Reproductive genetic screening for information: evolving paradigms?

Introduction

Reproductive genetic screening has introduced the possibility for pregnant women to learn, during the pregnancy or sometimes earlier, about the likelihood of their baby being affected with certain genetic conditions. As medicine progresses, the options afforded by this early information have expanded. This has led to a shifting paradigm in prenatal screening, wherein the early knowledge is seen as useful not solely for its inherent value to the pregnant woman, but also as enabling an expansion of conditions whose identification may allow early intervention and clinical impact. As the landscape of prenatal screening tests evolves, and the list of available target genetic conditions increases, it is worthwhile to evaluate what can be accomplished with today’s technology. There are three interesting areas of reproductive-related screening which will be considered here: expanded carrier screening, non-invasive prenatal screening (NIPS) for aneuploidies and selected microdeletions, and NIPS for single gene disorders.

What conditions do we want to screen for?

Trisomy 21 forms part of a routine offer of prenatal screening in a number of countries. Trisomy 21 was one of the first genetic conditions for which a cytogenetic cause was identified and it became possible to identify this prenatally using amniocentesis and karyotyping even in the early days of cytogenetics [1]. The association between altered levels of various serum markers and likelihood of trisomy 21 then allowed screening to be carried out to refine the risks for a pregnancy before offering amniocentesis [2]. This offering eventually expanded to include trisomies 13 and 18. However, these three trisomies only represent a small proportion of all of the genetic conditions which may affect an individual. Therefore, there is an argument that prenatal screening options should be expanded to include conditions that fulfill a considered set of criteria that make them appropriate for prenatal screening. Such criteria could include, for example, prevalence, penetrance, severity of phenotype and conditions where early knowledge could affect management, and have the potential to improve outcomes. This is particularly pertinent at this point in time when gene therapies are becoming available for a selection of genetic conditions. In general, the earlier a medical issue is identified and treatment is started, the better the likelihood of an improved outcome. With genetic conditions such as spinal muscular atrophy (SMA) this difference can be dramatic: without specific treatment, the progression of the disease can be rapid and devastating, whereas with early treatment the child may achieve milestones that would have been unthinkable previously [3].

Additionally, early information is valuable for a number of other reasons:

1. Information given in pregnancy allows the woman or couple time to prepare and to plan for the birth of a child who may have difficulties. This planning could be practical, such as meeting doctors who will be involved in their child’s care, or contacting associations, it could be financial, particularly in systems where there is no or limited public health care available, and it could be psychological, for example coming to terms with altered expectations and preparing the wider social circle for the new arrival.

2. In some circumstances the pregnant woman or couple may decide, having learned about the presence of a genetic condition in the fetus, that they will not continue with the pregnancy. Learning about the condition during pregnancy is the only way that they would have the option to exercise this aspect of reproductive autonomy.

3. For certain conditions, preimplantation genetic testing is available, involving undergoing IVF and testing embryos prior to implantation for a known genetic condition in the family.

4. For some conditions, immediate postnatal interventions are required for optimal outcomes, but appropriate screening tests may not be routinely available after birth, or results may only be available days or weeks after birth. In these cases, prenatal testing is the only way to ensure that these interventions are available in a timely manner. For example there is an expression that ‘time is motor neurons’ [4], referring to the importance of and advantage of early identification and commencement of treatment to maximize the benefits of knowledge and appropriate management.

Carrier screening

Carrier screening, which is designed to identify genetic variants in prospective parents that are associated with affected children, forms part of the prenatal screening paradigm as it can give information about the risk of passing on a genetic condition. It may be the only opportunity of finding out of such risk ahead of the birth of an affected child, as most of the conditions detectable by carrier screening are not screened for by routine prenatal screening. These conditions affect single genes rather than chromosomes. Common conditions seen on carrier screens include SMA or cystic fibrosis. It has been shown that as many as 88% of carriers of cystic fibrosis, SMA and fragile X syndrome have no known family history of the condition [5]. Carrier screening has traditionally been offered on the basis of ethnicity, so would be offered for specific conditions to groups known to be at increased risk of those conditions, for example Tay-Sach’s disease in the Ashkenazi Jewish population which was first introduced in the 1970s [6]. However there is increasing awareness that such an approach can miss a significant proportion of carriers, reflected in recent ACOG guidelines to offer screening for certain conditions, including cystic fibrosis and SMA, to all patients who are pregnant or considering pregnancy regardless of ethnicity [7]. The possibility of missing carriers with non-typical ethnicities for the condition applies even for conditions that have been strongly associated with particular populations. This has come to light partly because the advent of more widely available screening has made it possible to find carriers in populations that would previously not have been offered testing [8]. As ancestry DNA tests are showing, people may not be fully aware of the specific risk groups they may belong to, so they would not be offered appropriate screening for their ethnic background [9].

The value of carrier screening can be shown through the example of SMA screening. SMA, one of the most common autosomal recessive diseases, is a progressive neurodegenerative condition which is associated with muscle weakness and respiratory difficulties [3]. It is due to a deletion of the SMN 1 gene [3]. The carrier rate is around one in 50, and this is a pan-ethnic condition [10]. Until recently, the management of this condition was primarily supportive, but there have been two major developments. The first is a medication called Nusinersen, an antisense oligonucleotide that binds RNA. This targets a gene (SMN2), which is very similar to SMN1 and causes it to function more like SMN1 [11]. It has been shown to be associated with improvements in motor milestones and a reduction in mortality and there was indication that the efficacy might be improved by early therapy initiation [11]. Further developments have led to the development of a gene therapy for SMA [3]. Again data indicates that very early treatment is associated with better outcome [3]. Another example is cystic fibrosis, which now has a number of treatments available, including four designed to help to restore gene function [12]. Duchenne Muscular Dystrophy, another example, also has an increasing number of therapies that target gene function, and gene therapy trials are underway [13].

Why screen for a condition that has treatments available?

One question that could be asked is ‘why should we offer carrier screening for conditions where treatments are available?’. A goal of prenatal screening is to identify medical conditions to help to make choices regarding care and treatment during the pregnancy or after the baby is born [14]. Carrier screening offers this, and in fact goes further, providing information that allows couples to make decisions at every stage of the reproductive process. Carrier screening offers couples the opportunity to have information before even becoming pregnant, about what their chances might be of having a baby with certain specific genetic conditions. This allows them to decide whether they wish to progress with pregnancy naturally or whether to select other options that may be available to them such as preimplantation genetic diagnosis, adoption, or egg/sperm donation. If they do opt for natural pregnancy, they then have the option to confirm whether or not their baby will inherit the condition. Having this knowledge then gives them the opportunity to decide whether or not to continue the pregnancy and if so, to have the chance to prepare themselves and others. It also gives the opportunity for the baby to be given appropriate treatment at the earliest possible opportunity. Not all conditions screened for by carrier screening are currently offered as routine postnatal screens, and in some places no or little postnatal screening is available. It could thus be weeks, months, or years before the condition is detected.

If we accept that having the option to obtain information about important potential genetic conditions in the fetus is a valuable endeavor, then carrier screening can be considered an option that women and their partners should be informed about, ideally before pregnancy, and in fact this is the recommendation of the American College of Obstetrics and Gynecology [7].

Expanding the offer of non-invasive prenatal genetic screening

In 2011 tests using cell-free DNA, known as ‘NIPS became available to screen for trisomy 21 [15]. This approach represents a significant advance: rather than using proxy markers, DNA originating directly from the pregnancy is assessed for the genetic evidence of the additional chromosome material that is the hallmark of trisomy [15]. Although this technique targets the DNA that defines the condition, it is considered a screening test rather than diagnosis. One reason for this is that it is looking at cell-free DNA from the placenta and not directly from the fetus, and confined placental mosaicism can confound results [16]. Regardless, a head to head comparison of NIPS and standard first trimester screening incorporating maternal serum markers demonstrated significantly superior performance for NIPS for trisomy 21 [17].

More recently, some NIPS tests added a set of key microdeletions to their offering [18], and some NIPS have started offering genome-wide screening for large, unselected copy number variants [19]. If we adhere to the principles for prenatal screening outlined above, we might consider the addition of at least some microdeletions to the offer of prenatal genetic screening. Let us consider the case for microdeletion 22q11.2, now offered as part of several NIPS tests. This condition is the most common human microdeletion syndrome. Studies have indicated an incidence of between 1/1,000 and 1/6,000 [20], although the true prevalence is unknown as not all cases are detected. This is a serious condition which is associated with congenital cardiac defects, developmental delay and learning difficulties, immune deficiencies, palate malformations, hypocalcaemia, and psychiatric disorders among other clinical features [21]. The condition is variable, with some individuals being severely affected whereas others may be mildly or asymptomatic, but penetrance is complete in the majority of cases [21]. Whilst performance rates will vary according to the specific test used, detection rates for the common 2.91 Mb deletion of 90% have been published for the SNP NIPS technology [22], and a false positive rate of 0.07% [23]. It is important when thinking of expanding prenatal genetic screening to consider false positive rates, which are higher for copy number variants than for the common trisomies.

The advantages of prenatal screening for 22q include early information for parents and healthcare professionals to manage the pregnancy and prepare for the birth and potential health issues. In the immediate postnatal period, there are a number of interventions which may improve outcome, such as doing a detailed cardiac scan before the baby leaves hospital, and checking for hypocalcaemia, immune deficiency, and palatal anomalies [22]. Early intervention in speech and motor development, which has been advised to start before 12 months if possible [24] can be put into place. Children with undiagnosed 22q11 deletion may undergo a diagnostic odyssey in which multiple healthcare providers are consulted before an underlying explanation for the various developmental and health issues is found, and again prenatal screening could help to avoid this and maximize opportunities for early and appropriate management [22]. It is important to note that counseling for microdeletion 22q screening should include the fact that this is a variable condition, the severity of which cannot be determined in advance on an individual level, and that around 10% of cases are inherited [21]. A parent may therefore find out that they also have 22q11 deletion. This in turn has benefits as they can seek appropriate surveillance and also be given more accurate information about the likelihood of 22q11 in future pregnancies (50% for affected parents).

Single gene testing

One of the most recent advances in NIPS is the possibility to offer NIPS for some monogenic conditions [25]. Many of these would not be detected by routine prenatal screening, may be detected late, or involve non-specific ultrasound findings. Early knowledge of the likelihood of such a condition may help to avoid uncertainty when non-specific signs are detected, and to inform about the likelihood of a condition for which no ultrasound signs would be present, such as Rett syndrome [26]. This information may guide pregnancy and delivery management and care in the neonatal period and beyond. This type of testing may be of particular interest when there is advanced paternal age (generally considered to be 40 or above) [27], where there are non-specific ultrasound signs and diagnostic testing is unavailable or is refused by the couple, as well as prospective parents who want to increase the range of conditions that they are screening for in pregnancy.

Conclusions

Prenatal genetic screening has developed rapidly over the past decade. As it becomes possible to screen for more conditions, it is important to reflect on the risks and benefits of adding each condition. Just as it would be wrong to add a condition purely because it is technically possible, it is also important to review whether there are additional conditions which should be included, for the value of the information itself and for the clinical actionability. As genetic screening technology advances, there will be more options for prenatal genetic screening, which offer exciting opportunities to improve outcomes through early diagnosis and appropriate management. A well-thought-out offer of screening can include different types of genetic conditions – selected whole chromosome conditions, copy number variants and single gene changes, with the aim of maximizing the availability of useful information. Appropriate counseling is vital to help to support prospective parents to understand their options and to make informed decisions about what screening is right for them.