Does a Father’s Age Determine a Child’s Risk of Autism?

fertility problems in womenThe causes of autism are quite complicated, as it is determined on a case-by-case basis. Autism is a complex neurodevelopmental disorder that is most commonly associated with problems with communication, social interactions, as well as with repetitive interests and activities. The signs of autism usually develop gradually and are noticed by parents within the first few years of life. What causes autism is debatable, but there is no doubt that the rates of autism have increased dramatically in the last decade. The reason for this increase is a contentious topic but recent scientific research has suggested that paternal age may increase the risk of autism in children. Since paternal age is also steadily increasing in our society, this link may in part explain the increase in the number of children diagnosed with autism.

How common is autism?

The U.S. Center for Disease Control and Prevention estimates that autism affects 1 in 88 children in the United States and that it is more common in boys than in girls, with estimates of 1 in 54 boys. Alarmingly, the rate of autism is 78% higher than it was just 6 years ago and we still aren’t sure why that is. One explanation is that today we are better at diagnosing the causes of autism, even mild cases, and this is surely to be one aspect of it. However, many argue that this is not the whole story and that either our environment or genetics is to blame. It has been suggested that heavy metals, pesticides and even childhood vaccines may be responsible for the increased incidence of autism of late. However, there is no scientific evidence to backup these claims. Autism is known to have a strong genetic correlation but we are only beginning to understand the specific genes involved, and it is estimated that for over 70% of autism spectrum disorder cases, the underlying genetic cause is unknown.

Mutations linked to autism are inherited from fathers

A group of studies published in Nature in 2012 utilized gene sequencing to study the genetic basis of autism [1-3]. They found a striking genetic heterogeneity, with mutations in several hundred genes being linked to autism. Individuals affected with autism tend to have more spontaneous mutations, with one study finding that mutations occurred 40% more frequently in affected individuals than in unaffected siblings [1]. Strikingly, another study found that these mutations are primarily paternal in origin (4:1 bias) and positively correlated with paternal age [2]. However, not all of these mutations are directly connected to autism and those that are associated with an increased risk, are distributed across many genes and are not sufficient to cause disease [3]. These studies were able to point to some genes that are genuine risk factors (SCN2A, CHD8, NTNG1 and KATNAL2) as well as biological pathways for further study (β-catenin chromatin remodeling protein network)[1-3].

Older fathers pass on more mutations

The observations that new mutations are more likely to be paternal and that their number increases with the age of the father were intriguing, and were also supported by a study of an Icelandic population. This study found that the mutation rate is dominated by the age of the father at the time of conception. There is an increase of about 2 mutations per year, with paternal mutations doubling every 16.5 years. An Icelandic child born in 2011 will have on average 70 new mutations compared to 60 mutations for a child born in 1980, with the average age of fatherhood rising from 28 to 33 during that time [4]. The reason fathers pass on more mutations than mothers is due to inherent differences between the formation of eggs and sperm. Women are born with their lifelong supply of eggs, whereas men continually produce sperm, and new mutations may be acquired with each cell division. Most of these mutations are not harmful but the more mutations there are, the more likely that at least some harmful mutations will be present. In fact, the researchers identified some mutations that have previously been linked to an increased risk for autism and schizophrenia [4]. Furthermore, a Swedish study found that not only may older fathers transmit the risk of autism to their children, but they may transmit it to their grandchildren as well [5]. While thus far it is only a correlation and the observed risk is quite small, but if true, it would suggest that the risk for autism builds through generations.

While the general increase in paternal age may be a contributing factor to the increasing prevalence of autism, it is not likely to be the sole factor. Further studies will be required to better understand the genetic mechanisms underlying the causes of autism and to determine how these interact with our environment.


Reference:

1. Sanders, S.J., et al., De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature, 2012. 485(7397): p. 237-41.
2. O’Roak, B.J., et al., Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature, 2012. 485(7397): p. 246-50.
3. Neale, B.M., et al., Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature, 2012. 485(7397): p. 242-5.
4. Kong, A., et al., Rate of de novo mutations and the importance of father’s age to disease risk. Nature, 2012. 488(7412): p. 471-5.
5. Frans, E.M., et al., Autism risk across generations: a population-based study of advancing grandpaternal and paternal age. JAMA Psychiatry, 2013. 70(5): p. 516-21.

What’s next?

If you would like to learn more about autism, continue reading this related blog post: “Exome sequencing of Autism Spectrum Disorders provides insights on possible treatments”.

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