The role of genomics in investigating ultrasound identified fetal structural anomalies

Abstract

Ultrasound-detected structural anomalies have an impact on fetal mortality and morbidity. Prenatal Exome Sequencing is incorporated into clinical care pathways for paediatric populations but maybe used to delineate the prognosis of fetal structural anomalies. This paper reviews the literature defining the clinical utility of prenatal ES and discusses the potential promise and challenges for implementation of this technology into clinical practice. Prospective case selection with accurate and informative pre-test counselling by multidisciplinary, clinical genetic-led teams is imperative. Robust, regulated laboratory sequencing, informative bioinformatic pathways with variant identification and conservative matching with the phenotype (within clinical review panels) is also important.Existing prospective, prenatal exome sequencing studies.The majority of studies describing the use of prenatal exome sequencing are small, retrospective case series. An informative systematic review including data from peer reviewed published papers, published retrospective cohort series and published conference abstracts, (containing at least five cases) has been published by Chitty's group 9 . There were sixteen 'citations' which contained a range of inclusion criteria of babies with a structural anomaly were examined (including those associated with miscarriage, perinatal mortalityand termination of pregnancy). There were a range of isolated structural abnormalities , fetuses with multiple fetal abnormalities and those with an increased first trimester nuchal translucency (NT)(>3.5mm). Many reported fetus only)ES testing whilst others included 'trio testing' (fetus, mother and father), a method proven to increase diagnostic rate 10 . These papers reported a diagnostic rate that ranged from 6.2% 11 to 80% 12 . across sixteen studies [13][14][15][16][17][18][19][20][21][22][23][24][25][26] . However last year, two relatively large prospective -recruited cohort studies (from the United Kingdom and North America), targeting ES in fetuses with "unselected ultrasound" detected structural anomalies, were published in the Lancet, in early 2019 27,28 . A total 844 fetal probands (as eligible consented trios; when QF PCR and CMA was normal) were studied. In 76 probands (9%), a causative pathologic genetic variant was identified.The largest of these was the, Prenatal Assessment of Genomes and Exomes (PAGE) study which performed ES on 610 trios in cases of identified a fetal anomaly and CMA was negative. Overall, ES provided an additional 8.5% diagnostic yield of pathogenic variants compared with conventional genetic testing. In addition to pathogenic variants considered to directly cause the relevant fetal structural anomaly, variants of uncertain significance (VUS) and of potential clinical relevance were diagnosed in a further 4% of cases 27 . The second prospective prenatal series conducted by Columbia University reported an additional diagnostic yield of 10.3% (in 234 trios) 28 . Both these studies gave diagnostic yields that were part low...