This review will inform the UK NSC in their approach to evaluating WGS for newborn screening. The learning from this review is that a traditional review will unlikely be an effective approach for the evaluation of 200 conditions. We propose an alternative pragmatic approach focusing on first addressing the evidence for penetrance in the screening context for variants identified as actionable by current genomics projects like the Generation Study, a critical question with implications for screening benefits and harms for which appropriate quality evidence is currently not available. Penetrance may be defined differently for different conditions. A biochemical confirmatory test may be sufficient for some conditions to estimate penetrance if the link between biochemical and clinical disease is well understood and strong; for others, a follow-up test may not be sufficiently predictive of clinical disease, and, for those conditions without an available confirmatory test, follow-up to clinical symptoms is essential. Where there is good quality evidence for high penetrance, the evidence synthesis could be expanded to other questions relevant to the benefits and harms of screening.
The review may also prompt the UK NSC to discuss evidence requirements for decisions on screening programs for rare and ultra-rare genetic conditions. This will be useful as it will re-focus the discussion on evidence in relation to WGS for newborn sequencing.