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New Genomic Analysis Applied to Healthy Children


doi: 10.1097/01.NT.0000361421.42303.35
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Investigators catalogued 50,000 copy number variations in the genome of 2,000 healthy children and are comparing the data with that of children with various diseases.

Genetic analysis has moved from identifying single base pair deletions or insertions to finding and carefully considering cases where thousands of base pairs in a region of DNA are missing or duplicated. Now, the field is rethinking what these so-called genome copy number variation, or CNVs, mean to the health or disease risk of an individual.

Investigators at Children's Hospital of Philadelphia (CHOP) used the latest genetic technology to look for CNVs in 2,000 healthy children. Their map provides a higher resolution than most previous efforts and has over 50,000 CNVs catalogued throughout the genome. Three-quarters of these occurred in multiple unrelated individuals and therefore were not unique

More than half — 51.5 percent — of these “non-unique” CNVs were newly discovered. On average, the healthy subjects in the study have approximately 27 CNVs each.

This new map is now available to scientists worldwide who are interested in comparing these healthy CNV fingerprints to patients with a particular illness. (Visit

The study appeared Aug. 5 online in advance of the print edition of Genome Research, published by Cold Spring Harbor Laboratory.

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The way the gene is laid out — and its alphabetic code — provides different instructions for the genes to carry out their jobs. If strings of base pairs are like letters in the alphabet, CNVs are like large paragraphs of words, even pages, that are just missing, said the study author Peter S. White, PhD, associate professor of pediatrics at the University of Pennsylvania and the Children's Hospital of Philadelphia.

CNVs, and single nucleotide polymorphisms (SNPs) or single changes in a genetic letter, play a role in genetic diversity, he explained.

The team identified an average of 30 to 35 CNVs that differed among the samples tested. The majority had a loss of one of the two copies normally present in a region of the genome, some over two million base pairs in size.

“We all carry a number of these variations in our own genomes,” said Dr. White. “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.”

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A number of recent studies have pointed to large chunks of missing regions of the genome in people with schizophrenia and autism. “These findings got the field excited,” Dr. White explained. “Having large healthy control datasets such as this one can enable the field to apply these methods to many different disease sets.”

The scientist said that they are seeing more deletions than duplications. They have recently used the database to look at CNVs in children with attention deficit-hyperactivity disorder (ADHD) and found that a wide number of genes implicated in autism were also involved in increasing the risk for ADHD.

The group at CHOP is also using the healthy control genetic map to compare it to groups of children with specific diseases in an attempt to make more accurate diagnosis. But at this point, they said, it is unknown how these deletions and duplications affect disease burden.

For example, they analyzed CNVs from a child born with multiple congenital problems and identified 35 CNVs; three were unique to this child and were not found in the normal CNV database. Two of the CNVs were small, the scientists said, but one of the CNVs involved a region of chromosome 17 that has 51 genes; it is known that several of these genes are involved with early prenatal development.

In the study, the parents also underwent genetic screening for CNVs. In the case of this child, the three CNVs not found in the healthy controls were also not found in the DNA of the child's parents, indicating that these deletions were unique to the child. Dr. White said that it is thought that the vast majority of CNVs are inherited but that some are not, and CNVs are probably involved in all neurological conditions.

“I think it is great that they are making these data available to the public,” said Jonathan Sebat, PhD, an associate professor of genetics at Cold Spring Harbor Laboratory. Dr. Sebat is one of the scientists who originally discovered that CNVs are a major source of human genetic variation, and his group has also identified CNVs that contribute to psychiatric disorders such as schizophrenia and autism. “This new catalogue of CNVs will add substantially to the existing databases of structural variation.”

The study was funded by the NIH, the Pennsylvania Department of Health and the Cotswold Foundation.

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• Shaikh TH, Gai X, Hakonarson H, et al. High-resolution mapping and analysis of copy number variations in the human genome: A data resource for clinical and research applications. Genome Res 2009; E-pub 2009 Aug 5.
    • Elia J, Gai X, Xie HM, White PS, et al. Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol Psychiatry 2009: E-pub 2009 Jun 23.
      ©2009 American Academy of Neurology