Details of chromosome 22 structure offer clues to how genes are lost in a genetic disease

February 29, 2000

Philadelphia, Pa. -- Chromosome 22, a hot spot for human disease, yielded a few more of its secrets to genetics researchers at The Children's Hospital of Philadelphia who analyzed details of the chromosome's structure. Focusing on specific sites on the chromosome with repetitive sequences of DNA, the researchers found direct evidence that these sites are unstable areas where the chromosome is prone to rearrangements that cause a loss of important genes.

Reporting in the March issue of Human Molecular Genetics, the research team implicated the areas of instability, called low-copy repeats, in a relatively common genetic disorder, chromosome 22q11 deletion syndrome. Hundreds of patients are treated at The Children's Hospital of Philadelphia for that disorder, which includes heart defects, cleft palate, feeding problems, an abnormal thymus gland and learning disabilities. The researchers drew on a database of 200 patients, as well as the hospital's participation in the federally sponsored Human Genome Project, which announced in December that chromosome 22 was the first human chromosome to be fully sequenced. Sequencing chromosome 22 involved listing the order of 33 million DNA bases that comprise the chromosome's genes (In addition to the 22q11 deletion syndrome, separate genetic abnormalities on chromosome 22 are linked to certain leukemias and other cancers, mental retardation, schizophrenia and numerous other diseases).

"The ends of the areas deleted from chromosome 22 are more likely to be located where the low-copy repeats exist," said Beverly S. Emanuel, Ph.D., chief of Human Genetics and Molecular Biology at The Children's Hospital of Philadelphia and senior author of the paper. "We can begin to describe the molecular mechanism by which a deletion in a chromosome takes place." For instance, two areas along the chromosome, designated as low-copy repeats A and D, have portions with identical sequences. Because each chromosome must pair off with an identical chromosome before a cell divides to make an egg or sperm, portions A and D sometimes combine with each other and leave out the genes in between them. The result is a chromosome that is missing genesÐthe basis of the chromosome 22 deletion syndrome.

As the Human Genome Project moves forward quickly to compile sequences of all 23 human chromosomes Ð a result expected to be announced later this year Ð one challenge for scientists will be to interpret that enormous mass of information. "Chromosome 22q11 deletion syndrome is representative of an emerging field in genetic medicine, called genomic disease," said Dr. Emanuel. Genomic diseases are disorders originating in the structure of the genomeÐthe full complement of genes carried by a set of chromosomes. One group of genomic diseases originates in the low-copy repeats that cause unstable areas on their specific chromosomes. Occurring once in every 4,000 births, chromosome 22q11 deletion syndrome is the most prevalent such disease. Other such diseases include Williams syndrome, based on a deletion on chromosome 7, and Prader-Willi syndrome, in which a portion of chromosome 15 is missing. All three syndromes include defects in organs, distinctive facial features and learning disabilities.

"It's too early to know the clinical applications of our research yet," said Dr. Emanuel. "We're still seeking to better understand the molecular mechanisms. Perhaps we might eventually be able to predict subgroups in a population more likely to have this deletion syndrome." Upcoming investigations at Children's Hospital will study variations of the chromosome 22q11 deletion among patients and their parents and grandparents.

The genetics laboratory at The Children's Hospital of Philadelphia recently received a four-year renewal of its federal grant for the chromosome 22 deletion studies. The National Institutes of Health will provide $1.5 million per year for the next four years. "This represents continuing recognition of our longstanding work on chromosome 22," said Dr. Emanuel.
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The Children's Hospital of Philadelphia, the nation's first children's hospital, is a leader in patient care, education and research. This 373-bed multispecialty hospital provides comprehensive pediatric services, including home care, to children from before birth through age 19. The hospital is second in the United States among all children's hospitals in total research funding from the National Institutes of Health.

Children's Hospital of Philadelphia

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