Preconception carrier screening as an alternative reproductive option prior to newborn screening for severe recessive disorders

Newborn screening in Germany was the main topic of the last issue of this journal [1]. In the past years it has been extended in German speaking countries to include “classic” autosomal recessive diseases such as cystic fibrosis and infantile spinal muscular atrophy (SMA). Carrier frequencies are approximately 1 in 25 for cystic fibrosis [2] and 1 in 45 for SMA. Newborn screening for SMA has just been implemented in Germany in October 2021 (https://screening-dgns.de) and in Austria in June 2021 (https://www.neugeborenenscreening.at), given that an effective (but not curative) treatment is available. Nonetheless, most parents of affected children would rather not opt for early treatment after birth of an affected sibling, but would avoid having another child with the same condition. There is no doubt that an early diagnosis of a potential treatable disease, such as cystic fibrosis or SMA, is of great importance.

However, we believe that newborn screening is not the only answer towards the best time point of communicating a serious genetic diagnosis in a family. More than 90 % of patients with severe recessive conditions are born to parents with no family history of the disease, parents who had no idea what would happen to their family life. It was shown that the uptake of reproductive options is high in couples at risk identified by genetic screening [3].

Although most autosomal recessive disorders are rare, one should realize that overall about 1–2 % of all couples are at risk of having an affected child, which is in the range of the risk to a 35-year-old woman for the birth of a child with Down syndrome. Experience in genetic counseling shows that not only couples with an affected child themselves ask for reproductive options, but also close relatives are very often seriously concerned about their possible carrier status even for treatable conditions.

Historical development of carrier screening

Preconception carrier screening (PCS) is an option for reproductive decision making for individuals or couples at risk of conceiving children affected by serious autosomal recessive or X-linked diseases. PCS has long been established in the Mediterranean countries for thalassemia, organized as a prerequisite prior to marriage. It was first introduced in 2008 as a multiplex genetic screening test for the most prevalent autosomal recessive diseases (carrier frequency at least 1 %) in the Ashkenazi Jewish population [4] (Figure 1). The guidelines state that the offering of such testing should ideally take place before pregnancy, thereby giving individuals time to make appropriate reproductive decisions based on their own personal choices and cultural backgrounds. Genetic counseling is recommended if one partner turns out to be heterozygous [4].

Figure 1.

Timeline of important developments and statements for the implementation of preconception carrier screening in the normal population.

In 2010, the private company Counsyl developed a so-called Universal Carrier Test for 105 autosomal recessive disorders based on high throughput (next generation) sequencing. It allowed genetic testing of oral mucosa samples for a small budget [5]. However, the selection of genes included cancer syndromes and mild conditions with questionable relevance, as such the Universal Carrier Test was not promoted further.

Based on the better availability of high-throughput sequencing, several countries are thinking about strategies for the implementation of preconception carrier testing into the general healthcare system. In 2016, the first official statement of the European Society of Human Genetics (ESHG) was released as regards a reasonable implementation of expanded carrier screening (ECS) in the normal population [6]. Following the ESHG, the primary goal of an ECS is to facilitate informed reproductive decision making. High risk couples may decide to pursue a variety of preventive measures to decrease the risk of an affected child. These include prenatal or preimplantation genetic testing, the use of donor gametes, adoption, or remaining childless (Figure 2). ECS should allow testing regardless of ancestry or geographic origin (pan-ethnic). The best time to offer screening according to the ESHG is the preconception period to allow the greatest number of options. It was stated that ECS will have no lasting negative effect of carrier status on anxiety or stigma, but gaining valid consent of individuals to be screened may remain a challenge [6].

Figure 2.

Reproductive options for couples undergoing preconception genetic carrier screening. Underlying different legal regulations apply in German speaking countries.

* Preimplantation genetic diagnosis in Germany only after approval by an ethics committee

** Oocyte donation not allowed in Germany or in Switzerland, gamete donation possible in Austria

In 2017, the American College of Obstetricians and Gynecologists (ACOG) was the first academic society to recommend carrier screening for SMA and cystic fibrosis to all women who are considering pregnancy or are currently pregnant [2]. Moreover, expanded carrier screening following the ACOG opinion might include conditions with a carrier frequency of at least 1 %. Further calculations based on exomes data of 123.136 American probands have shown that screening of the most frequent 40 genes would identify more than 76 % of at risk-couples in a pan-ethnic panel [7].

Ethical implications

The implementation of PCS raises several ethical questions which are addressed in the literature from different points of view [8], [9], [10]. The arguments and concerns are not new and were already debated when invasive prenatal chromosome analysis was made available more than 50 years ago. They were reiterated with the introduction of chromosomal screening tests in pregnancy or in the context of preimplantation genetic diagnostics. In essence, it is the conflict between the question of reproductive autonomy and the concern of stigmatization and discrimination of living people with the respective genetic conditions. There is concern that an increased uptake of carrier screening may affect social norms and may even share some elements with eugenic programs of the past [9]. Although there is so far only little evidence that carrier screening might actually promote stigmatization, discrimination or even eugenics, these kinds of possible “slippery slope” arguments [10] should be taken very seriously.

Main open questions

Which diseases should be selected for PCS?

Commercial PCS panels often include a variety of disorders which are either mild or adult onset. Panels implemented in a health care system should be limited to severe childhood onset diseases with clear clinical significance. The question of clinical impact and cost-effectiveness has been addressed by a study conducted in the United States (US) by the company Myriad (former Counsyl) based on a 176-condition carrier screen in more than 60.000 probands [11]. Screening for the 10 most frequent conditions in a mixed US population (Table 1) would dramatically reduce incidences of affected children and corresponding costs for the health care system [11]. In Belgium carrier screening has been implemented in the healthcare system in 2017 (https://www.health.belgium.be/en/advisory-report-9240-carrier-screening) and covers up to 1124 genes. It is offered under the term BeGECS in all genetic centres in Belgium for couples who are willing to pay 1400 EUR. The test is couple-based and accompanied by an information leaflet (www.uza.be). The inclusion of genes for PCS has to take the ethnicity of the population, costs and resources of the healthcare system into account. In a mixed population of Middle European background it is advised to implement a pan-ethnic test regardless of ancestry or geographic origin of the couple [6].

Table 1.

The Top 10 of severe autosomal or X-linked recessive childhood onset diseases in a mixed US population (modified according to [11]).

Disease	Mode of inheritance	Gene	Disease frequency
Beta-hemoglobinopathy	AR	HBB	1 in 2.097
Fragile X syndrome	XL	FMR1	1 in 3.205
Cystic fibrosis	AR	CFTR	1 in 3.242
Dystrophinopathy	XL	DMD	1 in 3.374
GJB2 related deafness	AR	GJB2	1 in 5.733
Phenylalanine hydroxylase deficiency	AR	PAH	1 in 8.484
Congenital adrenal hyperplasia	AR	CYP21A2	1 in 9.962
Spinal muscular atrophy	AR	SMN1	1 in 11.096
Smith-Lemli-Opitz syndrome	AR	DHCR7	1 in 13.214
Fabry disease	XL	GLA	1 in 13.773

AR: autosomal recessive, XL: X-linked

When is the best time point for PCS?

It is generally agreed that the primary target group for PCS are couples planning a pregnancy. As such the screening program should actively be promoted by healthcare providers, gynecologists, fertility centres and general practioners (GPs). However, it does not seem to be realistic to exclude women who are already pregnant [3]. Since about 20 % of pregnancies are unplanned, many couples might miss the opportunity for preconceptual PCS. However, the highest levels of anxiety can be expected in couples who are already pregnant and might have to consider a termination. Since test acceptors should be able to give informed consent, PCS should only be offered to an adult population.

How can adequate informed consent and genetic counseling be provided?

There has been a long-standing debate if a carrier screening comprising a large number of rare diseases can rationally accompanied by valid consent. Following the ESHG recommendations, new models of a generic consent have to be developed [6]. It was shown that genetic literacy, a better education and prior knowledge increase uptake of screening and reduce psychological stress of individuals undergoing carrier screening. There is still not enough experience how genetic knowledge can best be achieved. In a study in the Netherlands, the effect of an educational video (https://www.youtube.com/watch?v=V9FKDNF_-tI) to explain ECS was compared to an educational text in the normal population [12]. Respondents who were offered a video had a better genetic knowledge and were more likely to participate in ECS [12]. Considering the tremendous increase in communication via social media, it might be helpful to develop applications for mobile devices and online videos as supportive tools to the genetic counseling process.

Comprehensive qualified genetic counseling is of utmost importance for a responsible handling of PCS test results in high risk couples. This, however, cannot be guaranteed today in view of the constantly growing number of genetic conditions and improving diagnostic possibilities. A central prerequisite for dealing responsibly with complex genetic information is the provision of skilled personnel, e. g. through the integration of genetic counsellors into interdisciplinary medical genetics teams.

Role model: The Netherlands

Meanwhile, the Netherlands have demonstrated how a couple-based ECS can be developed by the national academia and implemented in a publicly funded healthcare service. The selection of genes for ECS in the Dutch population was agreed upon by experts at the University of Groningen in 2013. Prior to its implementation a survey was developed to measure the intentions of the potential users as well as their ‘supply’ preferences [13]. Of the 500 respondents one third would take the offer of PCS, and about half of them would be willing to pay for the test. The majority (44 %) would like the test to be offered via their GP. More than one third of probands preferred a face to face consultation as pre-test information, but general information by means of a brochure was also regarded as important and the preferred option for 21 % [13].

The so-called UMCG panel covers 50–70 severe autosomal recessive childhood onset disorders – including SMA – with an a priori carrier probability of 1 in 150 for both parents in the Dutch population (https://www.umcg.nl/lDocuments/LABF024602E_UMCG_Conditions_and_genes_included_in_UCMG_preconception_screening_test.pdf). It is organized as a population-based couple test with a pre-test information via trained GPs [12]. The UMCG panel is offered since 2016 within a research setting conducted by the two involved universities in Amsterdam and Groningen. There is a huge framework of research as regards the feasibility of a test offer by GPs [14], informed decision making processes [12], psychological outcomes [15] and ethical issues [16]. The experiences in the Netherlands are encouraging and could serve as a role model for the German speaking countries. It is not the first time that we can learn a lot from our Dutch neighbors.