Thoughts on RNU4-2 Mutation Paper

A new preprint based on Genomics UK data has identified a set of single base insertion mutations (predominantly a specific A insertion)  in a spliceosomal RNA which is responsible for about 0.5% of previously undiagnosed genetic cases of syndromic neurodevelopmental disorders . That's a remarkably high frequency mutation which has gone unnoticed to date, but the fact it was hiding in a non-protein-coding RNA (a spliceosome component called RNU4-2) had much to do with that - this gene won't be in any exome panels. The mutation always appears to be de novo and therefore the pathogenic phenotype is dominant.   I'd like to write down a few other thoughts - mostly in the form of questions --  with the caveat that I've never worked on a rare disease project and to describe me as a detached armchair voyeur of the field would be far too generous.