Velo-cardio-facial syndrome: A distinctive behavioral phenotype

Abstract

Velo‐cardio‐facial syndrome (VCFS) is the most common contiguous gene disorder and one of the most common multiple anomaly syndromes in humans. Over 180 anomalies have been delineated in the syndrome; the most common of which are the behavioral manifestations. Learning disabilities, psychiatric illness, attention deficit disorder, and a variety of developmental disorders are nearly ubiquitous findings in VCFS and are not mutually exclusive, often overlapping to create a distinctive yet confusing phenotypic picture. In addition, standard treatments for each of these separate clinical findings may not be effective, and may even be potentially harmful in individuals with VCFS, such as the use of stimulants for hyperactivity. VCFS is caused by a small deletion of DNA from the long arm of chromosome 22. Researchers are currently studying the deletion located at 22q11.2 because of the possibility that a firm genetic link to psychiatric illness and learning disorders may be found. This report describes the behavioral manifestations of VCFS, emphasizing the overlap between the cognitive and psychiatric disorders that are so common in this syndrome. MRDD Research Reviews 2000;6:142‐147. © 2000 Wiley‐Liss, Inc.

Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia

“…76 However, two other studies in human post-mortem samples have shown no relationship between the Val 108/158 Met genotype and COMT mRNA expression, 77,78 and the former study did not show any difference in the laminar pattern of COMT mRNA expression related to the Val 108/158 Met genotype either. 77 As pointed out previously 76 demonstration of reduced expression of COMT fits the concept of haploinsufficiency: the deletions found in VCFS almost always include COMT 47,51,52 and are associated with an increase in psychosis. 50 This predisposition might arise from neurodevelopmental abnormalities in common with VCFS 54,79 and schizophrenia, 80,81 or perhaps through disturbances in catecholamine neurotransmission due to COMT (see below), although the evidence seems to more strongly support the neurodevelopmental hypothesis.…”

“…54 Another possibility is that various behavioral and psychiatric manifestations of VCFS, including psychosis, might be due to primary vascular dysgenesis and resultant abnormal blood supply in some brain regions. 47 Decreased expression also fits the hyperdopaminergic hypothesis of schizophrenia 82,83 if reduced COMT expression is expected to lead to increased dopamine. However, this may depend on the brain region in question.…”

“…Many anomalies have been reported in VCFS, with behavioral manifestations being the most common. 47 Approximately 30% of VCFS patients develop psychosis, largely schizophrenia, [48][49][50] and schizotypy scores are higher in nonpsychotic VCFS subjects than controls. 50 The region containing TXNRD2, COMT, and ARVCF is deleted in over 99% of VCFS cases.…”

“…50 The region containing TXNRD2, COMT, and ARVCF is deleted in over 99% of VCFS cases. 47,51,52 These deletions would lead to a hemizygous state over the deleted region, and likely haploinsufficiency for some of the gene products, which might predispose to psychosis. In any case, with the exceptions of being the monozygotic twin of a schizophrenic or being the offspring of two parents each having schizophrenia, 53 VCFS represents the highest known risk factor for developing schizophrenia.…”

Developmental trajectories of brain structure in adolescents with 22q11.2 deletion syndrome: A longitudinal study

“…Thus, 22q11.2DS is the most common microdeletion syndrome known in humans. The phenotypic expression of 22q11.2DS is extremely broad and includes physical anomalies, cognitive deficits, and psychiatric manifestations (Shprintzen, 2000).…”