PerkinElmer Genomics, PerkinElmer Inc, Pittsburgh, Pennsylvania.
ViaCord LLC, PerkinElmer Inc, Waltham, Massachusetts.
JAMA Netw Open. 2023 Jul 3;6(7):e2326445. doi: 10.1001/jamanetworkopen.2023.26445.
Although the clinical utility of genome sequencing for critically ill children is well recognized, its utility for proactive pediatric screening is not well explored.
To evaluate molecular findings from screening ostensibly healthy children with genome sequencing compared with a gene panel for medically actionable pediatric conditions.
DESIGN, SETTING, AND PARTICIPANTS: This case series study was conducted among consecutive, apparently healthy children undergoing proactive genetic screening for pediatric disorders by genome sequencing (n = 562) or an exome-based panel of 268 genes (n = 606) from March 1, 2018, through July 31, 2022.
Genetic screening for pediatric-onset disorders using genome sequencing or an exome-based panel of 268 genes.
Molecular findings indicative of genetic disease risk.
Of 562 apparently healthy children (286 girls [50.9%]; median age, 29 days [IQR, 9-117 days]) undergoing screening by genome sequencing, 46 (8.2%; 95% CI, 5.9%-10.5%) were found to be at risk for pediatric-onset disease, including 22 children (3.9%) at risk for high-penetrance disorders. Sequence analysis uncovered molecular diagnoses among 32 individuals (5.7%), while copy number variant analysis uncovered molecular diagnoses among 14 individuals (2.5%), including 4 individuals (0.7%) with chromosome scale abnormalities. Overall, there were 47 molecular diagnoses, with 1 individual receiving 2 diagnoses; of the 47 potential diagnoses, 22 (46.8%) were associated with high-penetrance conditions. Pathogenic variants in medically actionable pediatric genes were found in 6 individuals (1.1%), constituting 12.8% (6 of 47) of all diagnoses. At least 1 pharmacogenomic variant was reported for 89.0% (500 of 562) of the cohort. In contrast, of 606 children (293 girls [48.3%]; median age, 26 days [IQR, 10-67 days]) undergoing gene panel screening, only 13 (2.1%; 95% CI, 1.0%-3.3%) resulted in potential childhood-onset diagnoses, a significantly lower rate than those screened by genome sequencing (P < .001).
In this case series study, genome sequencing as a proactive screening approach for children, due to its unrestrictive gene content and technical advantages in comparison with an exome-based gene panel for medically actionable childhood conditions, uncovered a wide range of heterogeneous high-penetrance pediatric conditions that could guide early interventions and medical management.
尽管基因组测序在危重症儿童中的临床应用已得到广泛认可，但在主动儿科筛查中的应用尚未得到充分探索。
评估对表面健康的儿童进行基因组测序筛查与针对具有医学可操作性的儿科疾病的基因面板筛查的分子发现。
设计、地点和参与者：本病例系列研究在 2018 年 3 月 1 日至 2022 年 7 月 31 日期间对通过基因组测序（n=562）或 268 个基因的外显子组面板（n=606）进行主动遗传筛查的连续、表面健康的儿童中进行。
使用基因组测序或针对 268 个基因的外显子组面板对儿科疾病进行遗传筛查。
提示遗传疾病风险的分子发现。
在 562 名表面健康的儿童（286 名女孩[50.9%]；中位年龄，29 天[IQR，9-117 天]）中，46 名（8.2%；95%CI，5.9%-10.5%）被认为存在儿科疾病风险，包括 22 名（3.9%）有高外显率疾病风险的儿童。序列分析在 32 名个体（5.7%）中发现了分子诊断，而拷贝数变异分析在 14 名个体（2.5%）中发现了分子诊断，包括 4 名（0.7%）患有染色体水平异常。总体而言，有 47 个分子诊断，1 名患者有 2 个诊断；在 47 个潜在诊断中，22 个（46.8%）与高外显率疾病有关。在 6 名患者（1.1%）中发现了具有医学可操作性的儿科基因中的致病性变异，占所有诊断的 12.8%（6 例）。该队列中 89.0%（500 例）的患者至少有 1 个药物基因组学变异。相比之下，在 606 名接受基因面板筛查的儿童（293 名女孩[48.3%]；中位年龄，26 天[IQR，10-67 天]）中，只有 13 名（2.1%；95%CI，1.0%-3.3%）导致潜在的儿童期疾病诊断，显著低于基因组测序组（P<.001）。
在本病例系列研究中，由于其不受限制的基因内容和与针对具有医学可操作性的儿科疾病的外显子组基因面板相比在技术上的优势，基因组测序作为一种主动筛查方法在儿童中发现了广泛的异质性高外显率儿科疾病，这可以指导早期干预和医疗管理。
