--Benchmarking Copy Number Variations in Healthy People Will Assist with
                 Diagnosis and Studies of Gene Disorders--

    PHILADELPHIA, July 15 /PRNewswire-USNewswire/ -- Genetics researchers
have unveiled a powerful new resource for scientists and health providers
studying human illnesses -- a reference standard of deletions and
duplications of DNA found in the human genome. Drawn from over 2,000
healthy persons, the study provides one of the deepest and broadest sets of
copy number variations (CNVs) available to date, along with a new research
tool for diagnosing and identifying genetic problems in patients.

    A team from The Children's Hospital of Philadelphia published its
high-resolution map and analysis of CNVs in the human genome in the July 10
online edition of the journal Genome Research.

    In contrast to alterations to a single base of DNA, which are single
nucleotide polymorphisms, or SNPs, often referred to as "snips," CNVs are
larger variations in DNA structure. As changes to a single DNA letter, SNPs
might be considered misspellings or alternate spellings of a word, while
CNVs are losses of whole phrases, paragraphs or even pages (deletions), or
are repeated sections (duplications). Some CNVs are inserted stretches of
DNA from other parts of the genome. Both SNPs and CNVs contribute to
genetic diversity and disease by changing the action of genes for which DNA
carries coded instructions.

    "We all carry a number of these variations in our own genomes," said
study co-leader Peter S. White, Ph.D., a molecular geneticist and director
of the Center for Biomedical Informatics at Children's Hospital. "Some CNVs
contribute to a disorder, but most of them do not, and it is often
challenging to determine which are important. One approach is to compare
CNVs in healthy individuals to those in patients with a disease, to find
those CNVs that seem to occur primarily in people with a certain disease.
Our map provides a large and uniform baseline standard to indicate which
CNVs represent normal variation."

    The investigators analyzed DNA from blood samples taken from 2,026
subjects. The subjects were healthy children and their parents, all of them
drawn from primary care and well-child clinics in the Children's Hospital
health care network. Of the samples, 65 percent were from Caucasians and 34
percent from African Americans. The number of subjects makes this CNV
collection among the largest reported to date, and because all the samples
were collected and analyzed under the same protocols, using the same
technology, and at one institution, the results have a uniformity that
increases their value as benchmarks.

    The CNV map has a higher resolution than most previous efforts, say the
authors, with over 50,000 CNVs catalogued throughout the genome.
Three-quarters of these were "non-unique," occurring in multiple unrelated
individuals. A majority (51.5 percent) of these non-unique CNVs were newly
discovered. On average the healthy subjects in the study have approximately
27 CNVs each.

    The researchers have posted the full CNV database on the Hospital's
website, where it is freely available in searchable form to gene
researchers worldwide. The web browser also enables researchers to compare
specific CNVs to those collected in public data repositories from other
institutions.

    "This resource will be very important in enabling rapid and accurate
diagnoses of rare diseases resulting from CNVs," said lead author Tamim H.
Shaikh, Ph.D., a molecular geneticist at Children's Hospital. Often
puzzling to physicians, such genetic diseases may be individually rare, but
collectively occur at frequencies that are comparable to the incidence of
well-known disorders such as Down syndrome. "In order to pinpoint the one
CNV that is the cause of a disease, it is critical to quickly eliminate
those that are part of the spectrum of normal variation that exists in the
human genome. That's what this CNV data and other similar resources allow
us to do," Shaikh added.

    As an example of the clinical usefulness of their database, the authors
analyzed DNA from a child with multiple congenital problems, including
developmental delay and brain malformations. They found 35 CNVs, of which
32 were previously detected in healthy controls. Two of the patient's three
unique CNVs were relatively small in size, but the third CNV was a deletion
in chromosome 17 that encompassed 51 genes, including several that are
active in early prenatal development. Unlike most of the other CNVs, it did
not occur in the child's parents, strongly supporting the conclusion that
the chromosome deletion arose spontaneously in the patient and that it
caused the child's disease.

    To detect CNVs in the thousands of samples, the investigators used
highly automated gene-analyzing technology at the Center for Applied
Genomics at Children's Hospital, directed by Hakon Hakonarson, M.D., Ph.D.,
a co-leader of this study. "Although these CNVs were detected in healthy
children, they may have significant disease implications that may not
manifest until later in life," said Hakonarson. Earlier this year,
Hakonarson and colleagues published groundbreaking studies of CNVs in
autistic spectrum disorders and attention-deficit hyperactivity disorder.
Both studies found CNVs in gene regions involved in neurological
development during early childhood.

    The new database has another strength, added Shaikh. Because it
analyzed large numbers of samples from both Caucasians and African
Americans, it measured CNV levels that differ between the two ethnic
groups, and enables clinicians to make more precise diagnoses. Shaikh added
that the researchers expect to expand the database with larger sample sizes
and data from additional ethnic populations.

    In addition to its use in diagnosis, said White, the database may also
assist researchers studying molecular evolution, for example, those
investigating how genetic variations occurred as human populations spread
across continents.

    Funds from the National Institutes of Health, the Pennsylvania
Department of Health and the Cotswold Foundation supported this research.
In addition, the David Lawrence Altschuler Chair in Genomics and
Computational Biology at Children's Hospital contributed funds to the
study. Co-authors, including co-lead author Xiaowu Gai, represented both
Children's Hospital and the University of Pennsylvania School of Medicine.

    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.


    Contact: John Ascenzi
    Phone: (267) 426-6055
    Ascenzi@email.chop.edu



SOURCE The Children's Hospital of Philadelphia