very little financial benefit (Beaudet 1990). This debate was largely resolved over the next 10 years by an improvement in testing that increased detection rate, thereby reducing residual risk after negative CF carrier testing. By 2001, prenatal and preconception carrier screening for CF was S. Wienke : C. Strange Division of Pulmonary & Critical Care, Medical University of South Carolina, Charleston, SC, USA

Offering fragile X syndrome carrier screening: a prospective mixed-methods observational study comparing carrier screening of pregnant and non-pregnant women in the general population

IntroductionFragile X syndrome (FXS) is the leading cause of inherited intellectual and developmental disability. Policy development relating to carrier screening programmes for FXS requires input from large studies examining not...

Development of a fragile X syndrome (FXS) knowledge scale: towards a modified multidimensional measure of informed choice for FXS population carrier screening

Genetic carrier screening is increasingly possible for many conditions, but it is important to ensure decisions are informed. The multidimensional measure of informed choice (MMIC) is a quantitative instrument developed to evaluate informed choice in prenatal screening for Down syndrome, measuring knowledge, attitudes and uptake. To apply the MMIC in other screening settings, the knowledge scale must be modified. To develop and validate a modified MMIC knowledge scale for use with women undergoing carrier screening for fragile X syndrome (FXS). Responses to MMIC items were collected through questionnaires as part of a FXS carrier screening pilot study in a preconception setting in Melbourne, Australia. Ten knowledge scale items were developed using a modified Delphi technique. Cronbach's alpha and factor analysis were used to validate the new FXS knowledge scale. We summarized the knowledge, attitudes and informed choice status based on the modified MMIC. Two hundred and eighty-five women were recruited, 241 eligible questionnaires were complete for analysis. The FXS knowledge scale items measured one salient construct and were internally consistent (alpha=0.70). 71% (172/241) of participants were classified as having good knowledge, 70% (169/241) had positive attitudes and 27% (65/241) made an informed choice to accept or decline screening. We present the development of a knowledge scale as part of a MMIC to evaluate informed choice in population carrier screening for FXS. This can be used as a template by other researchers to develop knowledge scales for other conditions for use in the MMIC.

Carrier screening in preconception consultation in primary care

Discussing carrier screening during preconception consultation in primary care has a number of advantages in terms of promoting autonomy and enabling the greatest range of reproductive choices. For those with a family history of an inherited condition, this ought to be a routine discussion; however, this can be expanded to include the wider population, especially for those conditions for which carrier frequencies are considered relatively common. There is published literature from around the world regarding experiences with carrier screening in primary care for cystic fibrosis, haemoglobinopathies, fragile X syndrome, Tay-Sachs disease and spinal muscular atrophy, although many of these have tended to focus on consultations during rather than before pregnancy. Overall, these studies reveal that population carrier screening is well received by the participants with apparent minimal psychosocial harms; however, challenges exist in terms of approaches to ensure couples receive adequate information to make personally relevant decisions and for ongoing health professional engagement.

Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72 400 specimens

Spinal muscular atrophy (SMA) is a leading inherited cause of infant death with a reported incidence of ∼1 in 10 000 live births and is second to cystic fibrosis as a common, life-shortening autosomal recessive disorder. The American College of Medical Genetics has recommended population carrier screening for SMA, regardless of race or ethnicity, to facilitate informed reproductive options, although other organizations have cited the need for additional large-scale studies before widespread implementation. We report our data from carrier testing (n=72 453) and prenatal diagnosis (n=121) for this condition. Our analysis of large-scale population carrier screening data (n=68 471) demonstrates the technical feasibility of high throughput testing and provides mutation carrier and allele frequencies at a level of accuracy afforded by large data sets. In our United States pan-ethnic population, the calculated a priori carrier frequency of SMA is 1/54 with a detection rate of 91.2%, and the pan-ethnic disease incidence is calculated to be 1/11 000. Carrier frequency and detection rates provided for six major ethnic groups in the United States range from 1/47 and 94.8% in the Caucasian population to 1/72 and 70.5% in the African American population, respectively. This collective experience can be utilized to facilitate accurate pre- and post-test counseling in the settings of carrier screening and prenatal diagnosis for SMA.

Recessive Multiple Epiphyseal Dysplasia Double Carrier State Identified by Expanded Carrier Screening

BACKGROUND: General population carrier screening is now available for hundreds of Mendelian disease-causing mutations. Due to the cost-effectiveness of the technology, carrier screening can now be applied “universally” across all populations, reducing the use of racial and ethnic categorization in medicine. The lower cost of testing confers the benefits of decreased expenses for existing routine carrier screens and introduction of screening for other genetic diseases that are also prevalent, but were not routinely screened before the advent of a universal genetic test.

New Approaches in Molecular Diagnosis and Population Carrier Screening for Spinal Muscular Atrophy

Autosomal recessive spinal muscular atrophy, the leading genetic cause of infant death, is due to loss of functional SMN1 genes, mainly as a result of homozygous deletions. Carrier frequency in the general population varies widely from 1/50 to 1/125 and has significant counseling implications. In a cohort of 210 patients with spinal muscular atrophy confirmed at the molecular level, 91.9% had a homozygous deletion and 14 were compound heterozygotes. Two novel point mutations were detected (c.524delC and c.734dupC) and the 11 bp duplication c.770_780dup was found at a high frequency. We describe the development of a simple and robust method for homozygous deletion detection, which enabled us to simplify the diagnostic workup. Further, carrier frequency in our population was established by direct quantification with the commercially available MLPA kit, following optimization for the use of dried blood spots as sample specimens.

Population Carrier Screening for Spinal Muscular Atrophy: A Position Statement of the Association for Molecular Pathology

Spinal muscular atrophy is a common and often fatal autosomal recessive disorder for which carrier screening is available. The Association for Molecular Pathology has evaluated recent opinions regarding population carrier screening, reviewed the current literature, and developed a position statement that includes specific recommendations addressing both diagnostic and practical issues that affect implementation.

Spinal muscular atrophy: a time for screening

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron (SMN1) gene, affecting approximately 1 in 10,000 live births. Even though a specific therapy for SMA is not currently available, a newborn screening test may allow the child to be enrolled in a clinical trial before irreversible neuronal loss occurs and enable patients to obtain more proactive treatments. Until an effective treatment is found to cure or arrest the progression of the disease, prevention of new cases through carrier detection and prenatal diagnosis becomes extremely important. The correlation between the SMA phenotype and the SMN2 copy number and the demonstration that sufficient SMN protein from SMN2 in transgenic mice can ameliorate the disease has made the SMN2 gene an obvious target that is being modulated in current therapeutic trials. Most recent work, utilizing gene therapy, has also shown a rescue of the phenotype in the mouse model. Since SMA children are often asymptomatic at birth, newborn screening is a means which will allow the implementation of the most early intervention to take place, before the irreversible loss of motor neurons. Since there is no effective cure for SMA presently, prevention through the identification of carriers becomes an important alternative and has recently been initiated. Treatment and prevention of SMA are complementary responses to the scourge presented by SMA. This review first describes the molecular genetics of SMA and then focuses on newborn screening, as a means of ensuring the earliest intervention, and the prevention through population carrier screening.

Region-Specific Genetic Heterogeneity of HBB Mutation Distribution in South-Western Greece

β-Thalassemia (β-thal), is caused by reduced or absent synthesis of β-globin chains resulting in impaired erythropoiesis. It is the most common single gene defect disease in Greece, with heterozygous rates reaching, on average, 8% in the general population. Here, we performed molecular analyses on 199 unrelated β-thal and compound β-thal/sickle cell disease patients, of whom 157 originated from three prefectures of South-Western Greece, namely Achaia, Ilia and Etoloakarnania.Our results indicate that the frequency of specific HBB gene mutations, namely the HBB:c.118C>T (codon 39, C>T), HBB:c.92+6T>C (IVS-I-6, T>C), and HBB:c.20A>T [Hb S, β6(A3)Glu→Val, GAG>GTG], present distinct distribution patterns in the Achaia and Ilia prefectures (p < 0.001, p < 0.003 and p < 0.002, respectively). This detailed analysis of the distribution of the HBB gene mutations is useful for genetic counseling in the region, and illustrates that the identification of the HBB gene mutation spectrum in this region is necessary for population carrier screening and for efficient provision of prenatal diagnosis.

Carrier screening for Beta-thalassaemia: a review of international practice

β-thalassaemia is one of the most common single-gene inherited conditions in the world, and thalassaemia carrier screening is the most widely performed genetic screening test, occurring in many different countries. β-thalassaemia carrier screening programmes provide a unique opportunity to compare the delivery of carrier screening programmes carried out in different cultural, religious and social contexts. This review compares the key characteristics of β-thalassaemia carrier screening programmes implemented in countries across the world so that the differences and similarities between the programmes can be assessed. The manner in which thalassaemia carrier screening programmes are structured among different populations varies greatly in several aspects, including whether the programmes are mandatory or voluntary, the education and counselling provided and whether screening is offered pre-pregnancy or antenatally. National and international guidelines make recommendations on the most appropriate ways in which genetic carrier screening programmes should be conducted; however, these recommendations are not followed in many programmes. We discuss the implications for the ethical and acceptable implementation of population carrier screening and identify a paucity of research into the outcomes of thalassaemia screening programmes, despite the fact that thalassaemia screening is so commonly conducted.

Large-Scale Population Carrier Screening for Spinal Muscular Atrophy in Israel—Effect of Ethnicity on the False-Negative Rate

The carrier frequency of spinal muscular atrophy varies from 1:168 to 1:35. We analyzed the carrier rate in a large population in Israel, evaluated the false-negative rate based on the number of alleles with duplication of exon 7, and analyzed the ethnic differences in both parameters. Data were collected from two centers that conduct carrier screening using the multiplex ligation-dependent probe amplification kit. We studied the number of copies of exons 7 and 8 in our population, which we divided into six different ethnic groups. Statistical analysis was conducted using chi-square test. A total of 7308 healthy individuals were tested in an organized community health maintenance organization (HMO) program, and 1729 in a large hospital setup. The carrier rate was 1:62 and was not statistically different between the ethnic groups. Duplication was found in one in nine individuals (false-negative rate 5.5%) with a significant difference in frequency between the ethnic groups: 13.5% among Ashkenazim, 6% among North-African Jews (p < 0.001). This difference was consistent in both centers and in exon 8 as well. There is, therefore, a higher prevalence of false negative results in some ethnic groups. The discrepancy between the rates of deletions versus duplications can be explained by the genetic disadvantage of deletions.

“It's something I need to consider”: Decisions about carrier screening for fragile X syndrome in a population of non‐pregnant women

Population carrier screening for fragile X syndrome can provide women with information about their risk of having a child with fragile X syndrome and their risk of fragile X-associated primary ovarian insufficiency and fragile X-associated tremor ataxia syndrome. Few studies have explored women's decisions when offered carrier screening for fragile X syndrome. Interviews were conducted with 31 women who participated in a pilot study offering carrier screening to non-pregnant women. A qualitative approach was used to gain an in-depth understanding of women's experiences and examine their decision-making processes, including women who were tested and those who decided not to be tested. The decision-making process occurred in two phases. In the first phase, the participant's reproductive stage of life and experience with illness and disability were major factors influencing whether she would consider screening. In the second phase of decision-making, participants' perceptions of the value of knowing their carrier status was the most notable factor for influencing whether a woman actually had the carrier test. Some women appreciated having time for deliberation and those who were tested did not express regret about their decision. Our findings support offering carrier screening for fragile X syndrome to non-pregnant women and suggest that women from the general population will have specific informational and counseling needs when offered carrier testing. This study highlights the unique challenges encountered by women from the general population when making a decision about testing for fragile X syndrome carrier status and illustrates the importance of understanding how women make decisions.

A targeted population carrier screening program for severe and frequent genetic diseases in Israel

A national carrier screening program targeted at communities in which severe genetic diseases are present with a frequency higher than 1/1000 live births, has been in existence in Israel since 2002. Within the communities at risk, carrier screening is voluntary whereas genetic counseling and testing is provided free of charge. During the first 5 years of the program more than 13 000 tests were performed, and at the end of 2007 it was offered in 35 different localities/communities for a total of 36 diseases. Many of the couples identified to be at risk opted for prenatal diagnosis and in two cases an affected pregnancy was terminated. In some cases the couples declined prenatal diagnosis and two of those families gave birth to an affected child. Based on the experience learnt from this targeted screening program it appears that a knowledge-based, voluntary screening program operated within the community is an effective way to provide genetic services and test referrals. The community program directed toward couples in their reproductive period does not seem to have led to stigmatization at either the individual or the community level.

Carrier screening for spinal muscular atrophy

Carrier screening for spinal muscular atrophy

A model for offering carrier screening for fragile X syndrome to nonpregnant women: results from a pilot study

PurposeTo develop a model of offering population carrier screening for fragile X syndrome to nonpregnant women in primary care, using a program evaluation framework. MethodsA three-phase approach included: (I) needs assessment exploring staff and client attitudes, and informing development of educational materials, questionnaires and protocols; (II) offering screening to women, with questionnaires at baseline (Q1) and another (Q2) 1-month later; (III) genetic counseling for test-positive women and interviews with a subgroup of participants. ResultsOf 338 volunteering for Phase II, 94% completed Q1, 59% completed Q2, and 20% (N = 65) chose testing revealing one premutation carrier and three gray zone results; 31 women were interviewed. Tested women had more positive attitudes toward screening (Q1: P < 0.001; Q2: P < 0.001) compared with untested, although there was no significant difference in mean knowledge scores or anxiety. Women generally supported being offered prepregnancy screening; however, reasons against being tested included: not currently planning a family; perceiving benefits of screening as unimportant; and having to return for testing. ConclusionThis is the first prospective study exploring informed decision-making for fragile X syndrome carrier screening, using a thorough process of consultation, with no apparent harms identified. It provides a model for development of future genetic screening programs.