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Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study

Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study
Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study

Background: fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). 

Methods: in this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. 

Findings: the cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4–11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses). 

Interpretation: WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness. 

Funding: UK Department of Health and Social Care and The Wellcome Trust.

0140-6736
747-757
Lord, Jenny
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McMullan, Dominic J.
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Eberhardt, Ruth Y.
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Rinck, Gabriele
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Hamilton, Susan J.
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Quinlan-Jones, Elizabeth
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Prigmore, Elena
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Keelagher, Rebecca
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Berry, Ian R.
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Chandler, Kate E.
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Cilliers, Deirdre
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Wellesley, Diana G.
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Westwood, Paul
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White, Helen
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Parker, Michael
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Williams, Denise
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Jenkins, Lucy
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Scott, Richard H.
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Chitty, Lyn S.
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Hurles, Matthew E.
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Maher, Eamonn R.
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Bateman, Mark
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Campbell, Carolyn
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Campbell, Jenni
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Carey, Georgina
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Cohen, Kelly
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Lewis, Rebecca
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Taylor, Emma J.
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et al.
Prenatal Assessment of Genomes and Exomes Consortium
Lord, Jenny
e1909780-36cd-4705-b21e-4580038d4ec6
McMullan, Dominic J.
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Eberhardt, Ruth Y.
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Rinck, Gabriele
f0bff4e7-eeba-4ff9-b17a-84718228f64f
Hamilton, Susan J.
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Quinlan-Jones, Elizabeth
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Prigmore, Elena
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Keelagher, Rebecca
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Best, Sunayna K.
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Carey, Georgina K.
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Mellis, Rhiannon
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Robart, Sarah
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Berry, Ian R.
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Chandler, Kate E.
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Cilliers, Deirdre
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Cresswell, Lara
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Edwards, Sandra L.
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Gardiner, Carol
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Henderson, Alex
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Holden, Simon T.
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Homfray, Tessa
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Lester, Tracy
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Lewis, Rebecca
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Newbury-Ecob, Ruth
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Prescott, Katrina
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Quarrell, Oliver W.
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Ramsden, Simon C.
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Roberts, Eileen
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Tapon, Dagmar
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Tooley, Madeleine J.
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Vasudevan, Pradeep C.
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Weber, Astrid P.
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Wellesley, Diana G.
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Westwood, Paul
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White, Helen
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Parker, Michael
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Williams, Denise
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Jenkins, Lucy
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Scott, Richard H.
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Kilby, Mark D.
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Chitty, Lyn S.
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Hurles, Matthew E.
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Maher, Eamonn R.
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Bateman, Mark
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Campbell, Carolyn
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Campbell, Jenni
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Carey, Georgina
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Cohen, Kelly
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Lewis, Rebecca
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Taylor, Emma J.
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Lord, Jenny, McMullan, Dominic J., Eberhardt, Ruth Y., Rinck, Gabriele, Hamilton, Susan J., Quinlan-Jones, Elizabeth, Prigmore, Elena, Keelagher, Rebecca, Best, Sunayna K., Carey, Georgina K., Mellis, Rhiannon, Robart, Sarah, Berry, Ian R., Chandler, Kate E., Cilliers, Deirdre, Cresswell, Lara, Edwards, Sandra L., Gardiner, Carol, Henderson, Alex, Holden, Simon T., Homfray, Tessa, Lester, Tracy, Lewis, Rebecca, Newbury-Ecob, Ruth, Prescott, Katrina, Quarrell, Oliver W., Ramsden, Simon C., Roberts, Eileen, Tapon, Dagmar, Tooley, Madeleine J., Vasudevan, Pradeep C., Weber, Astrid P., Wellesley, Diana G., Westwood, Paul, White, Helen, Parker, Michael, Williams, Denise, Jenkins, Lucy, Scott, Richard H., Kilby, Mark D., Chitty, Lyn S., Hurles, Matthew E., Maher, Eamonn R., Bateman, Mark, Campbell, Carolyn, Campbell, Jenni, Carey, Georgina, Cohen, Kelly, Lewis, Rebecca and Taylor, Emma J. , et al. and Prenatal Assessment of Genomes and Exomes Consortium (2019) Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. The Lancet, 393 (10173), 747-757. (doi:10.1016/S0140-6736(18)31940-8).

Record type: Article

Abstract

Background: fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). 

Methods: in this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. 

Findings: the cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4–11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses). 

Interpretation: WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness. 

Funding: UK Department of Health and Social Care and The Wellcome Trust.

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e-pub ahead of print date: 31 January 2019
Published date: 23 February 2019

Identifiers

Local EPrints ID: 429600
URI: https://eprints.soton.ac.uk/id/eprint/429600
ISSN: 0140-6736
PURE UUID: bce8747a-64d4-4d46-98c6-181ca7033538
ORCID for Jenny Lord: ORCID iD orcid.org/0000-0002-0539-9343

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Date deposited: 01 Apr 2019 16:30
Last modified: 15 Aug 2019 00:21

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Contributors

Author: Jenny Lord ORCID iD
Author: Dominic J. McMullan
Author: Ruth Y. Eberhardt
Author: Gabriele Rinck
Author: Susan J. Hamilton
Author: Elizabeth Quinlan-Jones
Author: Elena Prigmore
Author: Rebecca Keelagher
Author: Sunayna K. Best
Author: Georgina K. Carey
Author: Rhiannon Mellis
Author: Sarah Robart
Author: Ian R. Berry
Author: Kate E. Chandler
Author: Deirdre Cilliers
Author: Lara Cresswell
Author: Sandra L. Edwards
Author: Carol Gardiner
Author: Alex Henderson
Author: Simon T. Holden
Author: Tessa Homfray
Author: Tracy Lester
Author: Rebecca Lewis
Author: Ruth Newbury-Ecob
Author: Katrina Prescott
Author: Oliver W. Quarrell
Author: Simon C. Ramsden
Author: Eileen Roberts
Author: Dagmar Tapon
Author: Madeleine J. Tooley
Author: Pradeep C. Vasudevan
Author: Astrid P. Weber
Author: Diana G. Wellesley
Author: Paul Westwood
Author: Helen White
Author: Michael Parker
Author: Denise Williams
Author: Lucy Jenkins
Author: Richard H. Scott
Author: Mark D. Kilby
Author: Lyn S. Chitty
Author: Matthew E. Hurles
Author: Eamonn R. Maher
Author: Mark Bateman
Author: Carolyn Campbell
Author: Jenni Campbell
Author: Georgina Carey
Author: Kelly Cohen
Author: Rebecca Lewis
Author: Emma J. Taylor

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