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

Ishida, M; Cullup, T; Boustred, C; James, C; Docker, J; English, C; GOSgene, .; ... Stanier, PM; + view all (2018) A targeted sequencing panel identifies rare damaging variants in multiple genes in the cranial neural tube defect, anencephaly. Clinical Genetics , 93 (4) pp. 870-879. 10.1111/cge.13189. Green open access

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Abstract

Neural tube defects (NTDs) affecting the brain (anencephaly) are lethal before or at birth, whereas lower spinal defects (spina bifida) may lead to life-long 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 (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.

Type: Article
Title: A targeted sequencing panel identifies rare damaging variants in multiple genes in the cranial neural tube defect, anencephaly
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/cge.13189
Publisher version: http://doi.org/10.1111/cge.13189
Language: English
Additional information: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Anencephaly; Craniorachischisis; Molecular diagnosis; Neural tube defects (NTDs); Targeted exome sequencing
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
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 > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
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
URI: https://discovery.ucl.ac.uk/id/eprint/10039560
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