The potential implementation into the prenatal diagnostic pathway in England.
A national NHS Genomic Medical Service infrastructure based around seven laboratory hubs across England is in place. It is envisaged that prenatal case selection will be by a multidisciplinary (tertiary) team, led by a clinical geneticist. Phenotype selection is paramount and is likely to focus upon fetuses with: i) multiple anomalies, ii) severe skeletal dysplasia, iii) non-immune hydrops or iv) structural anomalies where there is a strong suspicion of genetic aetiology (i.e. infantile polycystic renal disease; complex CNS anomalies and fetal arthrogryposis/fetal akinesia syndrome). The laboratories charged with providing prenatal ES would use a modified panel of pathologic variants identified in the PAGE study (DD-G2P/PAGE), using a traffic light rating and comprising 90-100 variants that have been chosen after expert review and agreed by NHS Genomic Medical Service sign off (https://panelapp.genomicsengland.co.uk/panels/478/)58. As indicated in early discussion within this review, the clinical infrastructure for delivery of this prenatal service needs to be conservative but robust. The desirable clinical and laboratory infrastructure required will be informed by prospective, NIHR-funded research through the EXPRESS study51. However, it is probable that both phenotypic inclusion, the pathologic variant list and the clinical infrastructure for delivery will remain under continuous review and there is a recognised need for the formal curation of pathologic, probable pathologic and VUS variants matched to detailed phenotyping within a database such asClinVar 39. It is also likely that a strategy for re-testing will be requested as noted to be important in paediatric testing strategies40.