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Study clarifies link between 15q duplication and autism

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Virginia Hughes
4 April 2013

Face facts: Children who carry one extra copy of 15q11-13 tend to have short noses and full cheeks.

Children who carry an extra copy of the 15q11-13 region of the genome usually have autism and sleep troubles, as well as distinctive brain-wave patterns and facial features, according to a report published 14 March in Autism Research1.

The study is the largest to date characterizing the effects of a rare type of duplication in this region. This large chromosomal region, dubbed '15q,' is the most common site for autism-related DNA deletions and duplications.

It's also famous for its complexity: Losing 15q on the maternal chromosome leads to Angelman syndrome, with developmental delay, seizures and a happy demeanor. Deletion of the paternal copy causes Prader-Willi syndrome, characterized by intellectual disability and obesity.

Carrying duplications in the region is a strong risk factor for autism. These duplications come in two types. Most common is 'isodicentric,' which stems from an extra chromosome and leads to two extra copies of 15q. The new study focuses on the rarer type, called 'interstitial' duplication, which occurs within a chromosome and results in just one extra copy of the region.

Children carrying interstitial duplications tend to have milder symptoms than those with isodicentric duplications, making it all the more difficult to find them.

Larry Reiter and his colleagues at the University of Tennessee Health Science Center evaluated 14 children aged 3 to 16 with interstitial duplications, making the study the largest published sample of this genetic abnormality. Previous reports were case studies of just one or two children.

"It’s important because this is a disorder that hasn’t been that well characterized," says Janine LaSalle, professor of medical microbiology and immunology at the University of California, Davis, who was not involved in the study. Still, she says, the findings leave unanswered many questions about the complex syndrome.

"It helps clear some things up, but it's not the easiest genetic disorder to study," LaSalle says. "We want it to be simple, but it's not."

Maternal link:

Reiter's team recruited the children from across the country and performed all of the clinical tests in Tennessee. These included a genetic screen, two standard diagnostic tests — the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R) — and an electroencephalogram (EEG), which uses electrodes on the scalp to measure brain waves.

For ten of the children, the duplication came from their mothers. Nine of these children have autism and one was not tested.

The fact that at least nine of the ten children with maternal duplications have autism "is huge," says Reiter, associate professor of neurology at the University of Tennessee.

One reason that's striking is because most deletions and duplications linked to autism have partial penetrance, meaning they sometimes lead to the disorder and sometimes don't.

Given the new results, "I can’t think of a more penetrant cause of autism," says Ed Cook, professor of psychiatry at the University of Illinois at Chicago, who was not involved in the study. Even if 15q's penetrance doesn't turn out to be 100 percent, Cook adds, "it's quite a bit higher than anything else that I’ve seen in the literature."

Another reason the maternal duplications are interesting is because of a gene in the 15q region called UBE3A. Mice carrying duplications of this gene alone show several autism-like behaviors.

This gene is paternally imprinted, meaning that the paternal copy is silenced. If UBE3A were the primary cause of autism symptoms in the 15q duplication syndrome, you would expect it to affect only the children whose duplication came from their mother.

It's not quite that simple, however.

Of the four children in the study whose duplication came from their father, two have autism and two do not. Because of the small numbers, "we can't quite get a handle on the paternals yet," Reiter says.

It may be that epigenetic influences, which affect the expression of genes without changing the underlying DNA code, are somehow un-silencing the paternal copy of UBE3A. "My guess is there's an epigenetic explanation," LaSalle says.

LaSalle's lab has focused on chromatin, which includes the proteins that help package DNA in the nucleus, in this region. "There's bizarre chromatic dynamics going on where the maternal and paternal chromosomes seem to communicate with each other," she says. "Having too many partners in the dance seems to alter the whole locus."

It may also be that one or more of the two dozen genes in the 15q region are driving the autism symptoms.

For example, the region holds several genes that code for parts of the gamma-aminobutyric acid (GABA) receptor, a protein that helps dampen brain signals. Some studies have identified people with autism who carry rare genetic variants in these GABA genes.

The EEG results also implicate GABA. Of the 14 children in the study, 10 show a distinctive pattern in their EEGs: spikes of so-called 'beta' brain waves, which move at 18 to 22 cycles per second. The same pattern is seen in the brains of children who are taking benzodiazepines, drugs that activate GABA receptors in the brain.

The unusual EEG patterns may be caused by the over-expression of the GABA-related genes in the 15q region, notes Gregory Barnes, director of the pediatric epilepsy monitoring unit at Vanderbilt University in Nashville, Tennessee. But it may also be a result of excess UBE3A or other genes in the region, he says.

Last year, Barnes and his colleagues reported that children with Angelman syndrome show a variety of abnormal EEG patterns, though they did not observe excess beta waves2.

Reiter says he plans to continue to study children with interstitial duplications. He aims to scan their brains using magnetoencephalography, or MEG, and investigate whether there are links between the size of their duplications and their expressive language skills.

"For me, it's important to understand phenotype-genotype correlations," Reiter says. "What is it that UBE3A does? What kind of autism is it?"

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1. Urraca N. et al. Autism Res. Epub ahead of print (2013) PubMed

2. Vendrame M. et al. Epilepsy Behav. 23, 261-265 (2012) PubMed

Comments

Name: Shree
9 April 2013 - 7:25PM

Have someone thaught of alienation syndrom that could depend upon the traditional environmental factor for the cause of Autism.Thank you.

Name: RA Jensen
13 April 2013 - 7:36PM

The Dup15 syndrome is nearly always sporadic. The error occurs in reproductive cells (egg or sperm)in karotype normal parents.

Interestingly Molina et al (2011) examined the sperm of ten healthy volunteer donors and found 15q11-13 duplications and deletions in all the volunteer donors.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613132/


Molina et al (2011). Sperm rates of 7q11.23, 15q11q13 and 22q11.2 deletions
and duplications: a FISH approach. Hum Genet (2011) 129:35–44 DOI 10.1007/s00439-010-0894-4

http://www.springerlink.com/content/d53g890m56w6825h/fulltext.pdf

Name: LT Reiter
17 April 2013 - 9:39PM

Thank you for the link to Molina et al (2011). I remember seeing this paper when it came out, but had forgotten about that rather striking result. I would not use the phrase "nearly always" however, since in our rather small study three individuals had inherited interstitial duplications (two different families). The paternal duplications are particularly hard to detect if they don't present with an autism phenotype and may be out there in typical control data sets.

Name: Mônica
18 April 2013 - 1:48AM

My son has this alteration.Do the kids involved in this research speak?

Name: LT Reiter
26 April 2013 - 6:00PM

In our study of 14 kids we only had one child who did not speak. Some other children had trouble speaking when they were younger.

Name: RA Jensen
18 April 2013 - 4:11PM

When I said the DUP15 was nearly always sporadic I was referencing Battaglia who pubished a review:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613132/

Here is the statement I quoted:

Genetic counseling.

Large SMC(15) (supernumerary marker chromosome), which include PWS/ASCR, or idic(15), are nearly always sporadic.

I do find it interesting that when parent to child transmission does occur, the parent(s)appear to be unaffected as far as strictly defined ASD is concerned. That would be consistent with a multifactorial condition.

Keep up the good work and someday effective treatments may be developed.

Name: LT Reiter
26 April 2013 - 5:56PM

To my knowledge you are correct that the idic 15 duplication is always sporadic. Thanks for the kind words about our study. I agree that you can't really address the underlying molecular issues until you have a clear vision of the phenotype.

Name: Mõnica
29 April 2013 - 2:12PM

My son has microarray exam with this alteration.Are you interested in study his exam.I can send to you.He is 5 years old and doesn´t speak.

Name: Monica
29 April 2013 - 5:27PM

What is the age of the children involved in the research?

Name: LT Reiter
29 April 2013 - 5:51PM

Monica: please contact me by e-mail to discuss. My mail is lreiter@uthsc.edu.

Name: Monica
30 April 2013 - 12:24PM

Ms Reiter, I didn´t manage to send the e-mail.See if is this e -mail:Ireiter@uths.edu.Is it corrrect?

Name: E-mail
15 May 2013 - 9:00PM

Monica, my contact info is:

Dr. Larry Reiter
Associate Professor, Department of Neurology
lreiter@uthsc.edu

Name: Veronica
9 July 2013 - 3:07AM

Our 4 1/2 yr old son with autism had 3 different DNA tests that all came back normal: no Fragile-X, chromosome analysis and micro-array all "normal." More research has been done since he had these tests almost two years ago. Where can I have his results reviewed by those researching the genetic causes of autism? Thank you.

Name: Veronica
9 July 2013 - 3:09AM

such as relates to GABA, etc. He is primarily non-verbal (mostly echoalic) thanks again

Name: Suzy
6 September 2013 - 1:45AM

Hello. My 9 year old son was diagnosed with a microduplication of 15 q 11.2 - 11.2. My husband and I are being tested. Is this interstitial and is it typically sporadic. We are wondering if we should have our daughter tested - she has no symptoms. Thank you.

Name: Christina
4 February 2014 - 11:29PM

My husband(38), Son (10), and daughter (8) have an interstitial duplication of 15q11.2. My daughter has also got a duplication on xp22.31 from myself. Would you be interested in more details? We live in the Uk.

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