More Gene Mutations Linked to Autism Risk

--Combination of Inherited and New Genetic Mutations Acting Together--

PHILADELPHIA, June 26 /PRNewswire-USNewswire/ -- More pieces in the complex
autism inheritance puzzle are emerging in the latest study from a research
team including geneticists from The Children's Hospital of Philadelphia, the
University of Pennsylvania School of Medicine and several collaborating
institutions. This study identified 27 different genetic regions where rare
copy number variations - missing or extra copies of DNA segments - were found
in the genes of children with autism spectrum disorders (ASDs), but not in the
healthy controls. The complex combination of multiple genetic duplications and
deletions is thought to interfere with gene function, which can disrupt the
production of proteins necessary for normal neurological development.

"We focused on changes in the exons of DNA--protein-coding areas in which
deletions or duplications are more likely to directly disrupt biological
functions," said study leader Hakon Hakonarson, M.D., Ph.D., director of the
Center for Applied Genomics at The Children's Hospital of Philadelphia and
associate professor of Pediatrics at the University of Pennsylvania School of
Medicine. "We identified additional autism susceptibility genes, many of
which, as we previously found, belong to the neuronal cell adhesion molecule
family involved in the development of brain circuitry in early childhood." He
added that the team discovered many "private" gene mutations, those found only
in one or a few individuals or families -- an indication of genetic
complexity, in which many different gene changes may contribute to an autism
spectrum disorder.

"We are finding that both inherited and new, or de novo, genetic mutations are
scattered throughout the genome and we suspect that different combinations of
these variations contribute to autism susceptibility," said co-author Maja
Bucan, Ph.D., professor of Genetics at the University of Pennsylvania School
of Medicine and Chair of the Steering committee for Autism Speaks' Autism
Genetic Resource Exchange (AGRE). "We are grateful to families of children
with autism spectrum disorders for their willingness to participate in genetic
studies because family-based studies have many advantages. We have learned a
lot both from genetic analyses of children with autism as well as analyses of
their patents and their unaffected siblings."

The researchers compared genetic samples of 3,832 individuals from 912
families with multiple children with ASDs from the AGRE cohort against genetic
samples of 1,070 disease-free children from The Children's Hospital of
Philadelphia. This study also uncovered two novel genes in which variations
were found, BZRAP1 and MDGA2 - thought to be important in synaptic function
and neurological development, respectively. Interestingly, key variants of
these genes were transmitted in some, but not all, of the affected individuals
in families.

The findings were published in the June 26 edition of the journal PloS
Genetics.

By further refining the genetic landscape of ASDs, the current study expands
the findings of two large autism gene studies published in April, led by
Hakonarson and co-authored by Gerard Schellenberg, Ph.D., professor of
Pathology and Laboratory Medicine at the University of Pennsylvania School of
Medicine, Bucan and others. One study was the first to report common gene
variants in ASDs. The other identified copy number variants that raise the
risk of having an ASD. Both studies found gene changes on two biological
pathways with crucial roles in early central nervous system development.
Hakonarson and Bucan said the latest findings reinforce the view that multiple
gene variants, both common and rare, may be interacting to cause the
heterogeneous group of disorders included under autism spectrum disorders.

AGRE, a program of Autism Speaks, provided genetic biomaterials and clinical
data from families having more than one member diagnosed with an ASD. Blood
samples donated by children and their families at Children's Hospital were
used as healthy controls. AGRE makes data publicly available to qualified
researchers worldwide.

About The Children's Hospital of Philadelphia
The Children's Hospital of Philadelphia was founded in 1855 as the nation's
first pediatric hospital. Through its long-standing commitment to providing
exceptional patient care, training new generations of pediatric healthcare
professionals and pioneering major research initiatives, Children's Hospital
has fostered many discoveries that have benefited children worldwide. Its
pediatric research program is among the largest in the country, ranking second
in National Institutes of Health funding. In addition, its unique
family-centered care and public service programs have brought the 430-bed
hospital recognition as a leading advocate for children and adolescents. For
more information, visit http://www.chop.edu.

About Autism Speaks
Autism Speaks is the nation's largest autism science and advocacy
organization, dedicated to funding research into the causes, prevention,
treatments and a cure for autism; increasing awareness of autism spectrum
disorders; and advocating for the needs of individuals with autism and their
families. Autism Speaks funds more than $30 million each year in new autism
research, in addition to supporting the Autism Treatment Network, Autism
Genetic Resource Exchange, Autism Clinical Trials Network, Autism Tissue
Program and a range of other scientific and medical programs. To learn more
about the Autism Genome Resource Exchange (AGRE), please visit
http://www.autismspeaks.org/science/programs/agre/index.php. To learn more
about Autism Speaks, please visit www.AutismSpeaks.org.

Contacts: John Ascenzi
The Children's Hospital of Philadelphia
(267) 426-6055
Ascenzi@email.chop.edu

Kim Guenther
University of Pennsylvania School of Medicine
(215) 200-2312
Kim.Guenther@uphs.upenn.edu

SOURCE The Children's Hospital of Philadelphia

John Ascenzi of The Children's Hospital of Philadelphia, +1-267-426-6055,
Ascenzi@email.chop.edu; or Kim Guenther of University of Pennsylvania School
of Medicine, +1-215-200-2312, Kim.Guenther@uphs.upenn.edu