ONE OF THE MOST FRIGHTENING THINGS ANY PARENT CAN HEAR IS THAT THERE MAY BE SOMETHING WRONG WITH THEIR UNBORN CHILD. AS OUR UNDERSTANDING OF GENETICS HAS ADVANCED, SO TOO HAS OUR ABILITY TO DIAGNOSE CONGENITAL CONDITIONS EARLY ON IN PREGNANCY, GIVING PARENTS THE BEST INFORMATION POSSIBLE AS SOON AS POSSIBLE. IN MANY CASES, THE TREATMENT OPTIONS FOR THESE CONDITIONS HAVE NOT KEPT PACE WITH OUR DIAGNOSTIC CAPABILITIES, BUT EVEN WHEN NOTHING CAN BE DONE TO CHANGE THE OUTCOME OF A PREGNANCY, IMPROVED PRENATAL DIAGNOSIS ENABLES PARENTS TO PREPARE THEMSELVES FOR THEIR CHILD'S CONDITION AND PLAN FOR THE OUTCOME.

Within Columbia’s Center for Prenatal Pediatrics, opened just two years ago and already seeing some 400 patients every year, women who know that their pregnancy involves a congenital abnormality, or merely suspect that they may have such a problem, are seen by a multidisciplinary team that includes genetic specialists, surgeons, cardiologists, radiologists, and other experts in the care of families coping with possible birth defects. One of the leaders of this team is Ronald Wapner, M.D., a pioneer in the development of the chorionic villus sampling test for genetic defects, who joined Columbia in 2005 as director of maternal-fetal medicine. Dr. Wapner’s work builds on the life’s work of Dorothy Warburton, Ph.D., professor of clinical genetics and development at P&S and considered to be one of the five most influential human geneticists of contemporary times. Director of NewYork-Presbyterian’s cytogenetics laboratory since 1969, Dr. Warburton uses karyotype analysis of blood samples to identify congenital anomalies, conducts prenatal diagnosis via amniocentesis or chorionic villus sampling, and, more recently, has used fluorescence in situ hybridization (FISH) as an adjunct diagnostic.
     Families seeking care for high-risk pregnancies at Columbia also benefit from the latest genetic research ongoing here. Investigators at the Morgan Stanley Children’s Hospital are involved in studies seeking the genetic factors involved in congenital heart disease, childhood cardiomyopathy, intrauterine growth restriction, and aneuploidy, a family of conditions involving abnormal numbers of particular chromosomes.

A new screening tool to detect congenital conditions combines blood tests with an ultrasound that measures the thickness of the fetus’s neck fold to diagnose Down syndrome in the first trimester. Ronald Wapner, M.D., director of maternal-fetal medicine, uses the new tool, which was validated by national research led by Columbia.

     The most common type of aneuploidy is Trisomy 21, also known as Down syndrome. For years, women at increased risk of having a child with Down syndrome (women who became pregnant after age 35, for example) were forced to wait until their second trimester of pregnancy before their fetus could be tested. A national trial led by Mary D’Alton, M.D., chair of obstetrics and gynecology at P&S, demonstrated that a first-trimester screening test is far more accurate. The newer test, which combines a blood test for levels of a particular hormone and protein with an ultrasound that measures the thickness of the developing baby’s neck fold, is 87 percent accurate, compared with only 81 percent accuracy for the best second-trimester screening methods. The study, known as the FASTER Trial (First and Second Trimester Evaluation of Risk), involved some 38,000 women at 15 centers nationwide. The results will change obstetrical practice in the United States. “Down syndrome screenings based on either maternal age alone, or an ultrasound or sonogram alone, are no longer justified protocols,” Dr. D’Alton says. She and other experts working with the Society for Maternal-Fetal Medicine have formed the Maternal-Fetal Medicine Foundation to facilitate physician training and quality review for the screening.
     While genetic links may be most obvious in areas like cancer, neurodegenerative disorders, and congenital anomalies, a surprising number of other conditions sometimes have genetic roots as well. Take blindness, for example. The most common cause of vision loss in older adults, a condition called age-related macular degeneration, or AMD, is at its heart a genetic disease. Columbia scientist Rando Allikmets, Ph.D., the William and Donna Acquavella Associate Professor of Ophthalmology and director of research at Harkness Eye Institute, pinpointed inflammation fed by variations in genes known as Factor B and Factor H as the cause of three out of four cases of AMD. “The two genes together explain about three-fourths of the disease,” says Dr. Allikmets. “I don’t know of any other complex disorder in which two genes explain so much.”
     Both genes are part of a pathway that regulates the immune response, called the alternative complement cascade: Factor H turns the pathway down after inflammatory response to triggers, such as infection, while Factor B turns the pathway up to intensify the response. “These are the direct targets right now for finding therapeutic remedies for AMD,” Dr. Allikmets says. Such treatments could be just around the corner, or they could take 10 years, he adds, but they are no doubt urgently needed: AMD affects about 30 percent of the over-70 population, damaging the vision of more than 12 million people in the United States alone.
     Discoveries like Dr. Allikmets’ and others from throughout Columbia’s departments, centers and institutions are being translated at the new Clinical Molecular Genetics Laboratory, opened in August of 2005. “We’ve taken everything from a genetic predisposition to primary pulmonary hypertension to seizure disorders and made available a CLIA-approved clinical lab where patients from around the world can be tested for rare genetic disorders,” says Wendy Chung. “It’s been explosive in terms of growth. Local patients can use it for diagnosis, but it’s also a resource for researchers from around the world. It’s very helpful for scientists who work on orphan diseases, because they can work on more samples and answer some of their most important clinical questions.”

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