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Impaired sperm production?
Probability of
x
x
‘classical PAE’ mutation
+ Selfish Selection
Milder selfish mutations
x
x
x x
‘Copy-error’ ~10-8
‘classical oncogenic’ mutation
Gain of
Susceptibility variants? Low penetrance variants?
ASD/SCZ? Cancer?
‘classical germline’ variant
~10-8
Contribution to genomic heterogeneity/disease burden?
Public health implications for an ageing reproductive population
years Median age of paternity (England & Wales)
2011: ~ 1/3 of children are born to fathers aged >35 years
Actionable? Unpredictable nature of de novo mutations
* Freeze sperm of young men?? Individual risk is likely to be low ≠ population risk
* Assisted reproduction: age limit on anonymous sperm donation (<40 yrs)
* Early Non-Invasive Prenatal Screening NIPS (cffDNA) can be offered as advanced screening test for de novo mutations associated with PAE disorders (FGFR2/3 NGS panel available)  other genomic locations? will require better understanding of PAE
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Embryonic lethality?
~100-1000x ~2-100x ?
function
transmission to next
generations