Discovery of the gene for Cornelia de Lange syndrome

May 17 2004

An international team of researchers has discovered the gene for Cornelia de Lange syndrome, a disabling, multisystem genetic disease that affects an estimated one in 10,000 children. The finding is expected to lead to a genetic test, enabling rapid and definitive diagnosis of the syndrome, as well as prenatal testing for families who already have one child with the disease.

Geneticists from The Children's Hospital of Philadelphia and Drexel University College of Medicine in Philadelphia led the study, which received advance online publication on May 17 on the web site of Nature Genetics. In pinpointing the gene, they used an innovative research approach that may lend itself to investigations of other genetic conditions, particularly "orphan diseases:" rare, poorly understood disorders.

The lead researchers, Ian D. Krantz, M.D., of Children's Hospital, and Laird G. Jackson, M.D., of Drexel University College of Medicine, together maintain the world's largest database of patients with Cornelia de Lange syndrome (CdLS), drawing on clinical records and genetic samples first gathered 30 years ago. Named for a Dutch physician who first described it in 1933, the syndrome often includes mental retardation, impaired growth, heart defects, gastroesophageal reflux and feeding problems, impaired vision, hearing loss, and upper limb abnormalities, including missing fingers or hands.

There are typically distinctive facial features, such as thin eyebrows that join together, long eyelashes, thin lips and excessive body hair. In the past, CdLS was often fatal in infancy; now, most children with the condition live into adulthood. Although CdLS has been known for decades, the disease is a challenge to scientists. "This syndrome has been confusing for a long time, because it's been difficult to trace one source for its multiple effects on many organs," said Dr. Krantz, the lead author and principal investigator of the study.

The disease is also variable - some patients have much milder forms of CdLS. In addition, because few individuals with CdLS had children, it is rare to find parents and children who both have the disease.

In the current study, the researchers analyzed the genomes (the entire genetic makeup in an individual's DNA) of 12 families having more than one member with CdLS. Through a process of elimination, they were able to identify four candidate regions for the CdLS gene. Further analysis narrowed the search to a region of chromosome 5. They combined this knowledge with cytogenetic data - the details of chromosomal rearrangements in a child with CdLS.

The team identified a large gene on chromosome 5, which they named NIPBL. Mutations giving rise to Cornelia de Lange syndrome occur at different locations within that gene. NIPBL stands for Nipped B-like, because the human gene produces proteins similar to those produced by the Nipped-B gene in fruit flies. "The insect gene was called `Nipped' because a mutation in that gene produces an abnormal fly wing that looks like it had a small bite taken out of it," said Dr. Jackson. Both the fruit fly gene and the human gene regulate biological signals that have wide-ranging effects during development, on a variety of organ systems. "This discovery is exciting for a number of reasons," said Julie Mairano, executive director of the Cornelia de Lange Syndrome Foundation, based in Avon, Conn. "It will pave the way for genetic tests to confirm a diagnosis and provide comfort for parents who already have one child with the syndrome. It will raise awareness of the disease among physicians and scientists, and, most importantly, focus interest on better treatments for children with Cornelia de Lange syndrome."

When a genetic test for CdLS is developed, said Dr. Krantz, physicians will be able to provide a definitive diagnosis to confirm or rule out a clinical diagnosis. The test will also assist genetic counselors. "Fortunately," says Dr. Krantz, "the disease has a low recurrence risk. Families having one child affected by CdLS have only a one percent chance that a subsequent child will be affected. When a prenatal test is developed, we will determine before birth whether the fetus is among that one percent."

At Children's Hospital, Dr. Krantz directs a full-service clinic for children with CdLS, the only program in the world offering comprehensive services for children with the condition. At this clinic, which attracts patients from around the globe, specialists from a variety of medical disciplines treat each child's specific constellation of symptoms. Treatments may include heart medications, tube feeding and hand surgery.

The long-term goal of the gene discovery, of course, is to improve clinical treatments for the syndrome. "One cannot predict the exact path science takes from a basic discovery to a practical therapy," said Dr. Jackson. "However, better understanding of the specific biological pathways by which a gene mutation affects health and development may lead to new therapies to intervene at different points along the path." The National Institute of Child Health and Human Development, part of the National Institutes of Health, funded the study. Drs. Krantz and Jackson are both long-standing members of the Cornelia de Lange Syndrome Foundation Clinical Advisory Board. Dr. Jackson was the first medical director of the Foundation.

The study's co-authors represent five hospitals and eight universities from four countries. In addition to The Children's Hospital of Philadelphia and Drexel University College of Medicine, co-authors participated from the University of Pennsylvania School of Medicine, Philadelphia; Nemours Children's Clinic, Wilmington, Del.; Geneva University Hospital, Switzerland; the University of Genoa, Italy; the University of Nevada School of Medicine; University Medical Centre, Hamilton, Ontario, Canada; Michigan State University; the University of Utah Health Sciences Center; and the University of California, Irvine. Founded in 1855 as the nation's first pediatric hospital, The Children's Hospital of Philadelphia is ranked today as the best pediatric hospital in the nation by U.S. News & World Report and Child magazine.

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 from before birth through age 19.

For more information, visit http://www.chop.edu. Drexel University College of Medicine is the largest private medical school in the nation and one of the largest centers for spinal cord research in the Mid-Atlantic region. Drexel's College of Medicine has participated in a pioneering clinical trial involving the world's first implantable artificial heart, developed an ob-gyn center overseen by internationally prominent specialists in maternal-fetal medicine, and created one of the largest centers for malaria study in the nation. It was the first medical school to train women to be physicians.