Natalie Chandler1, Sunayna Best1, Jane Hayward1, Francesca Faravelli1, Sahar Mansour2, Emma Kivuva3, Dagmar Tapon4, Alison Male1, Catherine DeVile5, Lyn S Chitty6,7. 1. North Thames NHS Regional Genetics Service, Great Ormond Street NHS Foundation Trust, London, UK. 2. South West Thames Regional Genetics Department, University of London & St George's University Hospitals NHS Foundation Trust, London, UK. 3. Peninsula Clinical Genetics, Royal Devon & Exeter NHS Foundation Trust, Royal Devon & Exeter Hospital, Exeter, UK. 4. Queen Charlotte's & Chelsea Hospital, Imperial College Healthcare NHS Trust, London, UK. 5. Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK. 6. North Thames NHS Regional Genetics Service, Great Ormond Street NHS Foundation Trust, London, UK. l.chitty@ucl.ac.uk. 7. Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK. l.chitty@ucl.ac.uk.
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.
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: Jenny Lord; Dominic J McMullan; Ruth Y Eberhardt; Gabriele Rinck; Susan J Hamilton; Elizabeth Quinlan-Jones; Elena Prigmore; Rebecca Keelagher; Sunayna K Best; Georgina K Carey; Rhiannon Mellis; Sarah Robart; Ian R Berry; Kate E Chandler; Deirdre Cilliers; Lara Cresswell; Sandra L Edwards; Carol Gardiner; Alex Henderson; Simon T Holden; Tessa Homfray; Tracy Lester; Rebecca A Lewis; Ruth Newbury-Ecob; Katrina Prescott; Oliver W Quarrell; Simon C Ramsden; Eileen Roberts; Dagmar Tapon; Madeleine J Tooley; Pradeep C Vasudevan; Astrid P Weber; Diana G Wellesley; Paul Westwood; Helen White; Michael Parker; Denise Williams; Lucy Jenkins; Richard H Scott; Mark D Kilby; Lyn S Chitty; Matthew E Hurles; Eamonn R Maher Journal: Lancet Date: 2019-01-31 Impact factor: 202.731
Authors: Zöe Powis; Kelly D Farwell Hagman; Kirsten Blanco; Margaret Au; John M Graham; Kathryn Singh; Natalie Gallant; Linda M Randolph; Meghan Towne; Jesse Hunter; Deepali N Shinde; Erika Palmaer; Brian Schoenfeld; Sha Tang Journal: Mol Genet Genomic Med Date: 2019-12-24 Impact factor: 2.183
Authors: Chantal Deden; Kornelia Neveling; Dimitra Zafeiropopoulou; Christian Gilissen; Rolph Pfundt; Tuula Rinne; Nicole de Leeuw; Brigitte Faas; Thatjana Gardeitchik; Suzanne C E H Sallevelt; Aimee Paulussen; Servi J C Stevens; Esther Sikkel; Mariet W Elting; Merel C van Maarle; Karin E M Diderich; Nicole Corsten-Janssen; Klaske D Lichtenbelt; Guus Lachmeijer; Lisenka E L M Vissers; Helger G Yntema; Marcel Nelen; Ilse Feenstra; Wendy A G van Zelst-Stams Journal: Prenat Diagn Date: 2020-05-05 Impact factor: 3.050