Chromosone 15 associated with Autism also linked to epilepsy

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Chromosome 15 region associated with autism also linked to epilepsy

Posted by: " Stacey Groder " sgroder@... staceygroder

Sun Feb 1, 2009 7:20 pm (PST)

Chromosome 15 region associated with autism also linked to epilepsy

Rae Chi

15 Jan 2009 2:25 PM

http://sfari.org/news/chromosome-15-region-associated-with-autism-also-linked-to\

-epilepsy

Missing link: Parts of the 15q13.3 region, shown here in red, are deleted in

some people with epilepsy, autism, schizophrenia and mental retradation.

A specific deletion on chromosome 15 occurs in one percent of people with a

common form of epilepsy, establishing the mutation as the most common risk

factor for the disorder, according to research published online January 11

in Nature Genetics 1.

Previous work has linked the same deletion, involving at least seven genes

in the 15q13.3 region, with autism, schizophrenia and mental retardation.

This study is the first to link the region to idiopathic generalized

epilepsy (IGE), a group of epilepsy disorders thought to have an underlying

genetic basis, broadening the range of disorders associated with the

deletion.

It's not unusual to have a specific deletion lead to diverse outcomes. For

example, a small region of chromosome 16 is deleted or duplicated in people

with autism as well as in a small proportion of the general population.

Certain regions of chromosome 15 are prone to recombination, sometimes

leading to missing or duplicated genetic material.

For instance, deletions in the 15q11-13 region can lead to

neuro-developmental disorders such as Angelman and Prader-Willi syndromes,

two clinically distinct disorders that share some genetic and behavioral

features of autism. Duplications of the same region are also found in up to

three percent of people with autism2.

In this study, researchers analyzed the genes of 1,223 people with

idiopathic generalized epilepsy. They uncovered the 15q13.3 deletion in 12

people, compared with none in the 3,699 healthy controls.

" The really striking finding is that [the deletion] explains one percent of

generalized epilepsy, which is huge because epilepsy is thought to be

multi-factorial with many genes involved, " says Evan Eichler, professor of

genome sciences at the University of Washington in Seattle who co-led the

study.

" To have one single mutation, which is this deletion, in this very

significant portion of individuals with generalized epilepsy was a

surprise, " Eichler adds.

Diverse outcomes:

Over the past few years, studies have revealed that 15q13.3 microdeletions -

dubbed 'micro' because they produce chromosomal changes too small to be seen

under a microscope - are enriched in small subsets of people with various

neuro-psychiatric conditions.

In 2006, Eichler's group found that the 15q13 region, along with four other

sites on the genome, is significantly rearranged in people with mental

retardation compared with healthy controls3.

After further analysis, the researchers identified specific microdeletions

in 15q13.3 in 6 of 2,082 - or 0.3 percent - people with mild to moderate

mental retardation, many of whom also have seizures4.

In September 2008, two studies showed that the 15q13.3 microdeletion occurs

in 0.2 to 0.3 percent of people with schizophrenia5,6.

A study published in November also linked microdeletions of 15q13.2 and

15q13.3 to autism spectrum disorder or features of autism7. In a second

study published in December, researchers identified three boys with autism

from one family with a 15q13.3 microdeletion8. None of the individuals with

autism in either study had had seizures.

Because each study used different cohorts, diagnoses seldom overlapped

across studies. In the latest study, Eichler says, there is no evidence of

autism or schizophrenia in the people with the 15q13.3 microdeletion. But

his group observed severe intellectual disability in 1, and mild disability

in 2, of the 12 people with the microdeletion.

Given the small numbers of people who have the microdeletion, the lack of

overlap in phenotypes is not surprising, says Dennis Wall, director of

Harvard Medical School's Computational Biology Initiative.

Larger studies with more detailed phenotyping may reveal whether people with

the microdeletion share any behavioral or biological characteristics, he

says.

But phenotyping, especially for multi-site studies, can vary widely -

" enough to leave open the possibility that these 12 may or may not have

other impairments that were simply missed, " Wall says.

In addition, says Christian, associate professor of human genetics at

the University of Chicago, there are likely to be other genetic interactions

involved in the different disorders.

" The microdeletion alone will not cause a particular disease but will

interact with other different mutated genes to cause the multiple

disorders, " she says.

Eichler's group is screening more individuals with idiopathic epilepsy to

determine whether specific genes are involved. At least one candidate,

CHRNA7, which regulates signaling between two nerve cells, has previously

been implicated in a rare form of epilepsy.

References:

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1.. Helbig I. et al. Nat. Genet. Epub ahead of print (2009) Abstract ?

2.. Cook E.H. Jr. et al. Am. J. Hum. Genet. 60, 928-934 (1997) PubMed ?

3.. Sharp A.J. et al. Nat. Genet. 38, 1038-42 (2006) PubMed ?

4.. Sharp A.J. et al. Nat. Genet. 40, 322-328 (2008) PubMed ?

5.. The International Schizophrenia Consortium Nature 455, 237-241 (2008)

PubMed ?

6.. Stefansson H. et al. Nature 455, 232-236 (2008) PubMed ?

7.. D.T. et al. J. Med. Genet. Epub ahead of print (2008) PubMed ?

8.. Pagnamenta A.T. et al. Eur. J. Hum. Genet. Epub ahead of print (2008)

PubMed ?