Genome Analysis in Sick Neonates and Infants: High-yield Phenotypes and Contribution of Small Copy Number Variations
Genome Analysis in Sick Neonates and Infants: High-yield Phenotypes and Contribution of Small Copy Number Variations
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DOI：
10.1016/j.jpeds.2022.01.033
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发表时间：
2022-05-06
影响因子：
5.1
通讯作者：
Takenouchi, Toshiki
中科院分区：
文献类型：
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作者：
Suzuki, Hisato;Nozaki, Masatoshi;Takenouchi, Toshiki
目的根据原发症状、小拷贝数变异的贡献以及分子诊断对临床管理的影响，描述医学外显子组、全外显子组和全基因组测序的诊断效力。研究设计这是一项前瞻性研究，在日本的17个三级医疗中心进行，于2019年4月至2021年3月期间进行。在新生儿重症监护病房和门诊招募危重新生儿和6个月以下的婴儿。患者接受了医学外显子组，全外显子组或全基因组测序作为第一层测试。医学外显子组或全外显子组测序后阴性结果的患者随后进行全基因组测序。结果85例患者中，41例（48%）有阳性结果。根据主要症状，代谢表型患者的诊断率最高（67%，4/6例患者），其次是肾脏（60%，3/5例患者）和神经系统表型（58%，14/24例患者）。其中，使用全基因组测序发现4例患者存在致病性小拷贝数变异。在41例患者的分子诊断，20（49%）的变化，在临床management.Conclusions基因组分析危重新生儿和婴儿有很高的诊断率代谢，肾脏和神经系统表型。使用全基因组测序检测到的小拷贝数变异有助于所有患者中5%的总体分子诊断。由此产生的分子诊断对临床管理产生了重大影响。
Objective To delineate the diagnostic efficacy of medical exome, whole exome, and whole genome sequencing according to primary symptoms, the contribution of small copy number variations, and the impact of molecular diagnosis on clinical management.Study design This was a prospective study of 17 tertiary care centers in Japan, conducted between April 2019 and March 2021. Critically ill neonates and infants less than 6 months of age were recruited in neonatal intensive care units and in outpatient clinics. The patients underwent medical exome, whole exome, or whole genome sequencing as the first tier of testing. Patients with negative results after medical exome or whole exome sequencing subsequently underwent whole genome sequencing. The impact of molecular diagnosis on clinical management was evaluated through contacting primary care physicians.Results Of the 85 patients, 41 (48%) had positive results. Based on the primary symptoms, patients with metabolic phenotypes had the highest diagnostic yield (67%, 4/6 patients), followed by renal (60%, 3/5 patients), and neurologic phenotypes (58%, 14/24 patients). Among them, 4 patients had pathogenic small copy number variations identified using whole genome sequencing. In the 41 patients with a molecular diagnosis, 20 (49%) had changes in clinical management.Conclusions Genome analysis for critically ill neonates and infants had a high diagnostic yield for metabolic, renal, and neurologic phenotypes. Small copy number variations detected using whole genome sequencing contributed to the overall molecular diagnosis in 5% of all the patients. The resulting molecular diagnoses had a significant impact on clinical management.