An appraisal of the Wilson & Jungner criteria in the context of genomic-based newborn screening for inborn errors of immunity

Abstract

Wilson and Jungner's recommendations for population-based screening have been used to guide decisions regarding candidate disease inclusion in newborn screening programs for the past 50 years. The advent of genomic-based technologies, including next-generation sequencing and its potential application to newborn screening, along with a changing landscape in terms of modern clinical practice and ethical, social, and legal considerations has led to a call for review of these criteria. Inborn errors of immunity (IEI) are a heterogeneous group of more than 450 genetically determined disorders of immunity, which are associated with significant morbidity and mortality, particularly where diagnosis and treatment are delayed. We argue that in addition to screening for severe combined immunodeficiency disease, which has already been initiated in several countries, other clinically significant IEI should be screened for at birth. Because of disease heterogeneity and identifiable genetic targets, a next-generation sequencing-based screening approach would be most suitable. A combination of worldwide experience and technological advances has improved our ability to diagnose and effectively treat patients with IEI. Considering IEI in the context of updated recommendations for population-based screening supports their potential inclusion as disease targets in newborn screening programs.

Future Perspectives of Newborn Screening for Inborn Errors of Immunity

“…Given the genetic and phenotypic heterogeneity of IEI, screening all of these diseases would require a range of different test modalities, which is unfeasible from a logistic or economic perspective in the context of NBS. Applying genomic sequencing techniques in NBS would allow parallel testing, using one platform to detect many clinically actionable diseases [ 14 ]. The future role of genomic technology in NBS for IEI has previously been discussed extensively, therefore, this review will summarize the discussion points [ 14 , 68 , 69 ].…”

“…Applying genomic sequencing techniques in NBS would allow parallel testing, using one platform to detect many clinically actionable diseases [ 14 ]. The future role of genomic technology in NBS for IEI has previously been discussed extensively, therefore, this review will summarize the discussion points [ 14 , 68 , 69 ].…”

“…NGS is very adaptable and could serve as a first-tier test to screen for monogenetic disease, however, exome-based targeted NGS will not be able to identify IEI with variants in genes not included in the gene panels or IEI with structural variants or intronic variants. Experts prefer WGS approaches as they are able to simultaneously sequence both intronic and exonic regions [ 14 ]. Although a proof-of-concept study for a WGS-based approach in screening for IEI has already been published, WGS poses significant challenges in the context of NBS [ 67 ].…”

“…With genome-wide association studies, relations between phenotype traits and genotype in IEI might be unraveled. It remains to be seen whether the genomic technology will be used as a primary ‘standalone’ screening approach, or as an addition to current screening methodologies [ 14 ].…”

“…More than 430 IEI have been described with the discovery of new IEI occurring at an impressive rate [ 12 ]. With the Wilson and Jungner screening criteria in mind, several IEI would qualify as serious conditions that cause an important health problem and would benefit from early detection and treatment by preventing severe infections, immune dysregulation, and auto-immunity [ 13 , 14 ]. For some monogenetic IEI allogeneic HSCT might be a curative approach and autologous gene therapy could serve as a possible alternative treatment in the future [ 15 ].…”