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A targeted sequencing panel identifies rare damaging variants in multiple genes in the cranial neural tube defect, anencephaly

Lookup NU author(s): Dr Carol English



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2018 John Wiley & Sons A/S. Neural tube defects (NTDs) affecting the brain (anencephaly) are lethal before or at birth, whereas lower spinal defects (spina bifida) may lead to lifelong neurological handicap. Collectively, NTDs rank among the most common birth defects worldwide. This study focuses on anencephaly, which despite having a similar frequency to spina bifida and being the most common type of NTD observed in mouse models, has had more limited inclusion in genetic studies. A genetic influence is strongly implicated in determining risk of NTDs and a molecular diagnosis is of fundamental importance to families both in terms of understanding the origin of the condition and for managing future pregnancies. Here we used a custom panel of 191 NTD candidate genes to screen 90 patients with cranial NTDs (n=85 anencephaly and n=5 craniorachischisis) with a targeted exome sequencing platform. After filtering and comparing to our in-house control exome database (N=509), we identified 397 rare variants (minor allele frequency, MAF<1%), 21 of which were previously unreported and predicted damaging. This included 1 frameshift (PDGFRA), 2 stop-gained (MAT1A; NOS2) and 18 missense variations. Together with evidence for oligogenic inheritance, this study provides new information on the possible genetic causation of anencephaly.

Publication metadata

Author(s): Ishida M, Cullup T, Boustred C, James C, Docker J, English C, Lench N, Copp AJ, Moore GE, Greene NDE, Stanier P

Publication type: Article

Publication status: Published

Journal: Clinical Genetics

Year: 2018

Volume: 93

Issue: 4

Pages: 870-879

Print publication date: 01/04/2018

Online publication date: 11/02/2018

Acceptance date: 27/11/2017

Date deposited: 27/02/2018

ISSN (print): 0009-9163

ISSN (electronic): 1399-0004

Publisher: Blackwell Publishing Ltd


DOI: 10.1111/cge.13189


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