Mutations in autism susceptibility gene increase risk in boys

July 12, 2012

Researchers at Emory University School of Medicine have identified five rare mutations in a single gene that appear to increase the chances that a boy will develop an autism spectrum disorder (ASD).

Mutations in the AFF2 gene, and other genes like it on the , may explain why autism spectrum disorders affect four times as many boys as girls.

The mutations in AFF2 appeared in 2.5 percent (5 out of 202) of boys examined. Mutations in X chromosome genes only affect boys, who have one X chromosome. Girls have a second copy of the gene that can compensate.

The results were published July 5 in the journal .

"Our data suggest that AFF2 could be one of the major X-linked risk factors for ASD's," says senior author Michael Zwick, PhD, assistant professor of at Emory University School of Medicine.

The finding bolsters a growing consensus among that rare variants in many different genes contribute significantly to risk for autism spectrum disorders. The mutations in the AFF2 gene probably do not cause ASDs all by themselves, Zwick says.

"We do not think that the variants we have identified are monogenic causes of autism," he says. "Our data does support the idea that this is an autism ."

In some situations, mutations in a single gene are enough by themselves to lead to a with autistic features, such as fragile X syndrome or tuberous sclerosis complex. But these types of mutations are thought to account for a small number of ASD cases.

Recent large-scale of autism spectrum disorders have identified several "rare variants" that sharply increase ASD risk. Scientists believe rare variants could explain up to 15 or 20 percent of ASD cases. However, until now no single variant has been found in more than one percent of ASD cases.

Working with Zwick, postdoctoral fellow Kajari Mondal and her colleagues read the sequence of the AFF2 gene in DNA from 202 boys diagnosed with . The patient samples came from the Autism Genetic Resource Exchange and the Simons Simplex Collection.

Tests showed that in four cases, the affected boys had inherited the risk-conferring mutations from their mothers. One boy had a "de novo" (not coming from the parents) mutation. Compared with X-linked genes in unaffected people, mutations in AFF2 were five times more abundant in the boys with ASDs.

The AFF2 gene had already been identified as responsible for a rare inherited form of intellectual disability with autistic features. This effect is seen when the AFF2 gene is deleted or silenced completely.

AFF2 has some similarity to FMR1, the gene responsible for . Like FMR1, it can be silenced by a triplet repeat. In these cases, the presence of the triplet repeat (three genetic bases repeated dozens of times) triggers a change in chromosomal structure that prevents the gene from being turned on.

In contrast, the mutations Zwick's team found are more subtle, slightly changing the sequence of the protein AFF2 encodes. Little is known about the precise function of the AFF2 protein (more?). A related gene in fruit flies called lilliputian also appears to regulate the development of neurons.

Zwick says one of his laboratory's projects is to learn more about the function of the AFF2 gene, and to probe how the mutations identified by his team affect the function. His team is also working on gauging the extent to which other genes on the X chromosome contribute to autism risk.

Explore further: Mutations in 3 genes linked to autism spectrum disorders

More information: K. Mondal, D. Ramachandran, V.C. Patel, K.R. Hagen, P. Bose, D.J. Cutler and M.E. Zwick. Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder. Hum. Mol. Genet. Advance access. (2012). doi: 10.1093/hmg/dds267

Related Stories

Mutations in 3 genes linked to autism spectrum disorders

April 4, 2012
Mutations in three new genes have been linked to autism, according to new studies including one with investigators at Mount Sinai School of Medicine. All three studies include lead investigators of the Autism Sequencing Consortium ...

Further support for a role of synaptic proteins in autism spectrum disorders

February 9, 2012
A new study combines genetic and neurobiological approaches to confirm that synaptic mutations increase the risk of autism spectrum disorders (ASDs). It also highlights a role for modifier genes in these disorders. Published ...

X marks the spot -- TBL1X gene involved in autism spectrum disorder

November 4, 2011
Autism Spectrum Disorder (ASD) affects about 1 in 100 children resulting in a range of problems in language, communication and understanding other people's emotional cues, all of which can lead to difficulties in social situations. ...

Study explains functional links between autism and genes

June 21, 2012
A pioneering report of genome-wide gene expression in autism spectrum disorders (ASDs) finds genetic changes that help explain why one person has an ASD and another does not. The study, published by Cell Press on June 21 ...

Technology targets genetic disorders linked to X chromosome

October 18, 2011
Geneticists at Emory University School of Medicine have demonstrated a method that enables the routine amplification of all the genes on the X chromosome. The technology allows the rapid and highly accurate sequencing and ...

Recommended for you

Late-breaking mutations may play an important role in autism

July 17, 2017
A study of nearly 6,000 families, combining three genetic sequencing technologies, finds that mutations that occur after conception play an important role in autism. A team led by investigators at Boston Children's Hospital ...

Females with autism show greater difficulty with day-to-day tasks than male counterparts

July 14, 2017
Women and girls with autism may face greater challenges with real world planning, organization and other daily living skills, according to a study published in the journal Autism Research.

Researchers investigate possible link between carnitine deficiency and autism

July 13, 2017
Researchers are always looking for new clues to the causes of autism, with special emphasis on prevention or treatment. At Baylor College of Medicine, Dr. Arthur Beaudet has been following clinical and genetic clues in patients ...

How children look at mom's face is influenced by genetic factors and altered in autism

July 12, 2017
New research has uncovered compelling evidence that genetics plays a major role in how children look at the world and whether they have a preference for gazing at people's eyes and faces or at objects.

Oxytocin improves social abilities in some kids with autism, study finds

July 10, 2017
Children with autism showed improved social behavior when treated with oxytocin, a hormone linked to social abilities, according to a new study by researchers at the Stanford University School of Medicine. Children with low ...

Possible early diagnosis of autism spectrum disorder

June 29, 2017
Measuring a set of proteins in the blood may enable earlier diagnosis of autism spectrum disorder (ASD), according to a study from the Peter O'Donnell Jr. Brain Institute at UT Southwestern Medical Center.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.