Mutations go up with paternal age. Generally, the increase is nearly linear with age, but a few increase far more rapidly. In those cases, a special mechanism is involved.
One of those cases is Apert syndrome, a nasty congenital disorder characterized by skeletal malformations (skull, face, hands , and feet). It’s rare, hitting about 1 in 100,000 kids.
It’s an autosomal dominant, caused by mutations in the FGFR2 gene (fibroblast growth factor receptor 2) . Oddly enough, almost all cases are caused by two particular mutations of the FGFR2 gene, either the S252W mutation or the P253R mutation. Which means that it ought to be far rarer than it actually is. The per-generation mutation rate per nucleotide is about 1 x 10-8, so with two possible sites, you’d expect to see a frequency of about 1 in fifty million. It’s 500 times more common than it should be.
You’re more likely to have heard of achondroplasia, standard dwarfism. It’s caused by mutations of the FGFR3 gene. Almost all cases are caused by a single mutation, a G-to-A transition at nucleotide 1138 that results ion a substitution of arginine for a glycine.. It’s not common – roughly 1 in 20,000 births – but it ought to be more like one in 100 million. Five thousand times more common that it ought to be.
The fact that these two genetic diseases are caused by two closely related genes, FGFR2 and FGFR3 is no coincidence.
Here’s what seems to be happening: you have cells in the testes that reproduce, producing one daughter cell like the parent and one that develops into a sperm cell. That’s the way it’s supposed to be. But carrying certain very specific mutations of FGFR2 or FGFR3 seem to cause occasional divisions that result in two daughter cells – so the pre-sperm cells that carry such mutations gradually become more and more common in the testes and produce a growing fraction of sperm with those mutations. It’s rather like cancer. You get clumps of cells producing the bad sperm.
Same things is happening with MEN2B (RET gene), which is also more common than it should be, although not as much so as achondroplasia.
Without this unusual mutational mechanism, there would be a shortage of dwarfs.