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 participant’s 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 four 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 two 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.

新生儿筛查 (NBS) 是 20 世纪 60 年代作为一项公共卫生计划建立的，对于促进某些医疗状况的发现至关重要，通过早期干预可以预防严重的、危及生命的健康问题。基因组测序有可能扩大罕见遗传性疾病的筛查范围，但围绕其用于此目的的可能性存在许多问题。我们研究了北卡罗来纳州新生儿外显子组测序通用筛查 (NC NEXUS) 项目中 NBS 的外显子组测序 (ES) 的使用情况，比较了筛查和诊断中使用的 ES 的产量。我们招募了健康新生儿和患有代谢疾病或听力损失的儿童（总共 106 名参与者）。ES 在 17 名患有代谢疾病的儿童中确认了 15 名 (88%) 参与者的基本诊断，在 28 名患有听力损失的儿童中确认了 5 名 (∼18%) 参与者的基本诊断。我们在四名参与者身上发现了标准 NBS 无法检测到的可操作的发现。一部分父母有资格为他们的孩子获得有关临床可操作性较低或无临床可操作性的儿童期发病状况、临床上可操作的成人发病状况以及常染色体隐性遗传病携带者状态的额外信息。我们在两名儿童中发现了与遗传性乳腺癌和/或卵巢癌相关的致病性变异，在一名儿童中发现了与 Lowe 综合征相关的基因中可能存在的致病性变异，对于携带者结果，每个孩子平均有 1.8 个可报告变异。这些结果凸显了使用基因组测序进行 NBS 的好处和局限性，以及在未来精准医学方法中使用此类技术的挑战。