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Title: Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing.
Authors: Stals, Karen L.
Wakeling, Matthew
Baptista, Júlia
Caswell, Richard
Parrish, Andrew
Rankin, Julia
Tysoe, Carolyn
Jones, Garan
Gunning, Adam C.
Lango Allen, Hana
Bradley, Lisa
Brady, Angela F.
Carley, Helena
Carmichael, Jenny
Castle, Bruce
Cilliers, Deirdre
Cox, Helen
Deshpande, Charu
Dixit, Abhijit
Eason, Jacqueline
Elmslie, Frances
Fry, Andrew E.
Fryer, Alan
Holder, Muriel
Homfray, Tessa
Kivuva, Emma
McKay, Victoria
Newbury-Ecob, Ruth
Parker, Michael
Savarirayan, Ravi
Searle, Claire
Shannon, Nora
Shears, Deborah
Smithson, Sarah
Thomas, Ellen
Turnpenny, Peter D.
Varghese, Vinod
Vasudevan, Pradeep
Wakeling, Emma
Baple, Emma L.
Ellard, Sian
First Published: 2-Nov-2017
Publisher: Wiley for International Society for Prenatal Diagnosis
Citation: Prenatal Diagnosis, 2018, 38 (1), pp. 33-43
Abstract: OBJECTIVE: Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred. METHOD: Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF < 0.001) in the same gene in both parents were selected for analysis. Likely, disease-causing variants were tested in fetal DNA to confirm co-segregation. RESULTS: Parental exome analysis identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%). Where 2 or more fetuses were affected, a genetic diagnosis was obtained in 18/29 cases (62%). In most cases, the clinical features were typical of the disorder, but in others, they result from a hypomorphic variant or represent the most severe form of a variable phenotypic spectrum. CONCLUSION: We conclude that exome sequencing of parental samples is a powerful strategy with high clinical utility for the genetic diagnosis of lethal or prenatal-onset recessive disorders. © 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.
DOI Link: 10.1002/pd.5175
ISSN: 0197-3851
eISSN: 1097-0223
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2017. This is an open-access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description: Additional Supporting Information may be found online in thesupporting information tab for this article.
Appears in Collections:Published Articles, Dept. of Genetics

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