Applying Genomic Analysis to Newborn Screening

Abstract

Large-scale genomic analysis such as whole-exome and whole-genome sequencing is becoming increasingly prevalent in the research arena. Clinically, many potential uses of this technology have been proposed. One such application is the extension or augmentation of newborn screening. In order to explore this application, we examined data from 3 children with normal newborn screens who underwent whole-exome sequencing as part of research participation. We analyzed sequence information for 151 selected genes associated with conditions ascertained by newborn screening. We compared findings with publicly available databases and results from over 500 individuals who underwent whole-exome sequencing at the same facility. Novel variants were confirmed through bidirectional dideoxynucleotide sequencing. High-density microarrays (Illumina Omni1-Quad) were also performed to detect potential copy number variations affecting these genes. We detected an average of 87 genetic variants per individual. After excluding artifacts, 96% of the variants were found to be reported in public databases and have no evidence of pathogenicity. No variants were identified that would predict disease in the tested individuals, which is in accordance with their normal newborn screens. However, we identified 6 previously reported variants and 2 novel variants that, according to published literature, could result in affected offspring if the reproductive partner were also a mutation carrier; other specific molecular findings highlight additional means by which genomic testing could augment newborn screening.

Parents’ interest in whole-genome sequencing of newborns

“…5 However, the increasing affordability of genetic sequencing technology has sparked new discussions about the incorporation of next-generation genetic sequencing into NBS programs. 6,7 In December 2010, the National Institute for Child Health and Development sponsored a symposium to develop a research agenda around the “application of new genomics concepts and technologies to newborn screening and child health.” 8 In addition, the National Institutes of Health recently published a request for proposals that will assess the potential value and challenges of integrating genomic sequencing into NBS programs. 9 …”

Clinical Genomic Database

“…However, genomic sequencing has myriad potential applications in more general clinical medicine, including in healthy individuals (3)(4)(5)(6)(7)(8).…”

Challenges of using next generation sequencing in newborn screening

“…These screening tests are based on blood levels of certain metabolites and the results are returned in a timely manner, so that medical or dietary treatment can be initiated promptly, before disease symptoms appear. Screening programs have been carried out for several decades in many countries with the goal of screening all infants born in a certain district or municipality (Goldberg & Sharp, 2012;Solomon et al, 2012;Goldenberg et al, 2014). While such screening could be expanded to include genetic tests for many more diseases, without effective treatment measures, this is of limited use.…”