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Effect of paternal age seen in girls with autism

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Sarah DeWeerdt
19 January 2012

Daddy’s girl: Girls with autism who have older fathers hint at the potential role of new mutations in the disorder.

Children with autism who have older fathers — with an average age of 41 — are more likely than those with younger fathers to be the only child with autism in their family, according to a new study1. The finding is especially striking for girls with older fathers, who are more than six times as likely as those with younger fathers to show this effect.

The results, published online 16 December in Autism, bolster the hypothesis that de novo, or non-inherited, mutations that accumulate in a man’s sperm cells as he ages may increase the risk of autism in his children.

“It suggests that girls with autism whose fathers are older are especially likely to have a disorder that is owing to some de novo event,” says lead investigator Jeremy Silverman, professor of psychiatry at Mount Sinai School of Medicine in New York.

The findings emphasize the importance of including girls in studies of the disorder, even though they are less likely to be affected than boys are.

“This is refocusing the attention on the females, and putting forth a potential model that makes a lot of sense,” says Rita Cantor, professor of human genetics at the University of California, Los Angeles, who was not involved in the work.

About four times more boys than girls have autism. However, this skewed sex ratio narrows among children with older fathers2, suggesting that some mechanism that affects boys and girls more equally may be at play in this group.

What’s more, researchers have found that people with sporadic autism — those who don’t have a family history of the disorder — have more de novo copy number variations (CNVs) than people with autism that runs in families or healthy individuals3. CNVs are a type of mutation in which chunks of genetic material are duplicated or deleted.

“There had been hints at this [study’s findings] in different ways,” Silverman says. “In some ways, we were just trying to put this stuff together.”

Separating simplex:

In the new study, Silverman and his colleagues analyzed data on 677 children with autism from 340 families enrolled in autism studies at Mount Sinai. “[Recruitment] took place before we were interested in paternal or maternal ages,” Silverman notes, “and so we feel pretty confident that there was no inherent bias” toward older parents.

Of these families, 90 are simplex families, meaning they have one child with autism, but unaffected parents and siblings. The remainder are multiplex families, in which at least two children are affected by the disorder.

The researchers divided the children into four groups based on the age of their fathers. They found that children with autism who have the oldest fathers, with an average age of 41 when their children were born, are more likely to be part of simplex families compared with those born to the youngest fathers, with an average age of 27.5 years.

As grouped, the youngest fathers of girls with autism were between 22 and 30 years old, and the youngest fathers of boys were between 20 and 29. The oldest fathers of girls were between 38 and 52, and the oldest fathers of boys between 37 and 62. But, notes Silverman, “the results could not be attributed to a few outliers — that is, to a few fathers with especially high ages.”

To the researchers’ surprise, though, the link between older paternal age and simplex families is much more pronounced in girls. Boys in the study who have the oldest fathers are one-and-a-half times as likely to be from a simplex family compared with boys who have the youngest fathers. By contrast, girls with autism and the oldest fathers are over six times more likely to belong to a simplex family compared with girls who have the youngest fathers. 

“Simplex girls are really driving that relationship,” Silverman says.

That’s consistent with the idea that new mutations can accumulate in the sperm of men as they age, increasing the risk of autism in their daughters, even when there’s no family history of the disorder.

The findings don’t preclude de novo mutations from also contributing to autism in boys. A link between paternal age and simplex autism may simply be harder to pick up in boys because there are more boys with the disorder, and a greater diversity of causative factors, Silverman suggests.

Common characteristics:

The study is small and must be validated in a larger sample, experts caution. “They only have 14 [girls with simplex autism] that establish this, which in the statistical world is quite small,” Cantor says.

Experts also note that while the results support a role for de novo mutations, they don’t rule out other possibilities. “Other things happen as men age, and those could be explanatory for their findings,” says Lisa Croen, director of the Autism Research Program at the health insurer Kaiser Permanente Northern California in Oakland, California, who was not involved in the study.

Other age-related factors could include environmental exposures or epigenetic changes, which affect gene expression without altering the underlying sequence.

Data from some large studies that collect genetic material and information on environmental exposures, such as the ongoing Study to Explore Early Development, could help confirm the new results, notes Croen.

Silverman plans to investigate whether there are other characteristics common to girls with simplex autism who have older fathers, such as the pattern or severity of their symptoms.

Last year, researchers led by Dolores Malaspina found that women with schizophrenia who have older fathers and no family history of the disease have more severe symptoms compared with other women who have schizophrenia4. The risk of schizophrenia, like that of autism, is greater in males and in children of older men.

Silverman says his team’s findings help point autism researchers toward the subpopulations that may be most useful for their studies. For example, those wanting to understand the role of de novo mutations in autism might want to focus on simplex girls with older fathers. Those interested in how autism susceptibility is transmitted down the generations might want to avoid that population.

References:

1: Puleo C.M. et al. Autism (2011) (Epub ahead of print) PubMed

2: Anello A. et al. J. Autism Dev. Disord. 39, 1487-1492 (2009) PubMed

3: Sebat J. et al. Science 316, 445-449 (2007) PubMed

 4: Rosenfield P.J. et al. Schizophr. Res. 116, 191-195 (2010) PubMed

Comments

Name: MNeely
20 January 2012 - 10:17PM

I have two daughters with autism; their father was 33 when the oldest was conceived and 34 when the younger was conceived. He's not "old" by this study's measure, but he is the youngest child in his family and he had old parents (mom was 45 when he was born and dad was 48). I've often wondered if and how my husband's genes were affected by having older parents.

Name: nustita
26 January 2012 - 3:23PM

So... this all makes me wonder what the actual risk is that an older man will father a child with autism. We know that the odds are worse than for a younger man, but what does that mean? Are the changes 1 in 1000? 1 in 100?
This is the key question for those of us with cute, but older, baby daddies.

Name: Jeremy Silverman & Abraham Reichenberg
3 February 2012 - 7:23PM

A recent study in Sweden [1] suggests that the rate for fathers above 55 may be 4 to 5 times as great as for fathers in their 30s. If the overall prevalence of autism is estimated at 1 in 100, this suggests a rate of about 5% for very elderly fathers.

1. Hultman CM, Sandin S, Levine SZ, Lichtenstein P, Reichenberg A. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol Psychiatry. 2011 Dec;16(12):1203-12

Name: RAJensen
10 February 2012 - 10:52AM

Evolutionary biologists are beginning to disentangle the underlying etiology of de novo mutations in humans. Molina et al (2011) studied sperm mutations in 10 healthy male volunteer donors focusing on three mutations identified in individuals with a genetic syndrome that also have high ASD risk. The three sperm mutations (deletions and duplications) that were specifically examined for in healthy donors were: 7q11.23 (Williams syndrome), 15q11-13 (Prader-Willi syndrome), and 22q11 (Di George/velo-cardio-facial syndrome) and most genetic and epigenetic cases of Williams syndrome, Prader-Willi syndrome and 22q11 deletion syndrome are caused by de novo mutations in contrast to being inherited events. All three sperm mutations (deletions and duplications) in all three regions were found in the sperm of all the volunteer donors (Beaudet 2008).

Name: RAJensen
10 February 2012 - 10:55AM

Several studies have been published in the field of evolutionary biology have tested the hypothesis that advancing age may be associated with increased frequency of sperm mutations in healthy volunteer donors. Bosch et al (2003) did indeed find that the frequency of chromosome 9 sperm mutations was found in all healthy donors segregated by age groups and does increase with advancing age. Sloter et al (2007) found that structural aberrations in chromosome 1 was present in the sperm of all volunteer donors and the frequency of sperm mutations significantly increased with advancing age. Klinefelter Syndrome is one of the most common mutations affecting 1 in 500-1,000 boys. The Klinefelter mutation is caused by a de novo mutation and is not inherited. Klinfelter Syndrome is associated with autism and may involve the neurexin–neuroligin genes (Bishop & Scerif 2011). Lowe et al (2001) examined the sperm of 38 fathers of Klinefelter boys and found the frequency of the XY sperm mutation is increased with advancing paternal age.

Name: RAJensen
10 February 2012 - 10:57AM

An important study was published a few months ago that examined the frequency of sperm mutations in workers at a benzene manufacturing plant in China. The study recruited 30 workers who had worked at the benzene manufacturing plant for more than a year and divided the workers into three groups, a low exposure group, a moderate exposure group and a high exposure group. The study included a control group of 11 unexposed workers from the same town.

Every participant in all four groups was found to have de novo sperm mutations including 1p36 sperm mutations. The frequency of the sperm mutations was lowest, but present, in the unexposed group, higher in the low exposed group, higher still in the moderate exposed group and highest in the high exposed group. The 1p36 deletion syndrome is present in 1 in 5,000 to 10,000 newborns:

http://ghr.nlm.nih.gov/condition/1p36-deletion-syndrome

The 1p36 deletion syndrome is also associated with co-occurring autism:

http://174.79.186.155/GeneDetail/MTHFR

This is the first study that has demonstrated a direct connection between a specific de novo sperm mutation (1p36 deletion), a specific severe genetic syndrome (1p36 deletion syndrome) and a specific environmental pathogen (benzene).
The CHARGE group published a study a year ago that found that living in close proximity (<309m) to heavily congested freeways in California was associated with increased risk for autism. Benzene, because of its high octane number, is an important component in the production of refined gasoline and diesel fuels and one has to consider the possibility that at least some of these cases might be related to de novo sperm mutations associated with long-lasting high exposure to benzene particles and other air borne environmental pathogens.

Name: RAJensen
10 February 2012 - 10:59AM

Partfour

REFERENCES

Beaudet (2008). Allan Award Lecture: Rare Patients Leading to Epigenetics and Back to Genetics. Am J Hum Genetics May 9: 82-(5):1034-1038.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2427262/

Bishop & Scerif (2011). Klinefelter syndrome as a window on the aetiology of language and communication impairments in children: the neuroligin–neurexin hypothesis. Acta Pediatr. 2011 June 100(6):903-907.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107947/

Bosch et al (2003). Linear increase of structural and numerical chromosome 9 abnormalities in human sperm regarding age. European Journal of Human Genetics (2003) 11, 754–759. doi:10.1038/sj.ejhg.5201049
http://www.ncbi.nlm.nih.gov/pubmed/14512965

Lowe et al (2001). Frequency of XY Sperm Increases with Age in Fathers of Boys with Klinefelter Syndrome. American Journal of Human Genetics 69(5) Nov 2001 1046-1054.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1274351/?tool=pubmed

Marchetti F, Eskanazi B, Weldon RH et al (2011). Occupational exposure to benzene and chromosomal structural aberrations in the sperm of Chinese men. Environ Health Perspect
Doi:10.1289/ehp.1103921.
http://ehp03.niehs.nih.gov/article/info:doi/10.1289/ehp.1103921

Molina et al (2011). Sperm rates of 7q11.23, 15q11q13 and 22q11.2 deletions and duplications: a FISH approach. Hum Genet. 2011 Jan;129(1):35-44. Epub 2010 Oct 8.
http://www.ncbi.nlm.nih.gov/pubmed/20931230

Sloter ED et al (2007). Frequency of human sperm carrying structural aberrations of chromosome 1 increases with advancing age. Fertil Steril. 2007 May;87(5):1077-86. Epub 2007 Apr 11.
http://www.ncbi.nlm.nih.gov/pubmed/17433321

Volk HE, Hertz-Picciotto I et al (2010). Residential proximity to freeways and autism in the CHARGE study. Environ Health Perspect 119(6):
Doi:10.1289/ehp.1002835 full text available at:
http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1002835

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