Medscape article on chromosomes

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Genetic " Hot Spots " for Autism Probed in 2 Studies

Busko

Medscape Medical News 2008. © 2008 Medscape

January 10, 2008 — Novel microdeletions and reciprocal microduplications in

chromosome 16 were found in about 1% of autism cases, and a common variant in

a gene on chromosome 7 was found to increase the risk of autism, in 2 recent

studies.

The first study is published online January 9 in the New England Journal of

Medicine, and the second study is published in the January issue of the

American Journal of Human Genetics.

One Piece of the Puzzle

" The genetics of autism . . . are basically puzzles with many pieces, and

this is 1 of those pieces, but there are many more that need to be found " to

provide insight into the disease mechanism, Mark J. Daly, PhD, from the Center

for Human Genetic Research at Massachusetts General Hospital, in Boston, a

coauthor of the first study, in the New England Journal of Medicine, told

Medscape Psychiatry. " It’s a small step, and obviously still miles away from

being

translated into a new avenue for therapy. "

Heritability in autism is about 90%, making it one of the most heritable

complex disorders, the group, led by A. Weiss, PhD, writes. About 10% of

cases can be explained by genetic syndromes and chromosomal abnormalities, but

genetic studies have not provided substantial insight into the 90% of cases

where autism is idiopathic.

The researchers used new DNA profiling technology to perform a

high-resolution genomewide analysis of 751 multiplex families with 2 or more

children with

autism or autism spectrum disorder, Dr. Daly explained. These families have

been collected for many years by a number of clinicians throughout North

America as part of the Autism Genetic Resource Exchange (AGRE), he noted. The

team used 2 novel algorithms to search for recurrent deletions or duplications

conferring a risk of autism.

They found that among the AGRE families, 5 children with autism in 4

independent families carried de novo deletions in a region on chromosome

16p11.2.

The investigators observed the identical microdeletions in 5 of 512 children

referred to the Children's Hospital Boston, in Massachusetts, for

developmental delay, mental retardation, or suspected autism spectrum disorder.

The deletions were also found in 3 of 299 samples from children in Iceland

with autism spectrum disorder and in 2 of 18,834 control subjects from

Iceland.

The researchers observed reciprocal duplication of this region in 7 children

with autism in the AGRE sample, 4 children from the Children's Hospital

Boston sample, and in no children from the Iceland sample.

" Deletion and duplication events [on a region of chromosome 16p11.2] were

observed in nearly 1% of multiplex families with autism [in AGRE], in 1% of

subjects with autism in Iceland, and in more than 1.5% of clinical samples from

subjects with developmental delay, " the group writes. This prevalence is

similar to that of the most common known cause of autism (duplication of the

Prader-Willi/Angelman region), which is estimated to occur in 1% of subjects

with

autism.

The team did not identify other regions with similar aggregations of large de

novo mutations, which suggests that these might explain only a fraction of

familial idiopathic autism, they write.

Editorial: " Like Peeling Layers of an Onion "

" Each new objective finding expands the number of forms of 'autisms' like

layers of an onion, " Evan E. Eichler, PhD, from the University of Washington, in

Seattle, and W. Zimmerman, MD, from s Hopkins University, in

Baltimore, land, write in an accompanying editorial in the New England

Journal of Medicine. The genomic region identified by Weiss et al corresponds

to 1

of approximately 150 regions of the human genome that are predicted to be

" hot spots " for recurrent deletion and duplication.

The study findings support the notion that large, spontaneous deletions and

duplications contribute to the molecular causes of autism, but the discovery

of significant associations for rarer loci may require screening tens of

thousands of DNA samples from patients rather than a few thousand samples, they

add. " Deeper sample collection and new cost-effective genomic techniques may be

needed to peel away the remaining layers of the onion, " they conclude.

Another Piece of the Puzzle

In the second study, in the American Journal of Human Genetics, Dan E.

Arking, PhD, and colleagues at s Hopkins University School of Medicine

report

that a common genetic variant in contactin-associated protein-like 2

(CNTNAP2) — a member of the neurexin family, which encodes a protein that

enables

brain cells to communicate with each other and may be involved in brain-cell

development — increases familial risk of autism.

" I think the uniqueness of the study is that we not only identified a gene —

CNTNAP2 — but we also found that a variant that is relatively common in the

general population increases the risk for autism, " coauthor Aravinda

Chakravarti, PhD, told Medscape Psychiatry.

The researchers genotyped samples from 72 multiplex families with 148

affected children from the National Institute of Mental Health Autism Genetic

Initiative.

Using genomewide linkage and association studies, they found that chromosome

7q35 appeared to be linked to autism. Further investigation showed that a

common polymorphism in the CNTNAP2 gene is significantly associated with

autism.

The children with autism tended to have inherited the thymine rather than

adenine variant of CNTNAP2.

This finding was validated in an independent sample of 1295 healthy children

with autism and their parents. Using combined data from the 2 samples, the

investigators found that children with autism were 20% more likely to have

inherited the thymine variant from their mothers than from their fathers.

" Why everyone who carries this variant does not have autism is currently

unknown, but a common explanation is that this variant is necessary but not

sufficient, " Dr. Chakravarti said. Other requirements could include other genes,

specific developmental factors, and environmental factors that have not yet b

een identified.

" Every time we identify a gene, it tells us a little bit of the puzzle of

autism and a little bit of the mechanism of autism, " he observed.

In the same issue of the journal, 2 other studies (Alarcón M et al. Am J Hum

Genet. 2008;82:150-159; Bakkaloglu B et al. Am J Hum Genet. 2008;82:165-173)

provide convergent evidence for involvement of CNTNAP2 in autism, he added.

Dr. Eichler reports receiving fees from Applied Biosystems. No other

potential financial conflicts of interest were reported.

N Engl J Med. Published online January, 9, 2008.

Am J Hum Genet. 2008;82:160-164. _Abstract_

(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=PubMed & list_uids=\

18179894 & dopt=Abstract)

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