Kansal Rina
Molecular Oncology and Genetics, Diagnostic Laboratories, Versiti Blood Center of Wisconsin, Milwaukee, WI 53233, USA.
Department of Pathology and Anatomical Sciences, The University at Buffalo, Buffalo, NY 14260, USA.
Children (Basel). 2025 Mar 28;12(4):429. doi: 10.3390/children12040429.
The completion of the Human Genome Project in 2003 has led to significant advances in patient care in medicine, particularly in diagnosing and managing genetic diseases and cancer. In the realm of genetic diseases, approximately 15% of critically ill infants born in the U.S.A. are diagnosed with genetic disorders, which comprise a significant cause of mortality in neonatal and pediatric intensive care units. The introduction of rapid whole-genome sequencing (rWGS) as a first-tier test in critically ill children with suspected, undiagnosed genetic diseases is a breakthrough in the diagnosis and subsequent clinical management of such infants and older children in intensive care units. Rapid genome sequencing is currently being used clinically in the USA, the UK, the Netherlands, Sweden, and Australia, among other countries. This review is intended for students and clinical practitioners, including non-experts in genetics, for whom it provides a historical background and a chronological review of the relevant published literature for the progression of pediatric diagnostic genomic sequencing leading to the development of pediatric rWGS in critically ill infants and older children with suspected but undiagnosed genetic diseases. Factors that will help to develop rWGS as a clinical test in critically ill infants and the limitations are briefly discussed, including an evaluation of the clinical utility and accessibility of genetic testing, education for parents and providers, cost-effectiveness, ethical challenges, consent issues, secondary findings, data privacy concerns, false-positive and false-negative results, challenges in variant interpretation, costs and reimbursement, the limited availability of genetic counselors, and the development of evidence-based guidelines, which would all need to be addressed to facilitate the implementation of pediatric genomic sequencing in an effective widespread manner in the era of precision medicine.
2003年人类基因组计划的完成推动了医学领域患者护理的重大进展，尤其是在遗传疾病和癌症的诊断与管理方面。在遗传疾病领域，美国出生的危重症婴儿中约15%被诊断患有遗传疾病，这是新生儿和儿科重症监护病房死亡的一个重要原因。将快速全基因组测序（rWGS）作为疑似患有未确诊遗传疾病的危重症儿童的一线检测方法，是重症监护病房中此类婴儿和大龄儿童诊断及后续临床管理的一项突破。目前，美国、英国、荷兰、瑞典和澳大利亚等国家正在临床应用快速基因组测序。本综述面向学生和临床从业者，包括遗传学非专家，为他们提供了历史背景以及相关已发表文献的编年回顾，内容涉及儿科诊断基因组测序的进展，直至在疑似但未确诊遗传疾病的危重症婴儿和大龄儿童中开发出儿科rWGS。文中简要讨论了有助于将rWGS发展成为危重症婴儿临床检测方法的因素以及局限性，包括对基因检测的临床效用和可及性、对家长和医疗服务提供者的教育、成本效益、伦理挑战、知情同意问题、次要发现、数据隐私问题、假阳性和假阴性结果、变异解读的挑战、成本与报销、遗传咨询师数量有限以及循证指南的制定等方面的评估，在精准医学时代，要以有效且广泛的方式促进儿科基因组测序的实施，所有这些都需要加以解决。
