Medical Exome As a First-Line Diagnostic Test in the Neonatal Intensive Care Unit: Experience in a Large Broad Cohort of 4,124 Neonates with Minimal Clinical Selection in China

Background: Rare genetic diseases underlie a significant portion of congenital anomalies and contribute to neonatal intensive care unit (NICU) admissions. A timely genetic diagnosis is important for medical decision making. Emerging evidence demonstrates the clinical utility of medical genomic applications in NICU patients with highly suspect genetic etiology. However, the diagnostic yield and utility of such applications remain unclear for large scale and non-selective NICU cohorts. Methods: Focused medical exome sequencing was used as a first-tier, singleton focused diagnostic tool for minimally selected 4,124 unrelated sick neonates from 2016 to 2018. Integrated analysis of single nucleotide variants, small insertions and deletions, and large copy number variants was performed on genes with established clinical validity and neonatal onset. Diagnostic yield, medically actionable incidental findings, and potential clinical predictors for a molecular diagnosis were analyzed. Findings: The overall diagnostic rate in this large NICU cohort is 7.1%, with an average turnaround time of 10 days and a cost of under $250 per patient. In addition, 2.0% patients had a reportable incidental finding. Multiple organ failure was the strongest positive predictor while hepatic/hyperbilirubinemia involvements were the strongest negative predictors for a diagnosis. Interpretation: Focused medical exome sequencing is a powerful first line test for timely molecular diagnosis and informed management of NICU patients. A genome-first approach such as medical exome sequencing can particularly benefit intensively ill neonates in a large patient population with a resource-constrained environment such as China, where well-trained clinical geneticists are scarce and comprehensive diagnostic tools are not readily available. Funding Statement: This work was supported by grants from the Shanghai Shen Kang Hospital Development Center (SHDC12017110), the Technology Major Project (2018SHZDZX01) and ZJLab, the Shanghai Municipal Commission of Health and Family Planning (GDEK201701), the Shanghai Municipal Science and Technology Major Project (2018SHZDZX05). Declaration of Interests: ZW, KM, TX, JZ, FC, LL, YD, CL, ST, and PF are employed by and receive a salary from WuXiNextCode Genomics. Medical exome testing is among the commercially available tests. All other authors declare no competing interests. Ethics Approval Statement: This study was approved by the ethics committees of Children’s Hospital of Fudan University (2015-169). The samples used in this study were collected with appropriate informed consent and approval of the ethics committee of Children’s Hospital, Fudan University. Written informed consent was obtained from parents or legal guardians of patients.