File:Impact of germline vs postzygotic mutations.jpg

English: (A) Germline mutations are present in the parental gametes (sperm and/or egg) and in all cells of the future embryo. For an autosomal dominant disorder, as illustrated here with bilateral lower limb lymphedema, the mutation will have happened in either the sperm or the egg whilst the other parental gamete does not harbor the germline mutation. If the mutation happened in e.g. RAF1 this would lead to Noonan syndrome, a RASopathy, for which some of the presenting features include webbed neck, low set ears and primary lymphedema of the lower limbs. (B-C) Sometimes the parental gametes do not harbor any disease-causing mutations, but a mutation can occur during fetal development or any time after birth in any cell of the body. The postzygotic mutation will happen in a single cell, but as all its daughter cells will also carry the mutation, the severity of the phenotype depends on the timing of the postzygotic mutation and which tissue has been affected. If the postzygotic mutational event happened early during embryonic development in e.g. PIK3CA it could lead to a severe overgrowth syndrome such as PIK3CA-Related Overgrowth Syndrome (PROS), which is asymmetrical and severely affecting much of the lower body in the case illustrated in B. If the postzygotic mutation happened later or after birth it could lead to a more localized problem, which is exemplified by a localized lymphatic malformation in the left upper arm as illustrated in C. If none of the postzygotic mutations happened in cells of the germline, they are not passed on to successive generations. (D) Postzygotic mutations in the PI3K/AKT/mTOR and RAS/MAPK signaling pathways have been associated with lymphatic malformations and/or primary lymphedema. The signaling cascades activated downstream of receptor tyrosine kinases corresponding to both pathways are depicted in the simplified diagram, together with the genes associated with mosaic disorders such as PROS (PI3K/AKT/mTOR). Disorders collectively named as RASopathies are caused by germline mutations in RAS/MAPK pathway genes, and it has been shown that mosaic mutations in some of the same genes can cause a mosaic disorder including a lymphatic phenotype.