A couple has a child with achondroplasia. Both parents have normal height and are clinically normal and neither has a family history of achondroplasia.
What is the probable explanation for achondroplasia in their child?
All achondroplastic individuals are heterozygous for exactly the same missense change, the replacement of glycine 380 by arginine in fibroblast growth factor receptor 3. More than 80% of these individuals have a de novo mutation. Such de novo mutations occur exclusively in the father’s germline and increase in frequency with advanced paternal age (>35 years).
What is the risk of recurrence in other children of this couple?
For unaffected parents with a child affected with achondroplasia, the risk for recurrence in their future children is low but probably higher than for the general population because mosaicism involving the germline, although extremely rare in achondroplasia, has been documented.
If the husband has another child by a different mother, what would the risk of achondroplasia be in that child?
The risk would be significantly lower since his first child’s case was a de novo mutation, however, more data would be needed to calculate the specific risk, especially if the father has germline mosaicism.
What is the risk that any offspring of the affected child will also have achondroplasia?
Since achondroplasia is an autosomal dominant disorder with full penetrance, in the case of their affected offspring, if they have a partner without the condition, the risk for recurrence in each child is 50%. However, if they end up having a partner who is also affected, each child they would have has a 50% risk for having achondroplasia, a 25% risk for having lethal homozygous achondroplasia, and a 25% chance of being of average stature.
Excerpts from Thompson & Thompson Genetics in Medicine (Nussbaum) and New Clinical Genetics (Read, Donnai)