부산대학교 도서관

Key words anomaly; exome sequencing; intrauterine growth restriction; next-generation sequencing; prenatal; short long bones; skeletal dysplasia; small-for-gestational-age Objective This study aimed to determine the incremental yield of prenatal exome sequencing over chromosomal microarray or G-banding karyotype in fetuses with: (1) intrauterine growth restriction related to placental insufficiency or (2) short long bones, in isolated and nonisolated instances for both scenarios. Data Sources Data were collected via electronic searches for relevant citations from January 2010 to April 10, 2022 in MEDLINE, Embase, Web of Science, and Cochrane, and using relevant bibliographies and data generated in-house. Study Eligibility Criteria Included were prospective or retrospective cohort studies and/or case series with: (1) n>5 cases of short long bones and/or intrauterine growth restriction undergoing prenatal sequencing with a clearly defined phenotype including assessment of placental function; (2) testing based on prenatal phenotype only; (3) a nondiagnostic chromosomal microarray/karyotype; and (4) known results of genetic testing. Methods Incremental yield was calculated for each study and as a pooled value for the aforementioned groups using a random-effects model. Results were displayed in forest plots with 95% confidence intervals. Heterogeneity was assessed statistically using Higgins' I.sup.2. Publication bias was assessed graphically using funnel plots. Quality assessment was performed using modified Standards for Reporting of Diagnostic Accuracy criteria (International Prospective Register of Systematic Reviews registration number CRD42022324680). Results Nineteen studies were included (n=452 cases). The apparent incremental yields with prenatal sequencing were: (1) 4% (95% confidence interval, -5.0 to 12; I.sup.2=0%) in isolated intrauterine growth restriction with evidence of placental insufficiency, (2) 30% (95% confidence interval, 13--47; I.sup.2=1%) in intrauterine growth restriction with additional structural anomalies, (3) 48% (95% confidence interval, 26--70; I.sup.2=73%) in isolated short long bones, and (4) 68% (95% confidence interval, 58--77; I.sup.2=51%) in short long bones with additional skeletal anomalies. Of the 37 short long bone cases with a diagnosis, 32 had a skeletal dysplasia, with thanatophoric dysplasia and osteogenesis imperfecta being the most common (both 21.6% [n=8/37]). In fetuses with short long bones and additional skeletal features, osteogenesis imperfecta was the most common diagnosis (28% [n=57/204]). Where documented, the inheritance patterns were de novo in 75.4% (n=150) of cases. Conclusion Prenatal sequencing adds substantially to incremental yield over chromosomal microarray in fetuses with short long bones or multisystem intrauterine growth restriction. Robust studies are required to assess the utility of fetal sequencing in isolated intrauterine growth restriction with evidence of placental insufficiency, which cannot be recommended on the basis of current evidence. Author Affiliation: (a) Centre for Public Health, Queen's University Belfast, Belfast, United Kingdom (b) Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health, UCL, London, United Kingdom (c) Praxis für Humangenetik Tübingen, Tübingen, Germany (d) Columbia University Irving Medical Center, New York, NY (e) Columbia University, New York, NY (f) Great Ormond Street Hospital for Children National Health Service (NHS) Foundation Trust, London, United Kingdom * Corresponding author: Fionnuala Mone, PhD. Article History: Received 4 August 2022; Revised 23 September 2022; Accepted 27 September 2022 (footnote) The authors report no conflict of interest. (footnote) The PAGE study was funded by the Health Innovation Challenge Fund from the UK Department of Health and Social Care and the Wellcome Trust (number HICF-R7-396). For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. The Columbia University Irving Medical Center study was supported by the Columbia University Institute for Genomic Medicine and Obstetrics and Gynecology departments. External funders of these studies had no role in study design, data collection, data analysis, data interpretation, or writing of the report. R.M. is wholly and L.S.C. partially funded by the National Institute for Health and Care Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. (footnote) International Prospective Register of Systematic Reviews registration: April 12, 2022 (CRD42022324680). Byline: Fionnuala Mone, PhD [f.mone@qub.ac.uk] (a,*), Rhiannon Mellis, MRCPCH (b), Heinz Gabriel, PhD (c), Caitlin Baptiste, MD (d), Jessica Giordano, MS (e), Ronald Wapner, MD (e), Lyn S. Chitty, PhD (b,f)