Researchers collaborate on major new federal study of how VCFS manifests in body

SYRACUSE, N.Y. — SUNY Upstate Medical University researchers Robert J. Shprintzen, Ph.D., and Wendy Kates, Ph.D., are participating in a four-year, $2 million National Institutes of Health (NIH) funded study of how Velo-Cardio-Facial Syndrome (VCFS) manifests itself within the human body.

VCFS is a multiple congenital anomaly disorder characterized by life-threatening heart defects, learning and/or behavioral disabilities, craniofacial malformations, immune deficiencies, and hypocalcaemia. It has also been linked to psychiatric disorders. Findings from the study may lead to the development of new therapies to help manage the effects of the syndrome, researchers say.

Shprintzen and Kates are collaborating with researchers from Albert Einstein College of Medicine in New York, the Children's Hospital of Philadelphia and Rockefeller University on the study, "Genetic Modifiers for 22q11.2 Deletion Syndrome." The study is funded by the NIH's Heart Development and Structural Disease Branch, Division of Cardiovascular Diseases of the National Heart, Lung and Blood Institute.

VCFS is caused by a small deletion of DNA-the 3 Mb deletion from chromosome 22, located at 22q11.2. One of the strongest candidate genes for VCFS is TBX1 that is expressed in the heart and pharynx during embryonic development.

According to Shprintzen, the major goal of the study is to identify genetic modifiers for VCFS by performing genotype to phenotype (interaction of genetics and the environment) correlations. "VCFS is fully penetrant but it varies in how it affects the body," said Shprintzen, professor and director of the International Center for Velo-Cardio-Facial Syndrome. "One of the greatest challenges in this field is to determine the basis for its varied expressivity and to obtain sufficient numbers of people to study. Through this collaboration, we are now able to combine patient populations to perform a broader-based study."

Shprintzen and Kates, associate professor of psychiatry and behavioral sciences, and their colleagues will collect clinical and molecular genetics data on more than 1,000 people with VCFS. The researchers will perform a whole genome association study on the DNA from 300 VCFS patients divided equally among those with and without significant heart defects. A biological replication on 700 patients and a joint statistical analysis will be performed. The researchers will also restratify the patient set for other clinical malformations.

The researchers will also assess genes in the genetic pathway of TBX1 in 1,000 individuals with VCFS who have the 3 Mb deletion. "It is likely that modifiers for the prominent malformations in the syndrome may confer susceptibility to sporadic birth defects with unknown causes," said Shprintzen.

VCFS is the most common microdeletion syndrome (contiguous gene disorder) and one of the most common multiple anomaly syndromes in humans. More than 180 anomalies have been delineated in the syndrome. VCFS affects 1 out of 2,000 individuals in the U.S..

For more information about VCFS, visit http://upstate.edu/uh/ent/vcf/ or http://www.vcfsef.org.