National Rapid Genome Sequencing in Neonatal Intensive Care

Daphna Marom, Adi Mory, Sivan Reytan-Miron, Yam Amir, Alina Kurolap, Julia Grinshpun Cohen, Yocheved Morhi, Tatiana Smolkin, Lior Cohen, Shmuel Zangen, Adel Shalata, Arieh Riskin, Amir Peleg, Karen Lavie-Nevo, Dror Mandel, Elana Chervinsky, Clari Felszer Fisch, Vered Fleisher Sheffer, Tzipora C. Falik-Zaccai, Jonathan RipsNoa Ofek Shlomai, Smadar Eventov Friedman, Calanit Hershkovich Shporen, Sagie Josefsberg Ben-Yehoshua, Aryeh Simmonds, Racheli Goldfarb Yaacobi, Sofia Bauer-Rusek, Hussam Omari, Karin Weiss, Ori Hochwald, Arie Koifman, Omer Globus, Nurit Assia Batzir, Naveh Yaron, Reeval Segel, Iris Morag, Orit Reish, Aviva Eliyahu, Leah Leibovitch, Marina Eskin Schwartz, Ramy Abramsky, Amit Hochberg, Anat Oron, Ehud Banne, Igor Portnov, Nadra Nasser Samra, Amihood Singer, Hagit Baris Feldman

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Importance: National implementation of rapid trio genome sequencing (rtGS) in a clinical acute setting is essential to ensure advanced and equitable care for ill neonates. Objective: To evaluate the feasibility, diagnostic efficacy, and clinical utility of rtGS in neonatal intensive care units (NICUs) throughout Israel. Design, Setting, and Participants: This prospective, public health care-based, multicenter cohort study was conducted from October 2021 to December 2022 with the Community Genetics Department of the Israeli Ministry of Health and all Israeli medical genetics institutes (n = 18) and NICUs (n = 25). Critically ill neonates suspected of having a genetic etiology were offered rtGS. All sequencing, analysis, and interpretation of data were performed in a central genomics center at Tel-Aviv Sourasky Medical Center. Rapid results were expected within 10 days. A secondary analysis report, issued within 60 days, focused mainly on cases with negative rapid results and actionable secondary findings. Pathogenic, likely pathogenic, and highly suspected variants of unknown significance (VUS) were reported. Main Outcomes and Measures: Diagnostic rate, including highly suspected disease-causing VUS, and turnaround time for rapid results. Clinical utility was assessed via questionnaires circulated to treating neonatologists. Results: A total of 130 neonates across Israel (70 [54%] male; 60 [46%] female) met inclusion criteria and were recruited. Mean (SD) age at enrollment was 12 (13) days. Mean (SD) turnaround time for rapid report was 7 (3) days. Diagnostic efficacy was 50% (65 of 130) for disease-causing variants, 11% (14 of 130) for VUS suspected to be causative, and 1 novel gene candidate (1%). Disease-causing variants included 12 chromosomal and 52 monogenic disorders as well as 1 neonate with uniparental disomy. Overall, the response rate for clinical utility questionnaires was 82% (107 of 130). Among respondents, genomic testing led to a change in medical management for 24 neonates (22%). Results led to immediate precision medicine for 6 of 65 diagnosed infants (9%), an additional 2 (3%) received palliative care, and 2 (3%) were transferred to nursing homes. Conclusions and Relevance: In this national cohort study, rtGS in critically ill neonates was feasible and diagnostically beneficial in a public health care setting. This study is a prerequisite for implementation of rtGS for ill neonates into routine care and may aid in design of similar studies in other public health care systems.

Original languageEnglish
Article numbere240146
JournalJAMA network open
Issue number2
StatePublished - 5 Feb 2024

Bibliographical note

Publisher Copyright:
© 2024 American Medical Association. All rights reserved.


The study was sponsored by a collaboration between the Israeli Ministry of Health, Illumina Inc, and the Genomics Center at the Tel-Aviv Sourasky Medical Center. The study was partially supported by Illumina Inc, with reagents, bioinformatic solutions, and editorial assistance

FundersFunder number
Ministry of Health, State of Israel


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