Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project

Abstract

Newborn screening (NBS) was established as a public health program in the 1960s and is crucial for facilitating detection of certain medical conditions in which early intervention can prevent serious, life-threatening health problems. Genomic sequencing can potentially expand the screening for rare hereditary disorders, but many questions surround its possible use for this purpose. We examined the use of exome sequencing (ES) for NBS in the North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) project, comparing the yield from ES used in a screening versus a diagnostic context. We enrolled healthy newborns and children with metabolic diseases or hearing loss (106 participants total). ES confirmed the underlying diagnosis in 15 out of 17 (88%) children with metabolic disorders, and in 5 out of 28 (~18%) children with hearing loss. We discovered actionable findings in 4 participants that would not have been detected by standard NBS. A subset of parents was eligible to receive additional information for their child about childhood-onset conditions with low or no clinical actionability, clinically actionable adult-onset conditions, and carrier status for autosomal recessive conditions. We found pathogenic variants associated with hereditary breast and/or ovarian cancer in 2 children, a likely pathogenic variant in the gene associated with Lowe syndrome in one child, and an average of 1.8 reportable variants per child for carrier results. These results highlight the benefits and limitations of using genomic sequencing for NBS and the challenges of using such technology in future precision medicine approaches.

NeoSeq: A New Method of Genomic Sequencing for Newborn Screening

“…To explore the effects of its clinical applications, we conducted a meta-analysis and comparison from a search of the literature (Table 3). Four groups have conducted studies since 2016, which include Newbie Seq 19 , NC NEXUS 15 , BabySeq 12 and Dale L' group 8 . All the studies were designed by combining a methodological comparison with the ndings from a retrospective cohort.…”

“…In addition, the false-positive rate of WGS was far lower than that of the traditional NBS 8 . BabySeq and NC NEXUS projects also reported 60.0-88.0% sensitivity and 100% speci city 12,15 . Our results showed similar speci city (99.4%), but the sensitivity was relatively lower (55.6%).…”

“…The study con rmed the positive screening results in 15 of 17 participants with metabolic disorders, and ve of 28 individuals in a hearing loss cohort. Additionally, it discovered four cases with positive results, which were not detected using standard NBS 15 . Although both the studies fully demonstrated the advantages and prospects of nGS in new-born screening, there are still many limitations.…”

An online compendium of treatable genetic disorders

“…Elective genomic testing (Lu et al, 2019) as an adjunct or replacement for newborn screening is being studied (Adhikari et al, 2020; Ceyhan‐Birsoy et al, 2019; Roman et al, 2020; Trier et al, 2020). The genetic diseases found at this website represent a useful starting point for programs planning to use genomic testing for newborn screening.…”

Genetic screening techniques and diseases for neonatal genetic diseases

“…生儿疾病筛查 [18] 。 1.2.3 全基因组测序 即对生物体整个基因组 序列进行测序，是检测基因突变的终极手段。全 基因组测序可以获得个体全部差异和变异信息， 较全外显子组测序覆盖的区域更广，且在鉴定单 碱基突变、插入缺失突变、拷贝数突变和结构突变 中更具优势 [19] 。目前，第二代 STATseq 项目可以 在 26 h内进行初步诊断，且敏感度和特异度均超 过 99.5% [20] 。但全基因组测序面临致病突变体的 鉴定、临床意义不明突变结果的解释、短时间内进 行大量数据储存和分析、相对高成本等诸多挑战， 其在临床的适用性仍须进一步评估。目前，全基 因组测序多用于临床疑似遗传病及现有检测技术 未能明确病因的患者，不适用于新生儿遗传病 筛查 [21] 。…”