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Multicenter Study
. 2024 Feb 5;7(2):e240146.
doi: 10.1001/jamanetworkopen.2024.0146.

National Rapid Genome Sequencing in Neonatal Intensive Care

Daphna Marom  1   2 , Adi Mory  1 , Sivan Reytan-Miron  1 , Yam Amir  1   2 , Alina Kurolap  1 , Julia Grinshpun Cohen  3 , Yocheved Morhi  4 , Tatiana Smolkin  5   6 , Lior Cohen  7   8 , Shmuel Zangen  8   9 , Adel Shalata  4   10 , Arieh Riskin  4   11 , Amir Peleg  4   12 , Karen Lavie-Nevo  4   13 , Dror Mandel  2   14 , Elana Chervinsky  4   15 , Clari Felszer Fisch  4   16 , Vered Fleisher Sheffer  6   17 , Tzipora C Falik-Zaccai  6   18 , Jonathan Rips  19   20 , Noa Ofek Shlomai  20   21 , Smadar Eventov Friedman  20   21 , Calanit Hershkovich Shporen  20   22 , Sagie Josefsberg Ben-Yehoshua  20   23 , Aryeh Simmonds  24   25 , Racheli Goldfarb Yaacobi  2   26 , Sofia Bauer-Rusek  2   27 , Hussam Omari  6   28 , Karin Weiss  4   29 , Ori Hochwald  4   30 , Arie Koifman  8   31 , Omer Globus  8   32 , Nurit Assia Batzir  33 , Naveh Yaron  20   34 , Reeval Segel  20   35 , Iris Morag  2   36 , Orit Reish  2   37 , Aviva Eliyahu  2   38 , Leah Leibovitch  2   39 , Marina Eskin Schwartz  8   40 , Ramy Abramsky  8   41 , Amit Hochberg  4   42 , Anat Oron  2   43 , Ehud Banne  2   44 , Igor Portnov  6   45 , Nadra Nasser Samra  6   46 , Amihood Singer  3 , Hagit Baris Feldman  1   2
Affiliations
Multicenter Study

National Rapid Genome Sequencing in Neonatal Intensive Care

Daphna Marom et al. JAMA Netw Open. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Marom reported receiving compensation for next-generation sequencing wet work from the Israeli Ministry of Health and receiving next-generation sequencing reagents, bioinformatics solution, editing assistance, and open access publication fee from Illumina during the conduct of the study and receiving speaking fees from Illumina Shine the Light Event and XPeer outside the submitted work. Dr Amir reported receiving compensation for next-generation sequencing wet work from the Israeli Ministry of Health and next-generation sequencing reagents, bioinformatics solution, editing assistance, and open access publication fee from Illumina during the conduct of the study. Dr Baris Feldman reported compensation for next-generation sequencing wet work from the Israeli Ministry of Health and next-generation sequencing reagents, bioinformatics solution, editing assistance, and open access publication fee from Illumina during the conduct of the study and receiving honorarium and travel expenses from Illumina and speaker’s fee from XPeer channel educational video. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Design, Enrollment, Timeline, and Results
A, Flowchart of the Baby Bambi pilot. Timelines are indicated are as follows: Time 0 to time 1: up to 1 day; time 1 to time 2: 1 to 5 working days; time 2 to time 3: 10 days. B, Flowchart depicting pilot referral, enrollment, and results. Of the 47 excluded patients, 8 could not provide biparental consent on account of religious beliefs. CNV indicates copy-number variation; MOH, Ministry of Health; NICU, neonatal intensive care unit; RF, requisition form; SNV, single-nucleotide variant; TASMC, Tel Aviv Sourasky Medical Center; UPD, uniparental disomy; VUS, variant of unknown significance.
Figure 2.
Figure 2.. Rapid Trio Genome Sequencing (rtGS) Results
A, Diagnostic efficacy of rtGS in full Baby Bambi cohort (130 neonates). B, Types and proportions of disease-causing variants identified in the Baby Bambi cohort (65 neonates). LP indicates likely pathogenic; P, pathogenic; SNV, single-nucleotide variant; VUS, variant of unknown significance.
See this image and copyright information in PMC

Comment in

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