Fig. 1.

Timing of de novo mutations. a De novo mutations (DNMs) can occur at any point prior or during development of the embryo, potentially resulting in mosaicism. The most common form of DNM (left) occurs in the parental gametes and is constitutive in the child. A postzygotic (PZM) DNM in the parent (middle) results in mosaicism across multiple parent tissues and a constitutively inherited variant in the child when the parental gametes are affected. A PZM DNM in the child (right) is not present in any parental tissue but is mosaic in the child. b Sibling recurrence risk varies with timing of PZM, from very low in child-PZM, to medium in parent-PZM, to high (50%) in affected parents with constitutive pathogenic variants. Different types of mosaic variants can be misclassified by standard variant callers, resulting in erroneous risk estimation or missed diagnoses