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Rapid prenatal diagnosis using targeted exome sequencing: a cohort study to assess feasibility and potential impact on prenatal counseling and pregnancy management.
Genet Med. 2018 11; 20(11):1430-1437.GM

Abstract

PURPOSE

Unexpected fetal abnormalities occur in 2-5% of pregnancies. While traditional cytogenetic and microarray approaches achieve diagnosis in around 40% of cases, lack of diagnosis in others impedes parental counseling, informed decision making, and pregnancy management. Postnatally exome sequencing yields high diagnostic rates, but relies on careful phenotyping to interpret genotype results. Here we used a multidisciplinary approach to explore the utility of rapid fetal exome sequencing for prenatal diagnosis using skeletal dysplasias as an exemplar.

METHODS

Parents in pregnancies undergoing invasive testing because of sonographic fetal abnormalities, where multidisciplinary review considered skeletal dysplasia a likely etiology, were consented for exome trio sequencing (both parents and fetus). Variant interpretation focused on a virtual panel of 240 genes known to cause skeletal dysplasias.

RESULTS

Definitive molecular diagnosis was made in 13/16 (81%) cases. In some cases, fetal ultrasound findings alone were of sufficient severity for parents to opt for termination. In others, molecular diagnosis informed accurate prediction of outcome, improved parental counseling, and enabled parents to terminate or continue the pregnancy with certainty.

CONCLUSION

Trio sequencing with expert multidisciplinary review for case selection and data interpretation yields timely, high diagnostic rates in fetuses presenting with unexpected skeletal abnormalities. This improves parental counseling and pregnancy management.

Authors+Show Affiliations

North Thames NHS Regional Genetics Service, Great Ormond Street NHS Foundation Trust, London, UK.North Thames NHS Regional Genetics Service, Great Ormond Street NHS Foundation Trust, London, UK.North Thames NHS Regional Genetics Service, Great Ormond Street NHS Foundation Trust, London, UK.North Thames NHS Regional Genetics Service, Great Ormond Street NHS Foundation Trust, London, UK.South West Thames Regional Genetics Department, University of London & St George's University Hospitals NHS Foundation Trust, London, UK.Peninsula Clinical Genetics, Royal Devon & Exeter NHS Foundation Trust, Royal Devon & Exeter Hospital, Exeter, UK.Queen Charlotte's & Chelsea Hospital, Imperial College Healthcare NHS Trust, London, UK.North Thames NHS Regional Genetics Service, Great Ormond Street NHS Foundation Trust, London, UK.Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK.North Thames NHS Regional Genetics Service, Great Ormond Street NHS Foundation Trust, London, UK. l.chitty@ucl.ac.uk. Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK. l.chitty@ucl.ac.uk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29595812

Citation

Chandler, Natalie, et al. "Rapid Prenatal Diagnosis Using Targeted Exome Sequencing: a Cohort Study to Assess Feasibility and Potential Impact On Prenatal Counseling and Pregnancy Management." Genetics in Medicine : Official Journal of the American College of Medical Genetics, vol. 20, no. 11, 2018, pp. 1430-1437.
Chandler N, Best S, Hayward J, et al. Rapid prenatal diagnosis using targeted exome sequencing: a cohort study to assess feasibility and potential impact on prenatal counseling and pregnancy management. Genet Med. 2018;20(11):1430-1437.
Chandler, N., Best, S., Hayward, J., Faravelli, F., Mansour, S., Kivuva, E., Tapon, D., Male, A., DeVile, C., & Chitty, L. S. (2018). Rapid prenatal diagnosis using targeted exome sequencing: a cohort study to assess feasibility and potential impact on prenatal counseling and pregnancy management. Genetics in Medicine : Official Journal of the American College of Medical Genetics, 20(11), 1430-1437. https://doi.org/10.1038/gim.2018.30
Chandler N, et al. Rapid Prenatal Diagnosis Using Targeted Exome Sequencing: a Cohort Study to Assess Feasibility and Potential Impact On Prenatal Counseling and Pregnancy Management. Genet Med. 2018;20(11):1430-1437. PubMed PMID: 29595812.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rapid prenatal diagnosis using targeted exome sequencing: a cohort study to assess feasibility and potential impact on prenatal counseling and pregnancy management. AU - Chandler,Natalie, AU - Best,Sunayna, AU - Hayward,Jane, AU - Faravelli,Francesca, AU - Mansour,Sahar, AU - Kivuva,Emma, AU - Tapon,Dagmar, AU - Male,Alison, AU - DeVile,Catherine, AU - Chitty,Lyn S, Y1 - 2018/03/29/ PY - 2017/10/29/received PY - 2018/01/16/accepted PY - 2018/3/30/pubmed PY - 2019/2/14/medline PY - 2018/3/30/entrez KW - exome sequencing KW - fetal skeletal dysplasias KW - pregnancy management KW - prenatal counseling KW - rapid prenatal diagnosis SP - 1430 EP - 1437 JF - Genetics in medicine : official journal of the American College of Medical Genetics JO - Genet Med VL - 20 IS - 11 N2 - PURPOSE: Unexpected fetal abnormalities occur in 2-5% of pregnancies. While traditional cytogenetic and microarray approaches achieve diagnosis in around 40% of cases, lack of diagnosis in others impedes parental counseling, informed decision making, and pregnancy management. Postnatally exome sequencing yields high diagnostic rates, but relies on careful phenotyping to interpret genotype results. Here we used a multidisciplinary approach to explore the utility of rapid fetal exome sequencing for prenatal diagnosis using skeletal dysplasias as an exemplar. METHODS: Parents in pregnancies undergoing invasive testing because of sonographic fetal abnormalities, where multidisciplinary review considered skeletal dysplasia a likely etiology, were consented for exome trio sequencing (both parents and fetus). Variant interpretation focused on a virtual panel of 240 genes known to cause skeletal dysplasias. RESULTS: Definitive molecular diagnosis was made in 13/16 (81%) cases. In some cases, fetal ultrasound findings alone were of sufficient severity for parents to opt for termination. In others, molecular diagnosis informed accurate prediction of outcome, improved parental counseling, and enabled parents to terminate or continue the pregnancy with certainty. CONCLUSION: Trio sequencing with expert multidisciplinary review for case selection and data interpretation yields timely, high diagnostic rates in fetuses presenting with unexpected skeletal abnormalities. This improves parental counseling and pregnancy management. SN - 1530-0366 UR - https://www.unboundmedicine.com/medline/citation/29595812/Rapid_prenatal_diagnosis_using_targeted_exome_sequencing:_a_cohort_study_to_assess_feasibility_and_potential_impact_on_prenatal_counseling_and_pregnancy_management_ L2 - https://doi.org/10.1038/gim.2018.30 DB - PRIME DP - Unbound Medicine ER -