Abstract
Purpose of ReviewThe 22q11.2 deletion syndrome (22q11DS) is associated with a broad spectrum of neurodevelopmental phenotypes and is the strongest known single genetic risk factor for schizophrenia. Compared to other rare structural pathogenic genetic variants, 22q11DS is relatively common and one of the most extensively studied. This review provides a state-of-the-art overview of current insights regarding associated neurodevelopmental phenotypes and potential implications for 22q11DS and beyond.Recent FindingsWe will first discuss recent findings with respect to neurodevelopmental phenotypic expression associated with 22q11DS, including psychotic disorders, intellectual functioning, autism spectrum disorders, as well as their interactions. Second, we will address considerations that are important in interpreting these data and propose potential implications for both the clinical care for and the empirical study of individuals with 22q11DS. Third, we will highlight variable penetrance and pleiotropy with respect to neurodevelopmental phenotypes in 22q11DS. We will discuss how these phenomena are consistently observed in the context of virtually all rare pathogenic variants and that they pose substantial challenges from both a clinical and a research perspective.SummaryWe outline how 22q11DS could be viewed as a genetic model for studying neurodevelopmental phenotypes. In addition, we propose that 22q11DS research can help elucidate mechanisms underlying variable expression and pleiotropy of neurodevelopmental phenotypes, insights that are likely relevant for 22q11DS and beyond, including for individuals with other rare pathogenic genetic variants and for individuals with idiopathic neurodevelopmental conditions.
Highlights
Purpose of Review The 22q11.2 deletion syndrome (22q11DS) is associated with a broad spectrum of neurodevelopmental phenotypes and is the strongest known single genetic risk factor for schizophrenia
The aims of the International 22q11DS Brain Behavior Consortium (IBBC) included the identification of genetic mechanisms modifying the variable expression of schizophrenia in this syndrome, as well as further characterization of other behavioral and cognitive consequences of the syndrome
Another observation in this regard is that, with the exception of psychotic disorders, studies have found no correlation between cognitive level and the risk for psychiatric disorders in individuals with 22q11DS [13, 92], recent evidence is emerging for an age-specific association between certain specific domains of cognition and psychopathology [93]. 22q11DS appears to have a specific impact on the behavioral phenotype, as well as on the cognitive phenotype
Summary
22q11.2 deletion syndrome (22q11DS) is caused by a heterozygous microdeletion of region 11.2 on the long arm of chromosome 22 [1]. After the discovery of the genetic etiology of this syndrome in the 1990s [1], studies emerged reporting an increased rate of schizophrenia and related psychotic disorders among individuals with 22q11DS [3–6] These observations prompted several investigators across different sites to examine cognitive and behavioral characteristics of individuals from early childhood to adulthood. As a high-risk group, it provides a magnifying lens to study how modifying factors such as additional genetic variability (including deletion size, breakpoints, structure of the intact chromosome, and other rare-rare or rarecommon variant interactions) may contribute to highly variable clinical presentations While results of such studies may be specific to 22q11DS, findings have implications beyond this specific disorder. Emerging data suggest that common and rare variants in the intact
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