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A higher impact of less specific preconception carrier screening: a plea for a “one size fits all” approach?
Abstract
When an autosomal recessive disorder is diagnosed in a child, this is often the first moment that parents find out that both of them are carriers of the same disorder. If they ask: “Could we have known beforehand that both of us are carriers of this disorder?”, the theoretical answer is “yes”, but the practical answer is often “no”, since carrier screening is not offered in the health care system in many places around the world. Yet, although these disorders are hereditary, most children with autosomal recessive disorders are born in families with a negative family history of the disease, and carrier screening would be the only effective strategy to inform couples of their risk before the birth of an affected child.
... These at-risk couples (ARCs; also referred to as 'carrier couples') have a one-in-four chance of conceiving an affected child with the disorder in each pregnancy [2]. However, because they are typically healthy and lack family history for the disorder, ARCs are usually unaware of their reproductive risk until their child is diagnosed with the disorder [3]. The goal of carrier screening is to identify unsuspecting ARCs prospectively, ideally prior to conception, to allow them to make informed reproductive choices. ...
Introduction: Carrier screening for recessive disorders is undertaken by prospective parents to inform their reproductive decisions. With the growing availability of affordable and comprehensive expanded carrier screening (ECS), it is expected that carrier screening will become a standard practice in the future. However, the impact of positive carrier screening results on the reproductive decisions of at-risk couples (ARCs) remains underexplored.
Areas covered: We performed a systematic literature review to identify peer-reviewed publications describing reproductive decisions of ARCs. Our search identified 19 relevant publications spanning the period 1994 - 2018. By synthesizing available evidence, we found that most ARCs chose to prevent the birth of an affected child and the decision to utilize preventive reproductive options was strongly influenced by the clinical nature of a disorder. However, there was also some heterogeneity in reproductive decisions within the same recessive disorders, suggesting that choices of ARCs can be influenced by factors other than the clinical nature of a disorder.
Expert opinion: ECS is becoming increasingly common, which will result in the routine identification of many ARCs. Reproductive decision-making by ARCs is a complex and emotionally challenging process, highlighting the critical role of genetic counseling in the care for these potentially vulnerable patients.
... Commercial providers have started offering panel tests for more than 100 diseases [5]. Expanded carrier tests offer the advantage that a larger proportion of potentially affected fetuses can be recognized [5,6]. A disadvantage, however, is that the person tested does not know the conditions that they can be tested for; therefore, the perceived sense of urgency may be limited and informed decision-making more difficult [7,8]. ...
... 2,3 As a consequence, it is common for couples to only find out about their carrier status after giving birth to an affected child. 4 Such couples could benefit from carrier screening, ideally before conception, to identify their reproductive risks and inform decisions. 5 If identified preconceptionally, couples can choose to pursue artificial reproduction through preimplantation genetic diagnosis or using egg or sperm from a non-carrier donor. ...
Background:
Expanded carrier screening (ECS), which can identify carriers of a large number of recessive disorders in the general population, has grown in popularity and is now widely accessible to prospective parents. This article presents a comprehensive overview of the characteristics of currently available ECS tests.
Methods:
To identify relevant ECS providers, we employed a multi-step approach, which included online searching, review of the recent literature, and consultations with researchers familiar with the current landscape of ECS.
Results:
As of January 2017, there were sixteen providers of ECS tests: 13 commercial companies, two medical hospitals and one academic diagnostic laboratory. We observed drastic differences in the characteristics of ECS tests, with the number of conditions ranging from 41 to 1700. Only three conditions (Cystic fibrosis, Maple syrup urine disease 1b, and Niemann-Pick disease) were screened for by all providers. Where the same disease gene was included by multiple providers, substantial differences existed in the mutations screened and/or variant interpretation/reporting strategies.
Conclusion:
Given the importance of carrier screening results in reproductive decision-making, the observed heterogeneity across ECS panels is concerning. Efforts should be made to ensure that clear and concrete criteria are in place to guide the development of ECS panels.
Preconceptiezorg geeft aanstaande ouders de kans om vóór de conceptie hun gezondheid te verbeteren en optimaal aan een zwangerschap te beginnen. Preconceptiezorg vergroot tevens de handelingsopties van toekomstige ouders, bijvoorbeeld wanneer er sprake is van een verhoogde kans op een kind met een erfelijke aandoening. De verwachting is dat de uitkomsten van de zwangerschap, zoals de kans op een gezond kind en een gezonde moeder, zullen verbeteren. Door de langdurige vertrouwensrelatie met hun patiënten zijn huisartsen in een uitstekende positie om preconceptiezorg te geven. Een belangrijk onderdeel is het vaststellen van risicofactoren. Op basis hiervan voert u lichamelijk en aanvullend onderzoek uit. Het verwijsbeleid is gebaseerd op de Preconceptie Indicatielijst (PIL) waarin de samenwerking van zorgverleners rondom preconceptiezorg is vastgelegd. De aanbeveling is om aan te sluiten bij regionale initiatieven om preconceptiezorg in uw regio te verbeteren.
The European Journal of Human Genetics is the official Journal of the European Society of Human Genetics, publishing high-quality, original research papers, short reports, News and Commentary articles and reviews in the rapidly expanding field of human genetics and genomics.
Importance:
Screening for carrier status of a limited number of single-gene conditions is the current standard of prenatal care. Methods have become available allowing rapid expanded carrier screening for a substantial number of conditions.
Objectives:
To quantify the modeled risk of recessive conditions identifiable by an expanded carrier screening panel in individuals of diverse racial and ethnic backgrounds and to compare the results with those from current screening recommendations.
Design, setting, and participants:
Retrospective modeling analysis of results between January 1, 2012, and July 15, 2015, from expanded carrier screening in reproductive-aged individuals without known indication for specific genetic testing, primarily from the United States. Tests were offered by clinicians providing reproductive care.
Exposures:
Individuals were tested for carrier status for up to 94 severe or profound conditions.
Main outcomes and measures:
Risk was defined as the probability that a hypothetical fetus created from a random pairing of individuals (within or across 15 self-reported racial/ethnic categories; there were 11 categories with >5000 samples) would be homozygous or compound heterozygous for 2 mutations presumed to cause severe or profound disease. Severe conditions were defined as those that if left untreated cause intellectual disability or a substantially shortened lifespan; profound conditions were those causing both.
Results:
The study included 346 790 individuals. Among major US racial/ethnic categories, the calculated frequency of fetuses potentially affected by a profound or severe condition ranged from 94.5 per 100 000 (95% CI, 82.4-108.3 per 100 000) for Hispanic couples to 392.2 per 100 000 (95% CI, 366.3-420.2 per 100 000) for Ashkenazi Jewish couples. In most racial/ethnic categories, expanded carrier screening modeled more hypothetical fetuses at risk for severe or profound conditions than did screening based on current professional guidelines (Mann-Whitney P < .001). For Northern European couples, the 2 professional guidelines-based screening panels modeled 55.2 hypothetical fetuses affected per 100 000 (95% CI, 51.3-59.3 per 100 000) and the expanded carrier screening modeled 159.2 fetuses per 100 000 (95% CI, 150.4-168.6 per 100 000). Overall, relative to expanded carrier screening, guideline-based screening ranged from identification of 6% (95% CI, 4%-8%) of hypothetical fetuses affected for East Asian couples to 87% (95% CI, 84%-90%) for African or African American couples.
Conclusions and relevance:
In a population of diverse races and ethnicities, expanded carrier screening may increase the detection of carrier status for a variety of potentially serious genetic conditions compared with current recommendations from professional societies. Prospective studies comparing current standard-of-care carrier screening with expanded carrier screening in at-risk populations are warranted before expanded screening is adopted.
This document of the European Society of Human Genetics contains recommendations regarding responsible implementation of expanded carrier screening. Carrier screening is defined here as the detection of carrier status of recessive diseases in couples or persons who do not have an a priori increased risk of being a carrier based on their or their partners’ personal or family history. Expanded carrier screening offers carrier screening for multiple autosomal and X-linked recessive disorders, facilitated by new genetic testing technologies, and allows testing of individuals regardless of ancestry or geographic origin. Carrier screening aims to identify couples who have an increased risk of having an affected child in order to facilitate informed reproductive decision making. In previous decades, carrier screening was typically performed for one or few relatively common recessive disorders associated with significant morbidity, reduced life-expectancy and often because of a considerable higher carrier frequency in a specific population for certain diseases. New genetic testing technologies enable the expansion of screening to multiple conditions, genes or sequence variants. Expanded carrier screening panels that have been introduced to date have been advertised and offered to health care professionals and the public on a commercial basis. This document discusses the challenges that expanded carrier screening might pose in the context of the lessons learnt from decades of population-based carrier screening and in the context of existing screening criteria. It aims to contribute to the public and professional discussion and to arrive at better clinical and laboratory practice guidelines.
Informed decision making about participation has become an explicit purpose in invitations for screening programmes in western countries. An informed choice is commonly defined as based on: (i) adequate levels of knowledge of the screening and (ii) agreement between the invitee's values towards own screening participation and actual (intention to) participation.
We systematically reviewed published studies that empirically evaluated the effects of interventions aiming at enhancing informed decision making in screening programmes targeted at the general population. We focused on prenatal screening and neonatal screening for diseases of the foetus/new-born and screening for breast cancer, cervical cancer and colorectal cancer. The Medline, EMBASE and Cochrane databases were searched for studies published till April 2012, using the terms 'informed choice', 'decision making' and 'mass screening' separately and in combination and terms referring to the specific screening programmes.
Of the 2238 titles identified, 15 studies were included, which evaluated decision aids (DAs), information leaflets, film, video, counselling and a specific screening visit for informed decision making in prenatal screening, breast and colorectal cancer screening. Most of the included studies evaluated DAs and showed improved knowledge and informed decision making. Due to the limited number of studies the results could not be synthesized.
The empirical evidence regarding interventions to improve informed decision making in screening is limited. It is unknown which strategies to enhance informed decision making are most effective, although DAs are promising. Systematic development of interventions to enhance informed choices in screening deserves priority, especially in disadvantaged groups.
Expanded universal carrier screening (EUCS) entails a twofold expansion of long-standing (preconception) carrier screening programmes: it not only allows the simultaneous screening of a large list of diseases ('expanded'), but also refers to a pan-ethnic screening offer ('universal'). Advocates mention three main moral advantages of EUCS as compared with traditional (targeted and/or ancestry-based) forms of carrier screening: EUCS will (1) maximise opportunities for autonomous reproductive choice by informing prospective parents about a much wider array of reproductive risks; (2) provide equity of access to carrier testing services; (3) reduce the risk of stigmatisation. This empirical ethics study aims to widen this account and provide a balanced picture of the potential pros and cons of EUCS. Semi-structured interviews were conducted with 17 health (policy) professionals and representatives of patient organisations about their views on carrier screening including a possible EUCS scenario. Stakeholders acknowledged the potential benefits of EUCS, but also expressed five main moral concerns: (1) Does EUCS respond to an urgent problem or population need? (2) Is it possible to offer couples both understandable and sufficient information about EUCS? (3) How will societal views on 'reproductive responsibility' change as a result of EUCS? (4) Will EUCS lead to a lower level of care for high-risk populations? (5) Will EUCS reinforce disability-based stigmatisation? While having the potential to overcome some moral limits inherent in traditional carrier screening, EUCS comes with moral challenges of its own. More research is needed to (further) anticipate the ethical and practical consequences of EUCS.European Journal of Human Genetics advance online publication, 28 September 2016; doi:10.1038/ejhg.2016.125.
The Jewish community has traditionally taken ownership of its health, and has taken great strides to raise awareness about genetic issues that affect the community, such as Tay-Sachs disease and Hereditary Breast and Ovarian Cancer syndrome. Thanks in part to these heightened awareness efforts, many Orthodox Jewish individuals are now using genetics services as they begin to plan their families. Due to unique cultural and religious beliefs and perceptions, the Orthodox Jewish patients who seek genetic counseling face many barriers to a successful counseling session, and often seek the guidance of programs such as the Program for Jewish Genetic Health (PJGH). In this article, we present clinical vignettes from the PJGH's clinical affiliate, the Reproductive Genetics practice at the Montefiore Medical Center. These cases highlight unique features of contemporary premarital counseling and screening within the Orthodox Jewish Community, including concerns surrounding stigma, disclosure, "marriageability," the use of reproductive technologies, and the desire to include a third party in decision making. Our vignettes demonstrate the importance of culturally-sensitive counseling. We provide strategies and points to consider when addressing the challenges of pre- and post-test counseling as it relates to genetic testing in this population.
An estimated 300,000 babies are born each year with a severe inherited disease of haemoglobin and that over 80 per cent of these births occur in low- or middle-income countries. As these countries go through the epidemiological transition, characterized by a reduction in childhood and infant mortality due to improved public health measures, infants who had previously died of these conditions before they were recognised are now surviving to present for diagnosis and treatment. For a variety of reasons, even in the rich countries there are limited data about the true frequency, natural history, and survival of patients with these disorders, information that is absolutely critical towards providing governments and international health agencies with accurate information about the true global health burden of these conditions. The situation can only be improved by major action on the part of the rich countries together with the formation of partnerships between rich and poor countries and input from the major international health agencies and funding organisations.