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Lessons learnt from prenatal exome sequencing

Chandler, Natalie J; Scotchman, Elizabeth; Mellis, Rhiannon; Ramachandran, Vijaya; Roberts, Rowenna; Chitty, Lyn S; (2022) Lessons learnt from prenatal exome sequencing. Prenatal Diagnosis 10.1002/pd.6165. (In press). Green open access

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Abstract

BACKGROUND: Prenatal exome sequencing (ES) for monogenic disorders in fetuses with structural anomalies increases diagnostic yield. In England there is a national trio ES service delivered from two laboratories. To minimise incidental findings and reduce the number of variants investigated, analysis uses a panel of 1205 genes where pathogenic variants may cause abnormalities presenting prenatally. Here we review our laboratory's early experience developing and delivering ES to identify challenges in interpretation and reporting and inform service development. METHODS: A retrospective laboratory records review from 01.04.2020 to 31.05.2021. RESULTS: Twenty-four of 116 completed cases were identified as challenging including 13 resulting in difficulties in analysis and reporting, nine where trio inheritance filtering would have missed the diagnosis, and two with no prenatal diagnosis; one due to inadequate pipeline sensitivity, the other because the gene was not on the panel. Two cases with copy number variants identified were not detectable by microarray. CONCLUSIONS: Variant interpretation requires close communication between referring clinicians, with occasional additional examination of the fetus or parents and communication of evolving phenotypes. Inheritance filtering misses ∼5% of diagnoses. Panel analysis reduces but does not exclude incidental findings. Regular review of published literature is required to identify new reports that may aid classification.

Type: Article
Title: Lessons learnt from prenatal exome sequencing
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/pd.6165
Publisher version: https://doi.org/10.1002/pd.6165
Language: English
Additional information: Copyright © 2022 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10148638
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