Gene selection for genomic newborn screening: Moving toward consensus?

PURPOSE: Gene selection for genomic newborn screening (gNBS) underpins the validity, acceptability, and ethical application of this technology. Existing gNBS gene lists are highly variable despite being based on shared principles of gene-disease validity, treatability, and age of onset. This study aimed to curate a gNBS gene list that builds upon existing efforts and provide a core consensus list of gene-disease pairs assessed by multiple expert groups worldwide. METHODS: Our multidisciplinary expert team curated a gene list using an open platform and multiple existing curated resources. We included severe treatable disorders with age of disease onset <5 years with established gene-disease associations and reliable variant detection. We compared the final list with published lists from 5 other gNBS projects to determine consensus genes and to identify areas of discrepancy. RESULTS: We reviewed 1279 genes and 604 met our inclusion criteria. Metabolic conditions comprised the largest group (25%), followed by immunodeficiencies (21%) and endocrine disorders (15%). We identified 55 consensus genes included by all 6 gNBS research projects. Common reasons for discrepancy included variable definitions of treatability and strength of gene-disease association. CONCLUSION: We have identified a consensus gene list for gNBS that can be used as a basis for systematic harmonization efforts internationally.

Comparative analysis of gene and disease selection in genomic newborn screening studies.

Genomic newborn screening (gNBS) is on the horizon given the decreasing costs of sequencing and the advanced understanding of the impact of genetic variants on health and diseases. Key to ongoing gNBS pilot studies is the selection of target diseases and associated genes to be included. In this study, we present a comprehensive analysis of seven published gene-disease lists from gNBS studies, evaluating gene-disease count, composition, group proportions, and ClinGen curations of individual disorders. Despite shared selection criteria, we observe substantial variation in total gene count (median 480, range 237-889) and disease group composition. An intersection was identified for 53 genes, primarily inherited metabolic diseases (83%, 44/53). Each study investigated a subset of exclusive gene-disease pairs, and the total number of exclusive gene-disease pairs was positively correlated with the total number of genes included per study. While most pairs receive "Definitive" or "Strong" ClinGen classifications, some are labeled as "Refuted" (n = 5) or "Disputed" (n = 28), particularly in genetic cardiac diseases. Importantly, 17%-48% of genes lack ClinGen curation. This study underscores the current absence of consensus recommendations for selection criteria for target diseases for gNBS resulting in diversity in proposed gene-disease pairs, their coupling with gene variations and the use of ClinGen curation. Our findings provide crucial insights into the selection of target diseases and accompanying gene variations for future gNBS program, emphasizing the necessity for ongoing collaboration and discussion about criteria harmonization for panel selection to ensure the screening's objectivity, integrity, and broad acceptance.

Genomic newborn screening: Are we entering a new era of screening?

Population newborn screening (NBS) for phenylketonuria began in the United States in 1963. In the 1990s electrospray ionization mass spectrometry permitted an array of pathognomonic metabolites to be identified simultaneously, enabling up to 60 disorders to be recognized with a single test. In response, differing approaches to the assessment of the harms and benefits of screening have resulted in variable screening panels worldwide. Thirty years on and another screening revolution has emerged with the potential for first line genomic testing extending the range of screening conditions recognized after birth to many hundreds. At the annual SSIEM conference in 2022 in Freiburg, Germany, an interactive plenary discussion on genomic screening strategies and their challenges and opportunities was conducted. The Genomics England Research project proposes the use of Whole Genome Sequencing to offer extended NBS to 100 000 babies for defined conditions with a clear benefit for the child. The European Organization for Rare Diseases seeks to include "actionable" conditions considering also other types of benefits. Hopkins Van Mil, a private UK research institute, determined the views of citizens and revealed as a precondition that families are provided with adequate information, qualified support, and that autonomy and data are protected. From an ethical standpoint, the benefits ascribed to screening and early treatment need to be considered in relation to asymptomatic, phenotypically mild or late-onset presentations, where presymptomatic treatment may not be required. The different perspectives and arguments demonstrate the unique burden of responsibility on those proposing new and far-reaching developments in NBS programs and the need to carefully consider both harms and benefits.

Phenotypes of undiagnosed adults with actionable OTC and GLA variants.

Inherited metabolic disorders (IMDs) are variably expressive, complicating identification of affected individuals. A genotype-first approach can identify individuals at risk for morbidity and mortality from undiagnosed IMDs and can lead to protocols that improve clinical detection, counseling, and management. Using data from 57,340 participants in two hospital biobanks, we assessed the frequency and phenotypes of individuals with pathogenic/likely pathogenic variants (PLPVs) in two IMD genes: GLA, associated with Fabry disease, and OTC, associated with ornithine transcarbamylase deficiency. Approximately 1 in 19,100 participants harbored an undiagnosed PLPV in GLA or OTC. We identified three individuals (2 male, 1 female) with PLPVs in GLA, all of whom were undiagnosed, and three individuals (3 female) with PLPVs in OTC, two of whom were undiagnosed. All three individuals with PLPVs in GLA (100%) had symptoms suggestive of mild Fabry disease, and one individual (14.2%) had an ischemic stroke at age 33, likely indicating the presence of classic disease. No individuals with PLPVs in OTC had documented hyperammonemia despite exposure to catabolic states, but all (100%) had chronic symptoms suggestive of attenuated disease, including mood disorders and migraines. Our findings suggest that GLA and OTC variants identified via a genotype-first approach are of high penetrance and that population screening of these genes can be used to facilitate stepwise phenotyping and appropriate care.

Newborn Screening Is on a Collision Course with Public Health Ethics.

Newborn screening was established over 50 years ago to identify cases of disorders that were serious, urgent, and treatable, mirroring the criteria of Wilson and Jungner. In the last decade, conditions have been added to newborn screening that do not strictly meet these criteria, and genomic newborn screening is beginning to be discussed. Some of these new and proposed additions to newborn screening entail serious public health ethical issues that need to be explored.

From newborn screening to genomic medicine: challenges and suggestions on how to incorporate genomic newborn screening in public health programs.

Newborn screening (NBS) programs are considered among the most effective and efficient measures of secondary prevention in medicine. In individuals with medical conditions, genomic sequencing has become available in routine healthcare, and results from exome or genome sequencing may help to guide treatment decisions. Genomic sequencing in healthy or asymptomatic newborns (gNBS) is feasible and reveals clinically relevant disorders that are not detectable by biochemical analyses alone. However, the implementation of genomic sequencing in population-based screening programs comes with technological, clinical, ethical, and psychological issues, as well as economic and legal topics. Here, we address and discuss the most important questions to be considered when implementing gNBS, such as "which categories of results should be reported" or "which is the best time to return results". We also offer ideas on how to balance expected benefits against possible harms to children and their families.

[Genomic newborn screening. Perspective from the Ethics Commission of the Spanish Society for Human Genetics. Part II: Ethical, legal and social issues (ELSIs) of the introduction of next generation sequencing technologies in a public health newborn screening program.] / Cribado neonatal genómico. Perspectiva de la Comisión de ética de la Asociación Española de Genética Humana. Parte II: Aspectos Éticos, Legales y Sociales (AELS) de la Introducción de las Tecnologías de Secuenciación Masiva (NGS) en un programa de cribado neonatal de Salud Pública.

Genome sequencing is a very attractive technology as it is also the idea of sequencing children at birth, with the aim to establish medical care and preventive actions during their whole life, tailored to the genome of each newborn. Part I of this article analyses limitations and opportunities of next generation sequencing technologies (NGS). Part II relates scientific knowledge with ethical, legal and social issues (ELSIs) concerning its application to a newborn screening program. This program is offered universally to a vulnerable and asymptomatic population and must be guided by principles of "do not harm" and to act in the "best interest of child". With this purpose, this article considers, first of all, ethical principles of bioethics and public health that govern newborn screening. Then it summarizes main issues of our legal framework. And finally, in social context, it analyzes influences of technological imperative, commercial actors and patient´s advocacy groups, as well as parent's perspective and psychosocial aspects. In this context, conclusion is that whole genome sequencing should not be implemented as universal newborn screening. Nevertheless, the use of NGS could be an opportunity to extend these programs, including treatable infantile diseases that cannot be detected with other technologies. That means realizing a directed approach in order to identify well known genomic variants, highly penetrant, that confer a high risk of preventable or treatable diseases for which treatment must begin at the neonatal period. The implementation of such directed genomic screening should follow current evidence based model for newborn screening. This model shows three features: recognition of the importance of the evaluation of empirical, epidemiological and clinical data before taking the decision to include a disease; evaluation of benefits and risks (proportionality) and evaluation of benefits and costs (distributive justice); and finally, consideration of public consensus, because this kind of decisions have a value that concerns society as a whole.

La secuenciación genómica es una tecnología extraordinariamente atractiva, tanto como lo es la idea de poder aplicarla a todos los recién nacidos, estableciendo con ello una etapa de cuidados médicos para toda la vida y acciones preventivas a medida del genoma de cada niño. En la parte I de este artículo se analizaron las limitaciones y oportunidades que presentan las tecnologías de secuenciación de nueva generación (NGS). La parte II relaciona el conocimiento científico con los aspectos éticos, legales y sociales (AELS) de su introducción en un programa de cribado neonatal de salud pública de aplicación universal a población vulnerable y asintomática, que debe ser guiada por los principios fundamentales de "no hacer daño" y de actuar "en el mejor interés del niño". Para ello se contemplan en primer lugar los principios éticos de la medicina y de la salud pública que rigen el cribado neonatal, a continuación se resumen los principales aspectos de nuestro marco legal al respecto y finalmente en el ámbito social se analizan la influencia del imperativo tecnológico, la de los actores comerciales, los grupos de apoyo de pacientes y por último la perspectiva de los padres y aspectos psicosociales. Las conclusiones son que en este contexto la secuenciación genómica completa no debe ser implementada como cribado neonatal universal, sin embargo el uso de las NGS podría ser una oportunidad para ampliar los programas incluyendo enfermedades infantiles tratables que no pudiesen ser detectadas con otros métodos. Realizando para ello una aproximación dirigida a enfermedades/genes concretos, a fin de identificar variantes genómicas bien conocidas, altamente penetrantes confiriendo riesgo elevado de enfermedad prevenible o tratable, para la cual el tratamiento deba iniciarse en el periodo neonatal. Su incorporación al cribado neonatal debería seguir el modelo actual basado en la evidencia, evaluando los datos empíricos, epidemiológicos y clínicos antes de tomar una decisión sobre la inclusión de una enfermedad, así como los beneficios y riesgos (proporcionalidad) y si los beneficios justifican los costes (justicia distributiva), tomando en consideración el consenso público en tanto que las decisiones tienen una carga de valores que conciernen a la sociedad en su conjunto.

[Genomic newborn screening. Perspective from the Ethics commission of the Spanish Society for Human Genetics. Part I. Next generation sequencing technologies applied to newborn screening. Challenges and opportunities.] / Cribado neonatal genómico. Perspectiva de la Comisión de ética de la Asociación Española de Genética Humana. Parte I. Las tecnologías de secuenciación masiva (NGS) y su aplicación al cribado neonatal. Desafíos y oportunidades.

In 2003 at the ending of the Human Genome Project, it aroused the idea that all newborns could be sequenced and its genome archived in the clinical record, in order to manage risks of diseases and response to medicaments along his whole life. Eighteen years later, promises of genomic medicine and tremendous decrease of costs of next generation sequencing technologies, continues feeding this dream that shows important practical, ethical and social challenges and genomic sequencing is presented as the next historical change in newborn screening programs. In this paper we analyze challenges and opportunities of next generation sequencing technologies, their real costs, problems associated to management, storage and protection of the enormous amount of genomic data produced and finally, according to conclusions of recent researches, there are considered the conclusions in two contexts, sick newborn with diagnostic purposes and healthy asymptomatic newborns with public health purposes (newborn screening programs). In a second part of this article it will be considered ethical, legal and social issues (ELSI). Final objective is to contribute to scientific, professional, ethics and social debate in order to promote that genome sequencing in newborn don't be used indiscriminately constituting a risk, but properly done, as a partner in the promotion of health and prevention of consequences of genetic diseases.

En 2003, cuando finalizó el Proyecto Genoma Humano, surgió la idea de secuenciar el genoma a todos los recién nacidos, archivarlo en la historia clínica y usarlo a lo largo de toda la vida para manejar riesgos de enfermedades y respuesta a medicamentos. Dieciocho años más tarde, las promesas de la medicina genómica y el extraordinario abaratamiento de las tecnologías secuenciadoras, siguen alimentando este sueño que todavía plantea grandes desafíos prácticos, éticos y sociales y la secuenciación genómica se presenta como el próximo gran cambio histórico en los programas de cribado neonatal. En el presente artículo, se analizan los retos y oportunidades de las tecnologías secuenciadoras de nueva generación, sus costos reales, la problemática inherente a la gestión, almacenamiento y protección de la enorme cantidad de datos genómicos que generan y finalmente, en base a las conclusiones de investigaciones recientes, se considera el potencial y limitaciones de su aplicación en dos escenarios, el recién nacido enfermo con finalidades diagnósticas y el recién nacido sano, asintomático, con finalidades de salud pública(programas de cribado neonatal). En una segunda parte de este artículo se tendrán en cuenta los aspectos éticos, legales y sociales (AELS). El objetivo final es contribuir al debate científico, profesional, ético y social, promoviendo que la secuenciación genómica en el recién nacido no sea usada indiscriminadamente constituyendo un riesgo, sino que bien empleada sea una aliada en la promoción de la salud y prevención de las consecuencias de las enfermedades genéticas.