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Subject: GENE SCAN FINDS LINK ACROSS ARRAY OF CHILDHOOD BRAIN DISORDERS

U.S. Department of Health and Human Services 
NATIONAL INSTITUTES OF HEALTH NIH News 
National Institute of Neurological Disorders and Stroke (NINDS)
<http://www.ninds.nih.gov/>
National Center for Research Resources (NCRR) <http://www.ncrr.nih.gov/>
National Institute of Mental Health (NIMH) <http://www.nimh.nih.gov/>
Embargoed for Release: Sunday, August 22, 2010, 1 p.m. EST

CONTACT: 
Daniel Stimson, NINDS, 301-496-5751,  <e-mail: [log in to unmask]>

GENE SCAN FINDS LINK ACROSS ARRAY OF CHILDHOOD BRAIN DISORDERS

Mutations in a single gene can cause several types of developmental brain
abnormalities that experts have traditionally considered different
disorders.  With support from the National Institutes of Health, researchers
found those mutations through whole exome sequencing - a new gene scanning
technology that cuts the cost and time of searching for rare mutations.

"This is going to change the way we approach single-gene disorders," said
lead investigator Murat Gunel, M.D., who is chief of the Neurovascular
Surgery Program and co-director of the Program on Neurogenetics at Yale
University in New Haven, Conn.  Whole exome sequencing can be applied to
dozens of other rare genetic disorders where the culprit genes have so far
evaded discovery, he said. 

Such information can help couples assess the risk of passing on genetic
disorders to their children.  It can also offer insights into disease
mechanisms and treatments.

The research is funded in part by a $2.9 million stimulus grant from NIH's
National Institute of Neurological Disorders and Stroke (NINDS) made
possible by the American Recovery and Reinvestment Act.

"This study demonstrates a powerful new tool for discovering the cause of
tough-to-crack genetic disorders," said NINDS director Story Landis, Ph.D.
"It also exemplifies how Recovery Act support to the NIH community is
successfully driving biomedical technology and innovation."

The study appears in Nature, and focuses on children with malformations of
cortical development (MCD).  These are severe abnormalities of the cerebral
cortex, the brain's outermost layer, which normally contains complex folds
that are densely packed with brain cells.  In MCD, the cortex is smaller and
its folds are less complex.  Affected children have severe intellectual
disabilities and may not reach developmental milestones.

Different types of MCD are recognized based on anatomy.  They carry names
like microcephaly (small brain and head), schizencephaly (fluid filled
clefts in the brain), pachygyria (a cortex with thicker, fewer folds) and
polymicrogyria (cortex with many small folds).  These conditions reflect a
failure of brain cells to grow and reach their proper places during
development.  They can result from prenatal exposure to alcohol, drugs and
some viruses. In many cases, the cause is genetic, but the specific genetic
lesion is often unknown.

Through whole exome sequencing, the new study found a single gene at the
root of seemingly distinct types of MCD in children from multiple families.
Rather than scanning a person's entire genome for mutations, this technique
focuses on the protein-coding bits of DNA, or exome, which makes up about
1.5 percent of the genome.

Genetic forms of MCD occur worldwide and in all kinds of families, but the
highest incidence is among children born to parents who are related.  Dr.
Gunel and his colleagues at Yale teamed up with investigators in Turkey to
study Turkish families with MCD.  The country has a tradition of first- and
second-cousin marriages, and thus a relatively high incidence of MCD.

The study began by focusing on two related children who were diagnosed with
microcephaly.  Whole exome sequencing revealed that both children had
mutations in a gene called WDR62.  As the study grew to include children
from other families with microcephaly, many of the children were found to
have mutations in the same gene.  Unexpectedly, brain imaging revealed that
the children also tended to have other types of MCD, superimposed with
microcephaly.  In all, the investigators found 6 unique mutations in the
WDR62 gene among 30 families.

Those results show that a single gene "is required for strikingly diverse
aspects of human cortical brain development," said Dr. Gunel.

No one knows precisely what WDR62 does, but related proteins are known to
regulate the processing of RNA (the intermediate between DNA and protein).
The researchers found that in the developing mouse and human brain, WDR62 is
enriched in a band of brain tissue that contains neural stem cells.  They
plan to explore the exact functions of WDR62 in mouse studies.  Meanwhile,
they will use their Recovery Act grant to extend whole exome sequencing to
hundreds of additional families with MCD.

The technology should prove to be quick and cost effective for identifying
the roots of other rare genetic disorders too, according to Dr. Gunel.  In
his laboratory, whole genome sequencing takes several weeks and costs about
$50,000, while whole exome sequencing takes 9 days and costs about $3,500,
he said. 

In addition to NINDS, other support for the study came from a Clinical and
Translational Science Award from NIH's National Center for Research
Resources, and from NIH's National Institute of Mental Health.

NINDS (www.ninds.nih.gov) is the nation's leading funder of research on the
brain and nervous system.  The mission of NIMH (www.nimh.nih.gov) is to
reduce the burden of mental and behavioral disorders through research on
mind, brain and behavior.  NCRR (www.ncrr.nih.gov) provides laboratory
scientists and clinical researchers with the resources and training they
need to understand, detect, treat and prevent a wide range of diseases.

The National Institutes of Health (NIH) -- The Nation's Medical Research
Agency -- includes 27 Institutes and Centers and is a component of the U.S.
Department of Health and Human Services. It is the primary federal agency
for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and its programs,
visit <www.nih.gov>.
------------------
The html version of this release contains an image at:
<http://www.ninds.nih.gov/img/CT_scan_microcephaly.jpg>.
------------------------
The activities described in this release are being funded through the
American Recovery and Reinvestment Act. More information about NIH's
Recovery Act grant funding opportunities can be found at
<http://grants.nih.gov/recovery/>. To track the progress of HHS activities
funded through the Recovery Act, visit www.hhs.gov/recovery. To track all
federal funds provided through the Recovery Act, visit <www.recovery.gov>.
-----------------
Reference:  Bilguvar K, Ozturk AK et al.  "Whole exome sequencing identifies
WDR62 mutations in severe brain cortical malformations."  Nature, published
online August 22, 2010.

##

This NIH News Release is available online at:
<http://www.nih.gov/news/health/aug2010/ninds-22.htm>.

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