Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
Am J Hum Genet. 2020 Oct 1;107(4):596-611. doi: 10.1016/j.ajhg.2020.08.001. Epub 2020 Aug 26.
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）于 20 世纪 60 年代作为一项公共卫生计划建立，对于发现某些疾病至关重要，因为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对罕见遗传性疾病的筛查，但围绕其可能用于此目的的许多问题。我们检查了外显子组测序（ES）在北卡罗来纳州新生儿外显子组测序用于普遍筛查（NC NEXUS）项目中的应用，比较了在筛查和诊断环境中使用 ES 的效果。我们招募了健康的新生儿和患有代谢疾病或听力损失的儿童（共 106 名参与者）。ES 在 17 名患有代谢障碍的儿童中确认了 15 名（88%）和 28 名患有听力损失的儿童中的 5 名（约 18%）参与者的潜在诊断。我们在 4 名参与者中发现了标准 NBS 无法检测到的可采取行动的发现。一部分父母有资格获得有关其孩子的额外信息，包括儿童期发病但临床可操作性低或无、成人期发病且具有临床可操作性的疾病、常染色体隐性疾病的携带者状态。我们在 2 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 1 名儿童中发现了与 Lowe 综合征相关的基因的可能致病性变异，以及每个儿童平均有 1.8 个可报告的变异用于携带者结果。这些结果突出了使用基因组测序进行 NBS 的益处和局限性，以及在未来精准医学方法中使用这种技术的挑战。
