When it doesn’t run in a family, is there any understanding of when the mutation occurs? Is it always pre-fertilisation or is there evidence that it can happen during development and then you get mosaicism?

Mosaicism has been recorded for RAS-MAPK pathway disorders but it is thought to be exceptionally rare, and where there is an enrichment for the spontaneous mutation is in the spermatogenesis where sperm are turning over all the time, there’s lots of cell division, there’s lots of DNA copying that needs to happen and therefore there’s a much greater chance that it happens in the sperm generation as opposed to the eggs that just sit there and don’t have to do lots of dividing. So, the evidence is that over 90% of new mutations will be of sperm origin. There are also emerging studies on older fathers whose sperm generating cells have had more cell divisions having a higher chance in actuarial terms, going from one in an extremely large number to one in a slightly less extremely large number as the decades pass. There is a study that’s just staring in Oxford looking at the origin of mutations which might be relevant in the future to understand that further.