From the Guidelines
Advanced paternal age is associated with an increased risk of autism in offspring, and men over 40 have a higher risk of having a child with autism compared to younger men. As men age, their sperm accumulates more genetic mutations and DNA damage, which can contribute to neurodevelopmental disorders like autism in children 1. The link between older men and spermatozoa with autism is thought to be related to de novo (new) mutations that occur during sperm production, which becomes less efficient with age. Some key points to consider include:
- Advanced paternal age increases de novo intra- and inter-genic germline mutations, sperm aneuploidy, structural chromosomal aberrations, sperm DNA fragmentation, birth defects, and genetically-mediated conditions (eg, chondrodysplasia, schizophrenia, autism) in the offspring 1
- Genetic counseling may be considered for couples with advanced paternal age to discuss the low absolute risk (but high relative risk) of increased paternal age on at least certain genetic risks in their offspring, including de novo gene mutations as well as multiple medical conditions including schizophrenia and autism 1
- While advanced paternal age is just one risk factor among many for autism, and most children born to older fathers do not develop autism, this association highlights the importance of considering paternal age when evaluating reproductive risks. Some of the key factors that contribute to this risk include:
- De novo mutations that occur during sperm production
- Epigenetic changes in older men's sperm that may alter gene expression patterns in offspring
- Increased sperm DNA fragmentation and aneuploidy with age.
From the Research
Link between Older Men and Spermatozoa with Autism
- The relationship between advancing paternal age and the risk of autism spectrum disorder (ASD) in offspring has been investigated in several studies 2, 3.
- A study published in 2006 found a significant monotonic association between advancing paternal age and risk of ASD, with offspring of men 40 years or older being 5.75 times more likely to have ASD compared to offspring of men younger than 30 years 2.
- Another study published in 2011 found that autism risk increased monotonically with increasing paternal age, with offspring of men aged 50 years or older being 2.2 times more likely to have autism than offspring of men aged 29 years or younger 3.
- The potential biological mechanisms underlying this association include de novo mutations associated with advancing age or alterations in genetic imprinting 2, 3.
- A study published in 2020 found that quantification of male sperm mosaicism can stratify autism spectrum disorders recurrence risk due to de novo mutations, and identified novel mosaic variants at risk for transmission to a future offspring 4.
- Another study published in 2021 identified a DNA methylation signature in sperm as a potential biomarker to identify paternal offspring autism susceptibility, with a validation accuracy of approximately 90% 5.
Spermatozoa and Autism
- Sperm DNA methylation epimutation has been correlated with ASD, and a study found a highly significant set of 805 differential DNA methylation regions (DMRs) in sperm that can potentially act as a biomarker for paternal offspring autism susceptibility 5.
- Sperm DNA fragmentation (SDF) has been implicated in male infertility and adverse reproductive outcomes, but its relationship to autism is not well established 6.
- Further research is needed to fully understand the link between older men, spermatozoa, and autism, and to develop effective biomarkers for paternal offspring autism susceptibility 4, 5.