Advanced Paternal Age and Risk of Achondroplasia
Yes, the risk of having a child with achondroplasia is significantly increased with advanced paternal age (≥40 years). 1
Paternal Age Effect on Achondroplasia Risk
Advanced paternal age is a well-established risk factor for achondroplasia due to specific genetic mechanisms:
The American Urological Association (AUA) and American Society for Reproductive Medicine (ASRM) guidelines explicitly state that advanced paternal age increases de novo intra- and inter-genic germline mutations, leading to genetically-mediated conditions including chondrodysplasia (achondroplasia) 1
The mutations causing achondroplasia occur almost exclusively on the paternally derived chromosome 2
Approximately 97% of achondroplasia cases are caused by specific mutations (G1138A and G1138C) in the fibroblast growth factor receptor 3 (FGFR3) gene 2
In sporadic (non-familial) cases, which represent more than 90% of all achondroplasia cases, the mutation occurs during spermatogenesis 3
Magnitude of Risk Increase
The risk increase with paternal age is substantial:
Fathers older than 34 years have a significantly higher risk of having infants with de novo achondroplasia compared to younger fathers 4
Approximately 50% of achondroplasia cases are born to fathers above age 35 years 5
The increase in relative incidence with paternal age follows an exponential curve 5
The AUA/ASRM guidelines note that while the relative risk is high, the absolute risk remains low 1
Clinical Implications
For healthcare providers counseling patients:
Genetic counseling should be considered for couples with advanced paternal age (≥40) to discuss the increased risk of achondroplasia and other genetic conditions in offspring 1
Clinicians should explicitly advise couples with advanced paternal age that there is an increased risk of adverse health outcomes for their offspring 1
The risk discussion should emphasize that while the relative risk increases significantly with paternal age, the absolute risk remains low 1
Biological Mechanism
The paternal age effect is attributed to:
Lifelong spermatogonial stem cell divisions unique to male germ cell production 6
Factors influencing DNA replication or repair during spermatogenesis that may predispose to the occurrence of FGFR3 mutations 2
Possible selection for sperm carrying the mutation or age-dependent increase in unrepaired premutagenic lesions 6
This paternal age effect is particularly pronounced for achondroplasia compared to some other genetic conditions, likely due to the specific location and nature of the FGFR3 gene mutation.