More Evidence Men Pass on Point Mutations etc. As They Age and Cause De Novo Autism

Letter to the Editor
Molecular Psychiatry (2008) 13, 243–244; doi:10.1038/sj.mp.4002102

Do autism-related personality traits explain higher paternal age in autism?
C M Puleo1, A Reichenberg1,2, C J Smith1, L A Kryzak1 and J M Silverman1

1Department of Psychiatry, One Gustave Levy Place, Mount Sinai School of Medicine, New York, NY, USA
2Department of Psychological Medicine, King's College London, Institute of Psychiatry, De Crespigny Park, London, UK




"This null result suggests that genetic autism risk is unrelated to paternal age in familial ASD. While this finding does not preclude a different result in a different sample, if our negative findings reflect the general reality for these families, it would be unexpected to observe a positive result in a sporadic sample and, furthermore, difficult to explain through the genetic mechanism examined here. Rather, these results support our original de novo mutation hypothesis regarding autism risk and paternal age. According to mutagenesis, de novo mutations spontaneously arise and accumulate in successive generations of spermatogonia (sperm-producing cells), increasing the likelihood that men will pass on a point mutation or structural chromosomal abnormality as they age.8, 9 As higher rates of de novo mutations have been implicated in autism cases as compared to controls,10 it is likely that such a mechanism may influence our paternal age finding. BAP traits were no less apparent in the mothers and fathers as age at paternity increased (that is, genetic liability was equivalent); thus it seems probable that the interaction of these mutations with pre-existing autism susceptibility genes may have a cumulative effect, resulting in a genetically distinct and perhaps more easily expressed form of the disorder.

Our sample was primarily composed of parents of affected sibling pairs, and thus may over-represent cases in which autism is, in part, genetically determined. The increased genetic loading likely in these families should make associations between BAP traits and paternal age particularly apparent. That no association was nevertheless found emphasizes the need for further exploration of de novo events and their potential role in paternal age–autism risk association."