The Intersection Between Genetic Reproductive Carrier Screening and Genomic Newborn Screening: Implications for Clinical Practice

What is already known about this topic? Genetic reproductive carrier screening and genomic newborn screening are increasingly becoming available. A substantial number of genes are screened in both though there is wide variability. What does this study add? The difference in aims and purpose and the interplay between genetic reproductive carrier screening and genomic newborn screening is important to consider and understand. Harmonising gene content and having a clear understanding of how these two screening tests complement each other is essential for good patient care and informed consent. Genomic sequencing enables the simultaneous analysis of thousands of genes. Virtual gene panel application is a common strategy that limits analysis to a preselected number of genes, targeting it to the clinical indication for testing. This increases efficiency and scalability, and provides an opportunity to develop and maintain evidence-based analysis approaches in diagnostic and screening settings [1]. Two emerging genomic screening tests of relevance to perinatal care are genetic reproductive carrier screening (RCS) and genomic newborn screening (gNBS). These tests have different but complementary aims. RCS identifies couples with a high chance of having a child with a genetic, treatable or untreatable childhood-onset condition with the aim of increasing parental reproductive autonomy. gNBS typically targets childhood onset treatable diseases in newborns with the aim of improving health outcomes. It is proposed as a complementary test and program to established newborn screening which traditionally uses biochemical methods. RCS typically aims to identify couples at risk of autosomal recessive or X-linked recessive disorders, whereas gNBS is not constrained by considering modes of inheritance and can identify dominant disorders that may have been inherited from a parent or occurred de novo in the infant. An understanding of how these emerging tests differ and intersect is essential for accurate information provision to facilitate informed choices by families. The challenges of this are complex as the virtual gene panels used vary widely between different test providers in number and type of genes analysed [2, 3] and secondly, these have generally been designed independently, without consideration of the potential for overlap and the nuanced implications of this for counselling. The concept of RCS began in high risk populations with founder variants, for example testing people of Ashkenazi Jewish descent for Tay–Sachs disease [4]. Many RCS test providers now offer hundreds or thousands of genes for analysis, based on emerging evidence that this is the most effective strategy for identifying couples with increased chance of rare diseases [5]. By contrast, gNBS is mostly still in the pilot phase, with multiple research studies currently running worldwide, some aiming to enrol up to 100,000 infants [6]. Commercial, user—paid genomic sequencing tests are also increasingly available for newborns. There is a growing body of research indicating high acceptability of gNBS for a broad range of treatable and early onset conditions, with many parents indicating they would opt for an even wider range of conditions including those that are untreatable [7]. The selection of genes for both these categories of screening tests varies according to the process undertaken by the individual test provider or study team. Considerations may include the strength of evidence for gene-disease association, disease prevalence, technical limitations, cost, local healthcare availability and infrastructure. We used the online open access platform, PanelApp Australia, to compare the content of the gene panel developed by the Australian national expanded RCS study (Mackenzie's Mission) with that developed by a gNBS study (BabyScreen+) [8] to enable a detailed understanding of how these two screening tests intersect and complement each other. This process allowed us to create accurate education and information so that families offered both types of screening can opt for testing that is most in keeping with their values. The expanded RCS virtual gene panel includes genes associated with autosomal recessive or X-linked conditions that have an onset in childhood (< 18 years), which can be screened using the study technology (exome sequencing), have a severe impact on the affected individual, and have limited and/or burdensome treatment [9]. Testing is only available as couple-based screening. This streamlines analysis, shortens time to definitive results and reduces anxiety and genetic counselling burden. The final number of genes included was 1300; however, review of the list continued over the course of the study. The method of development of the virtual gene panel used in our gNBS pilot, BabyScreen+, is published elsewhere [2] but summarised here. The criteria for genes to be included are: the variant spectrum is currently reliably detectable by the platform (genome sequencing), the gene-disease relationship is well established, the disease manifests exclusively or predominantly in early childhood (< 5 years) causing significant morbidity or mortality and has an effective treatment available that alters the natural history of disease (e.g. medication, dietary supplement, enzyme replacement therapy, transplantation, gene therapy). The list leveraged existing gene list curation efforts by other international gNBS pilot studies. The total number of genes currently included is 604. These expanded RCS and gNBS panels share 318 genes that represent severe early—onset conditions with some treatment available. This, for example, includes many severe immunodeficiencies where the treatment is bone marrow transplant. Although bone marrow transplantation is curative, the treatment is associated with substantial morbidity and mortality. These conditions fulfil the criteria for both types of screening tests as some families would utilise the information prior to or during pregnancy to enable choice regarding how to conceive or manage a pregnancy. For others, this information would only be utilised after birth to optimise health outcomes for a child. BabyScreen+ has 286 genes that are unique, including 73 dominant conditions and conditions amenable to less burdensome treatments. Some of these dominant conditions, for example FBN1 associated with Marfan syndrome, are frequently inherited from an affected parent but have highly variable expression. Parents need to understand the possibility of receiving a diagnosis for themselves when they consent to gNBS. This possibility exists in both screening tests, for example identifying manifesting carriers in RCS, for example, DMD variants causing cardiomyopathy in females and is an important part of pre-test counselling. Expanded RCS has 982 unique genes associated with conditions that are largely untreatable or have later onset in childhood/adolescence Figure 1. Hence, the task of clinicians is to help families understand the complementary nature of these tests, facilitate informed decision-making based on family values, and appropriately anticipate possible outcomes such as identifying additional affected family members. Relationship between gNBS (BabyScreen+) and expanded RCS (Mackenzies Mission). The perinatal genetic testing landscape is complex with the availability of an increasing number of genetic tests including RCS, first trimester combined screen; non-invasive prenatal testing, in vitro fertilisation pre-implantation genetic diagnosis (for some), fetal microarray and exome or genome (for some); and increasingly gNBS. Helping families navigate this complex screening and diagnostic landscape requires increasing levels of genomic literacy among pregnancy healthcare providers (obstetricians, midwives and general practitioners), the development of clear information resources and decision support tools, expansion of the genetic counselling workforce and careful consideration of when and how different testing options are presented. Further harmonisation of the virtual gene panels used in expanded RCS and gNBS will be critical in ensuring consistency and evidence-based practice. Initiatives such as ClinGen, the Gene Curation Coalition and platforms like PanelApp contribute to this effort by promoting the use of standardised frameworks, allowing open access to evidence summaries and enabling discordance resolution [1, 10]. Harmonisation is urgent: recent analyses demonstrate just 55 genes in common across gNBS pilot studies [2] and only 15 across existing carrier screening panels [3]. This increases the potential not only for confusion among health professionals and families but also for inequitable outcomes from screening. Some reasons for these discrepancies include: the starting point on which a gene list is created, cost considerations or the use of criteria such as prevalence of a condition. Many gene lists are created ad hoc using previously compiled lists or genes proposed by experts in a field. Ideally, all genes with a known disease association that is robust should be considered for inclusion against a standardised set of criteria that represents the aim of the test and are aligned with the principles developed by Wilson and Jungner, taking into account the specific issues raised by genomic technology [11]. With ongoing gene discovery and increased knowledge, this scale of gene curation is likely to require a collaborative effort to be achievable. Similarly, coordinating and collaborating on an approach to designing genomic screening tests to refine previously accepted principles is essential. An example of this is the consideration of the prevalence of a condition or the inclusion of a rare cause of a genetically heterogenous disease. This is much less relevant when utilising genomic technology as the incremental cost of including additional genes is negligible and exclusion only further disadvantages those with rarer diseases. The genetics workforce is recognised to be inadequate for the mainstream use of genomic technology in healthcare. Mainstreaming of genomic testing necessitates urgent, evidence-based education on genetics, genomics and genomic screening tests for non-genetic health professionals. Simplifying and harmonising the gene panel content for screening tests will enable a greater degree of consistency and this will translate into more equitable outcomes for families. Decision aids and decision support tools will also be essential in helping to convey this complex information at scale and allow families to choose genomic screening tests that are congruent with their values and beliefs. The BabyScreen+ team; Jade Caruana, Kate Scarff, Nitzan Lang, Alison Archibald, Stephanie Best, John Christodoulou, Clara Gaff, Ilias Goranitis, Christopher Gyngell, Danya Vears, Fiona Lynch, Riccarda Peters, Sophie Bouffler, Erin Tutty, Nathasha Kugenthiran, Anaita Kanga-Parabia, Xiuqin Xiong, Meg Wall, Ronda Greaves, Simon Sadedin, Stefanie Eggers, Paul De Fazio, Sebastian Hollizeck, Crystle Lee, Ming Wong, Melanie Marty and Michelle Torres. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians. This project received ethics approval from the Royal Children's Hospital Melbourne Research Ethics Committee: HREC/91500/RCHM-2023, HREC/90929/RCHM-2022 and HREC/91392/RCHM-2022. The authors have nothing to report. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.