ORCID
- Júlia Baptista: 0000-0003-0915-5028
Abstract
AbstractObjectiveRare 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.MethodExome 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.ResultsParental 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.ConclusionWe 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
DOI
10.1002/pd.5175
Publication Date
2018-01-01
Publication Title
Prenatal Diagnosis
Volume
38
Issue
1
ISSN
0197-3851
First Page
33
Last Page
43
Recommended Citation
Ellard, S., Stals, K., Wakeling, M., Baptista, J., Caswell, R., Parrish, A., Rankin, J., Tysoe, C., Jones, G., Gunning, A., Lango, A., Bradley, L., Brady, A., Carley, H., Carmichael, J., Castle, B., Cilliers, D., Cox, H., Deshpande, C., Dixit, A., Eason, J., Elmslie, F., Fry, A., Fryer, A., Holder, M., Homfray, T., Kivuva, E., McKay, V., Newbury‐Ecob, R., Parker, M., Searle, C., Shannon, N., Shears, D., Smithson, S., Thomas, E., Turnpenny, P., Varghese, V., Vasudevan, P., Wakeling, E., Baple, E., & Ellard, S. (2018) 'Diagnosis of lethal or prenatal‐onset autosomal recessive disorders by parental exome sequencing', Prenatal Diagnosis, 38(1), pp. 33-43. Available at: 10.1002/pd.5175
