ESPEYB16 14. Year in Science and Medicine 2019 (1) (18 abstracts)
14.14. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study
Lord J , McMullan DJ , Eberhardt RY , Rinck G , Hamilton SJ , Quinlan-Jones E , Prigmore E , Keelagher R , Best SK , Carey GK , Mellis R , Robart S , Berry IR , Chandler KE , Cilliers D , Cresswell L , Edwards SL , Gardiner C , Henderson A , Holden ST , Homfray T , Lester T , Lewis RA , Newbury-Ecob R , Prescott K , Quarrell OW , Ramsden SC , Roberts E , Tapon D , Tooley MJ , Vasudevan PC , Weber AP , Wellesley DG , Westwood P , White H , Parker M , Williams D , Jenkins L , Scott RH , Kilby MD , Chitty LS , Hurles ME & Maher ER
Prenatal Assessment of Genomic Exomes Consortium, Department of Medical Genetics, University of Cambridge, Cambridge, UK; Cambridge Biomedical Research Centre, National Institute for Health Research, Cambridge, UK. erm1000@medschl.cam.ac.uk
To read the full abstract: Lancet 2019;393:747–757. .
This large prospective cohort study recruited from 34 UK fetal medicine units to evaluate the use of prenatal whole genome sequencing in 610 fetuses with a structural abnormality detected on antenatal ultrasound scanning and no chromosomal abnormality. Overall, a diagnostic genetic mutation was identified in 8.5% of fetuses, and more commonly in those fetuses with multisystem anomalies (15.4%), skeletal anomalies (15.4%), or cardiac anomalies (11.1%). The lowest yield, only 3.2%, was in fetuses with isolated increased nuchal translucency in the first trimester.
Currently, when a structural abnormality is found on antenatal ultrasound, it is routine practice to offer testing of fetal DNA, obtained from chorionic villi, amniotic fluid, or fetal blood, for chromosomal aneuploidy and other copy number variants. The current study collected DNA samples left over from those routine tests and showed that whole genome sequencing adds significantly to the yield of genetic diagnoses. However, the overall detection rate here (8.5%) is much lower than that reported elsewhere for genome sequencing of children with neuro-developmental disorders and other undiagnosed postnatal disease (30–40%).
Furthermore, the use antenatal genetic testing throws up specific ethical issues. None of the genetic diagnoses would have led to a prenatal treatment, and would have only rarely enabled better postnatal management. Instead, if the genetic information had been given in real-time, it could have negatively affected decisions to proceed with the pregnancy – two-thirds of diagnostic genetic variants were additionally associated with learning disabilities.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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