Advances in next-generation sequencing are expanding the ability of newborn screening programs to detect genetic diseases earlier.
Next-generation sequencing has evolved as a tool capable of improving routine newborn screening (RNS), as discussed in a recent review published in Pediatric Investigation.1
Routine screening is provided to millions of newborns annually to identify inherited disorders prior to symptom emergence. Traditionally, these programs utilize biochemical markers to identify conditions, but concerns have arisen that this method is not adequate to detect genetically driven diseases.
“Conventional NBS methods are inherently constrained by their reliance on measurable biochemical abnormalities,” said Zhelan Huang, PhD, researcher from the Children’s Hospital of Fudan University. “While effective for disorders like phenylketonuria or congenital hypothyroidism, many genetic diseases do not produce detectable metabolic signals during the neonatal period.”
The review was conducted to highlight the transition from traditional NBS to genomic NBS (gMBS).2 This method, defined as identification of specific genetic variants in a patient’s DNA using molecular biology techniques, has been linked to significant increases in disease detection capacity per test.
Increased attention has been given to gMBS in multiple countries as screening costs decline and sequencing technology improves. This has led to a series of gNBS projects testing models adapted to local genetic landscapes, often using whole-exome sequencing or whole-genome sequencing (WGS) with predefined gene panels.
These programs include research launched by the National Institutes of Health in the United States to provide empirical evidence about the utility of genomic sequencing. The first of these programs evaluated screening for immunodeficiencies in newborns, as these phenotypes are often difficult to diagnose early in life.
The study utilized a panel of immunodeficiency-related genes to assess newborn genomes, finding limitations in the sensitivity and specificity of WGS because of the study’s mostly healthy population cohort. In comparison, a 2020 study that enrolled newborns and children with metabolic diseases or hearing loss reported a definitive diagnosis in 88% and 18%, respectively.
Investigators also highlighted detection by gNBS in 4 patients who were missed by standard gNBS, providing evidence of this method’s value. Additionally, one project developed a 954-gene panel to perform gNBS for treatable and untreatable childhood-onset disorders and carrier settings, finding efficacy toward finding these in conditions not captured by existing methods.
Experts plan to expand on these findings with larger projects. This includes the Genomic Uniform Screening Against Rare Diseases in All Newborns program, which recently published its findings. The initial cohort included 4000 newborns, 72% of who’s families consented to participation.
A successful genome sequencing rate of 99.6% was reported among participants, with a screen-positive rate of 3.7% reported from a predefined gene panel. These results, alongside preliminary efforts in China, some European countries, and more regions are providing evidence about the feasibility of genome sequencing for NBS across a diverse patient population.
According to investigators, these findings highlight challenges and opportunities. While gNBS is currently viewed as a secondary-tier screening tool, it may evolve to a first-line modality over time.
Currently, gNBS is restricted by cost, turnaround time, principles for gene and disease selection, ethical and psychological considerations, and interpretation of variants of uncertain significance. However, research continues to optimize technology and support the adoption of gNBS into clinical practice.
“With declining costs and refinement of supportive policy frameworks, gNBS is expected to gradually integrate with or even replace conventional NBS methods in the future,” wrote investigators.
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