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Fetal central nervous system anomalies: When should we offer exome sequencing?

Fetal central nervous system anomalies: When should we offer exome sequencing?
Fetal central nervous system anomalies: When should we offer exome sequencing?
Objective
To investigate the detection of pathogenic variants using exome sequencing in an international cohort of fetuses with central nervous system (CNS) anomalies.

Methods
We reviewed trio exome sequencing (ES) results for two previously reported unselected cohorts (Prenatal Assessment of Genomes and Exomes (PAGE) and CUIMC) to identify fetuses with CNS anomalies with unremarkable karyotypes and chromosomal microarrays. Variants were classified according to ACMG guidelines and association of pathogenic variants with specific types of CNS anomalies explored.

Results
ES was performed in 268 pregnancies with a CNS anomaly identified using prenatal ultrasound. Of those with an isolated, single, CNS anomaly, 7/97 (7.2%) had a likely pathogenic/pathogenic (LP/P) variant. This includes 3/23 (13%) fetuses with isolated mild ventriculomegaly and 3/10 (30%) fetuses with isolated agenesis of the corpus callosum.

Where there were multiple anomalies within the CNS, 12/63 (19%) had LP/P variants. Of the 108 cases with CNS and other organ system anomalies, 18 (16.7%) had LP/P findings.

Conclusion
ES is an important tool in the prenatal evaluation of fetuses with any CNS anomaly. The rate of LP/P variants tends to be highest in fetuses with multiple CNS anomalies and multisystem anomalies, however, ES may also be of benefit for isolated CNS anomalies.
0197-3851
736-743
Baptiste, Caitlin
037d8249-b433-4be7-8a82-132cd284c121
Mellis, Rhiannon
899ec278-b19d-4daf-ba7a-0e80f64b9801
Aggarwal, Vimla S.
47f6f546-d4cd-4b6a-863b-1ec9b9078b29
Lord, Jenny
e1909780-36cd-4705-b21e-4580038d4ec6
Eberhardt, Ruth Y.
e37e84f9-2995-4c17-9a7a-95bdb728dee9
Kilby, Mark D.
dc85a6f2-acb0-4a0b-afbc-2aed41cb9ad5
Maher, Eamonn R.
577b8856-f8a8-49c2-9484-288d9f964aed
Wapner, Ronald
37cf61bc-857e-4ae2-b2b8-62e07c14d1ab
Giordano, Jessica
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Chitty, Lyn
6eb70c08-df83-481c-bb0e-a558901daf03
Baptiste, Caitlin
037d8249-b433-4be7-8a82-132cd284c121
Mellis, Rhiannon
899ec278-b19d-4daf-ba7a-0e80f64b9801
Aggarwal, Vimla S.
47f6f546-d4cd-4b6a-863b-1ec9b9078b29
Lord, Jenny
e1909780-36cd-4705-b21e-4580038d4ec6
Eberhardt, Ruth Y.
e37e84f9-2995-4c17-9a7a-95bdb728dee9
Kilby, Mark D.
dc85a6f2-acb0-4a0b-afbc-2aed41cb9ad5
Maher, Eamonn R.
577b8856-f8a8-49c2-9484-288d9f964aed
Wapner, Ronald
37cf61bc-857e-4ae2-b2b8-62e07c14d1ab
Giordano, Jessica
3bee9562-1695-47ba-be7b-3991811c083b
Chitty, Lyn
6eb70c08-df83-481c-bb0e-a558901daf03

Baptiste, Caitlin, Mellis, Rhiannon, Aggarwal, Vimla S., Lord, Jenny, Eberhardt, Ruth Y., Kilby, Mark D., Maher, Eamonn R., Wapner, Ronald, Giordano, Jessica and Chitty, Lyn (2022) Fetal central nervous system anomalies: When should we offer exome sequencing? Prenatal Diagnosis, 42 (6), 736-743. (doi:10.1002/pd.6145).

Record type: Article

Abstract

Objective
To investigate the detection of pathogenic variants using exome sequencing in an international cohort of fetuses with central nervous system (CNS) anomalies.

Methods
We reviewed trio exome sequencing (ES) results for two previously reported unselected cohorts (Prenatal Assessment of Genomes and Exomes (PAGE) and CUIMC) to identify fetuses with CNS anomalies with unremarkable karyotypes and chromosomal microarrays. Variants were classified according to ACMG guidelines and association of pathogenic variants with specific types of CNS anomalies explored.

Results
ES was performed in 268 pregnancies with a CNS anomaly identified using prenatal ultrasound. Of those with an isolated, single, CNS anomaly, 7/97 (7.2%) had a likely pathogenic/pathogenic (LP/P) variant. This includes 3/23 (13%) fetuses with isolated mild ventriculomegaly and 3/10 (30%) fetuses with isolated agenesis of the corpus callosum.

Where there were multiple anomalies within the CNS, 12/63 (19%) had LP/P variants. Of the 108 cases with CNS and other organ system anomalies, 18 (16.7%) had LP/P findings.

Conclusion
ES is an important tool in the prenatal evaluation of fetuses with any CNS anomaly. The rate of LP/P variants tends to be highest in fetuses with multiple CNS anomalies and multisystem anomalies, however, ES may also be of benefit for isolated CNS anomalies.

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More information

Accepted/In Press date: 7 April 2022
e-pub ahead of print date: 20 April 2022
Published date: May 2022
Additional Information: © 2022 John Wiley & Sons Ltd.

Identifiers

Local EPrints ID: 468082
URI: http://eprints.soton.ac.uk/id/eprint/468082
ISSN: 0197-3851
PURE UUID: b956258c-1472-43c5-92bd-fe3dc8fe41ef
ORCID for Jenny Lord: ORCID iD orcid.org/0000-0002-0539-9343

Catalogue record

Date deposited: 01 Aug 2022 16:53
Last modified: 03 Sep 2022 02:03

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Contributors

Author: Caitlin Baptiste
Author: Rhiannon Mellis
Author: Vimla S. Aggarwal
Author: Jenny Lord ORCID iD
Author: Ruth Y. Eberhardt
Author: Mark D. Kilby
Author: Eamonn R. Maher
Author: Ronald Wapner
Author: Jessica Giordano
Author: Lyn Chitty

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