Newborn Screening for Genetic Diseases: An Overview of Current and Future Applications

Abstract

Newborn screening (NBS) for inborn errors of metabolism (IEM) was introduced more than 50 years ago with the testing of phenylketonuria (PKU) using blood spots deposited on a filter paper after heel prick. NBS aims to identify early after birth inherited disorders for which clinical management and pre-symptomatic treatment will significantly decrease morbidity and mortality. While NBS for a few other disorders was implemented in some specific jurisdictions over the following decades, it is with the introduction of tandem mass spectrometry (MSMS) by the end of the 1990's that NBS expansion really took place. MSMS has had a tremendous impact on NBS, but led to heterogeneity in NBS disorders panel between jurisdictions that have introduced new conditions at various rates using different decision-making processes. In addition to disorders tested by MSMS, many programs have included other inherited disorders using various testing methodologies, including cystic

Next-Generation Sequencing in Newborn Screening: A Review of Current State

“…Since the first idea of using genetic methods in the NBS setting, numerous authors presented several concerns regarding the technical feasibility of using genomic technologies for NBS: possibility to achieve appropriate turnaround time, accuracy of the obtained results, ability to correctly interpret the results, confirmation of the results with an independent method, and safe storage of sequenced data ( Friedman, 2015 ; Howard et al, 2015 ; Reinstein, 2015 ; Berg et al, 2017 ; Bouvier and Giguère, 2019 ).…”

“…The suitable candidate conditions would have to have a clear Mendelian inheritance pattern and clear genotype–phenotype correlation. There should be ample knowledge of known variants present in the gene, high penetrance, and effective presymptomatic intervention ( Howard et al, 2015 ; Berg et al, 2017 ; Bouvier and Giguère, 2019 ). If we consider the current set of core conditions included in NBS programs, some of them do not meet the above criteria, so could not be included in NGS screening, but would have to be screened with existing methods ( Green et al, 2006 ; Rastogi and LaFranchi, 2010 ; Howard et al, 2015 ).…”

“…In the 1970s, the screening began for congenital hypothyroidism (CH), and in the next two decades, a few other disorders like congenital adrenal hyperplasia (CAH), hemoglobinopathies, biotinidase deficiency, cystic fibrosis (CF), and tyrosinemia type I (HT1) were added sporadically to the different NBS programs in different states and countries ( Dussault et al, 1975 ; Wilcken and Wiley, 2015 ). With the development and the accessibility of electrospray ionization (ESI) tandem mass spectrometry (TMS) in the 1990s, the ability to quantitate multiple metabolites simultaneously and, thus, the simultaneous detection of multiple inborn errors of metabolism (IEM) facilitated the first big expansion of the NBS programs around the globe, though the less developed countries did generally not share the progress ( Sweetman, 1996 ; Levy, 1998 ; Bennett and Rinaldo, 2001 ; Groselj et al, 2014a , b ; Bouvier and Giguère, 2019 ). Different tests are continuously developed spurred by the development of clinical treatments for conditions such as severe combined immunodeficiencies (SCID), spinal muscular dystrophy (SMA), and lysosomal storage diseases ( Spacil et al, 2013 ; Chien et al, 2017 ; Puck, 2019 ; Czibere et al, 2020 ).…”

“…Wilson and Jungner proposed 10 criteria that should be met for the disease to be included in screening programs, which were later further revised ( Wilson et al, 1968 ; Andermann, 2008 ). Since the first idea of using NGS in the framework of NBS, several concerns have been raised, among them technical, medical, legal, economical, ethical, psychological, and sociological ( Friedman, 2015 ; Howard et al, 2015 ; Reinstein, 2015 ; Berg et al, 2017 ; Murray et al, 2018 ; Bouvier and Giguère, 2019 ; de Wert et al, 2020 ). In this review, we will discuss the recent advances in the use of NGS in the context of NBS, the remaining obstacles in its implementation in NBS, and the wider implications of its use in the NBS program.…”

Expanded Neonatal Bloodspot Screening Programmes: An Evaluation Framework to Discuss New Conditions With Stakeholders

“…While significant treatment- and test-driven expansions are seen in several NBS programmes worldwide, other NBS programmes expand at a slower rate ( 7 ). This illustrates that even though screening tests and treatments are available, the local context will determine the NBS program put in place ( 5 , 8 ).…”