Genetics of Childhood Disorders: XXV. Velocardiofacial Syndrome

Abstract

Velocardiofacial syndrome (VCFS) is a genetic syndrome with a range of psychiatric symptoms. Identification of the gene(s) involved in its expression should lead to an improved understanding of both normal CNS development and how specific mutations contribute to psychiatric disorders. VCFS was first defined by Robert Shprintzen more than 20 years ago. Only in recent years, with the increased interest in molecular biology in psychiatry, has it received wider recognition. VCFS has an estimated prevalence of 1 in 4,000, making it the second most common genetic syndrome after Down syndrome. It is caused by a microdeletion in the long arm of chromosome 22. Several disorders, such as DiGeorge syndrome, some cases of Pierre-Rubin syndrome, and other rarer syndromes, are caused by a seemingly identical microdeletion. Identification of the gene(s) that are affected by the deletion will be required before it is known whether the same or different genes contribute to the expression of these disorders. Together with VCFS, they are collectively referred to as the 22q11 deletion syndromes (22qDS). Ninety percent of patients with 22qDS have a deletion of approximately 3 million base pairs, while 7% have smaller deletions of 1.5 million bases. Similar to other syndromes caused by a microdeletion, the molecular diagnosis of 22qDS is usually made by fluorescence in situ hybridization (FISH) (Ward et al., 1999). In FISH, a fluorescently labeled sequence of a few thousand nucleotides is constructed in the laboratory. This sequence is used as a probe that will bind to the complementary sequence of bases on chromosome 22. As there are two copies of each chromosome, two hybridization signals will appear on the FISH examination in the normal individual. In those cases in which a deletion is present, fluorescence will be detected on only one chromosome (Fig. 1). Ninety-five percent of 22qDS can be detected with this technique. The rest fail to be detected because they are caused by unique deletions or unbalanced translocations. There are several major clinical characteristics of 22qDS. Congenital heart disease is present in 74% of patients with 22qDS. The most common are tetralogy of Fallot, interrupted aortic arch, and ventricular septal defect. Screening of patients with cardiac anomalies ascertained at cardiac clinics determined that the deletion is present in 3% to 15% of them. The prevalence of the deletion among cardiac patients is highest for