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Genomic Risk and Resilience in 22q11 Deletion Syndrome: A Window into the Genetic Architecture of Mental Disorders

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Thomas Lehner, Ph.D., M.P.H.
Director, Office of Genomics Research Coordination


The goal of this initiative is to use 22q11 deletion syndrome (DS) as a model to study and discover genetic risk and resilience factors and pathways for neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. The projects funded by this initiative will leverage the International 22q11DS Research Consortium and its relationships with the 22q11DS patient community, and will include the majority of subjects currently enrolled in scientific studies.


Children born with 22q11DS (variants of which are known as DiGeorge Syndrome or velo-cardio-facial syndrome) frequently suffer from cardiac and craniofacial abnormalities. Intriguingly, in addition to these malformations, these children also frequently express a variety of neuropsychiatric disorders. Patients have a high prevalence of ADHD, anxiety, depression, autistic, and psychotic features, and up to 30% of adolescents and adults with the syndrome develop schizophrenia or psychosis. Even children who do not have a clinical neuropsychiatric diagnosis often show variable deficits in neurocognitive domains across all stages of development. Thus 22q11DS offers a unique window into studying the genetic architecture of neuropsychiatric disorders, with a particular focus on the impact of particular genomic risk and resilience factors during the course of development.

In the past, 22q11DS research has been hindered by a lack of integration and standardization of phenotypic methods and limited use of cutting-edge genomics technologies. Moreover, the field has been fragmented into many research groups each studying a small number of patients, making it is unlikely that any individual group would be able to gather sufficient samples to reach statistical power to draw genetic conclusions about the etiology of the disorders expressed by the syndrome. The 22q11DS Research Consortium (the Consortium) is a group of approximately 120 investigators from more than 20 countries and 3 continents that self-organized with the goal to further the study of 22q11DS and its associated phenotypes. Although 22q11DS is the most common genomic microdeletion syndrome, it is nevertheless rare, occurring in approximately 1:4,000 births. Researchers estimate that there are only 3,000-4,000 subjects with the syndrome enrolled in medical genetic studies worldwide, and the majority of these cases are affiliated with Consortium researchers. Most of these studies are very small (20-100 subjects) and are funded by a variety of US and international, government and non-government mechanisms.

Thus, this initiative aims to support a collaborative project with the goal of integrating all existing samples, to standardize existing phenotypic data, and to apply sophisticated genomic technologies to the study of the brain-behavior phenotypes and disorders associated with 22q11DS. The research will focus on the deletion region and its interaction with other functional elements of the genome, with the goal to discover risk and resilience factors for mental disorders. In addition, the diversity of neuropsychological and neuropsychiatric phenotypes associated with 22q11DS provides a rich opportunity for a dimensional exploration of genetic risk in the framework of the Research Domain Criteria (RDoC) Project.

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