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.