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Sequencing Could Augment Other Newborn Screening Approaches, NC NEXUS Study Finds

NEW YORK – Sequencing-based approaches may not replace biochemical- or phenotypic-based newborn screening, but may supplement those approaches, according to a new study.

Newborn screening began in the 1960s to detect conditions like phenylketonuria and has since expanded as there are now some 35 core and 26 secondary conditions that guidelines recommend be included in newborn screening programs.

As part of the North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) project, researchers examined the yield of sequencing among more than 100 newborns — some known to have a metabolic disorder or hearing loss and some healthy — in both a screening and a diagnostic scenario. 

As the team led by the University of North Carolina at Chapel Hill's Jonathan Berg and his colleagues reported in the American Journal of Human Genetics on Wednesday, they found sequencing could identify most of the children with a metabolic disorder, but only a small portion of those with hearing loss. Sequencing could, though, uncover a range of variants linked to other childhood- or adult-onset conditions, including clinically actionable findings.

"In the context of NBS, sequencing-based approaches cannot fully replace biochemical or phenotypic screens because of etiologic heterogeneity and the challenges of variant interpretation," Berg and his colleagues wrote in their paper. "However, sequencing approaches have the advantage of being able to identify virtually any condition with a known genetic cause. Thus, augmentation of newborn screening with some form of genomic sequencing seems inevitable."

The researchers recruited 17 children with inborn errors of metabolism, 28 children with hearing loss, and 61 well infants into their study. Each child underwent next-generation sequencing-based newborn screening using a panel of 466 genes. Of the 46 variants detected in this cohort through exome sequencing, 43 were confirmed orthogonally in a CLIA-certified lab. 

Within the metabolic cohort, sequencing-based screening uncovered an abnormal result in 15 of the 17 participants. For instance, seven children previously found to have phenylketonuria had pathological variants in PAH, seven children with medium-chain acyl-coA dehydrogenase deficiency had pathogenic variants in ACADM, and one child with primary carnitine deficiency was homozygous for a pathogenic SLC22A5 missense variant.

Screening, however, did not uncover pathogenic variants in two members of the metabolic cohort. But when the researchers unblinded their cohort, they noted that these two patients had suggestive, though not conclusive, variants associated with their conditions.

In the hearing loss cohort, though, next-generation sequencing-based newborn screening returned positive results for only five of the 28 participants. Among those were two children who were compound heterozygotes for variants in an Usher syndrome gene and one child who had a one-base pair frameshift deletion in the GJB2 gene, which is linked to DFNB1 nonsyndromic deafness.

But sequencing-based screening was unable to catch most cases of hearing loss. The researchers noted this could be due to non-genetic influences that contribute to hearing loss such as environmental factors, infections, and premature birth.

In the full cohort, sequencing-based screening identified four children with positive results — a variant linked to familial hypercholesterolemia, a missense variant associated with mild OTC deficiency, a splice-site variant in DSC2 tied to autosomal-dominant arrhythmogenic right ventricular dysplasia, and two F11 variants linked to autosomal recessive factor XI deficiency. 

This low number of positive results was expected, the researchers noted, as they set a high threshold for determining an abnormal result since their cohort was at population-level risk for monogenic diseases.

As sequencing-based screening missed some metabolic and hearing loss results, the researcher noted that it likely would not replace current screening approaches, but could be used in addition to them. "These findings suggest that sequencing might be useful as an adjunct to traditional NBS methods, and that with improved detection of variants … and more extensive interpretive databases, the positive predictive value of genomic screening may improve," the researchers wrote in their paper.

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