PURPOSE To investigate the impact of rapid-turnaround exome sequencing in critically ill neonates using phenotype-based subject selection criteria. METHODS Intensive care unit babies aged <6 months with hypotonia, seizures, a complex metabolic phenotype, and/or multiple congenital malformations were prospectively enrolled for rapid (<7 day) trio-based exome sequencing. Genomic variants relevant to the presenting phenotype were returned to the medical team. RESULTS A genetic diagnosis was attained in 29 of 50 (58%) sequenced cases. Twenty-seven (54%) patients received a molecular diagnosis involving known disease genes; two additional cases (4%) were solved with pathogenic variants found in novel disease genes. In 24 of the solved cases, diagnosis had impact on patient management and/or family members. Management changes included shift to palliative care, medication changes, involvement of additional specialties, and the consideration of new experimental therapies. CONCLUSION Phenotype-based patient selection is effective at identifying critically ill neonates with a high likelihood of receiving a molecular diagnosis via rapid-turnaround exome sequencing, leading to faster and more accurate diagnoses, reducing unnecessary testing and procedures, and informing medical care.

中文翻译：

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用于快速外显子组测序的危重新生儿的前瞻性、表型驱动选择与高诊断率相关。

目的 使用基于表型的受试者选择标准研究快速周转外显子组测序对危重新生儿的影响。方法 前瞻性招募 6 个月以下患有肌张力减退、癫痫发作、复杂代谢表型和/或多种先天性畸形的重症监护病房婴儿进行快速（<7 天）基于三重奏的外显子组测序。与呈现表型相关的基因组变体被送回医疗团队。结果 50 例 (58%) 测序病例中有 29 例获得了基因诊断。27 名 (54%) 患者接受了涉及已知疾病基因的分子诊断；另外两个病例（4%）通过在新疾病基因中发现的致病变异得到解决。在解决的 24 例病例中，诊断对患者管理和/或家庭成员产生了影响。管理变化包括转向姑息治疗、药物变化、其他专业的参与以及对新实验疗法的考虑。结论基于表型的患者选择可有效识别危重新生儿，通过快速周转的外显子组测序获得分子诊断的可能性很高，从而导致更快和更准确的诊断，减少不必要的测试和程序，并为医疗保健提供信息。