A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome.

This review looks at 22q11.2 deletion syndrome as a way to better understand autism and schizophrenia. People with this genetic condition have increased chances of developing these conditions, but not everyone with the deletion develops the same problems. Researchers are studying this genetic change to understand why some people are more affected than others and how genetics influences autism and schizophrenia development.

This comprehensive review examines 22q11.2 deletion syndrome (22q11DS) as a model for understanding the genetic basis of autism and schizophrenia spectrum disorders. The authors explore how rare pathogenic genetic variants contribute to variable risks for neurodevelopmental conditions including ASD, schizophrenia, and intellectual disability. Using 22q11DS as a paradigm, the review addresses three key questions: integrating genetic findings with current psychiatric classification systems, learning from individuals with shared genetic bases for ASD/schizophrenia, and understanding variable penetrance and pleiotropy. The authors synthesize findings from clinical and preclinical studies to elucidate genotype-phenotype associations and mechanisms underlying variable expression of neuropsychiatric phenotypes, concluding with research priorities for developing novel therapeutics.

This genetics-first approach may inform diagnostic practices by integrating genetic testing with behavioral assessments. Understanding variable expression of neuropsychiatric phenotypes in 22q11DS could guide personalized intervention strategies and help identify individuals at risk for developing autism or schizophrenia spectrum disorders earlier in development.

As a review article, this study does not present new empirical data. The abstract does not specify the methodology for study selection or quality assessment of included research, limiting evaluation of the comprehensiveness and rigor of the synthesis.

Recently, increasing numbers of rare pathogenic genetic variants have been identified that are associated with variably elevated risks of a range of neurodevelopmental outcomes, notably including Autism Spectrum Disorders (ASD), Schizophrenia Spectrum Disorders (SSD), and Intellectual Disability (ID). This review is organized along three main questions: First, how can we unify the exclusively descriptive basis of our current psychiatric diagnostic classification system with the recognition of an identifiable, highly penetrant genetic risk factor in an increasing proportion of patients with ASD or SSD? Second, what can be learned from studies of individuals with ASD or SSD who share a common genetic basis? And third, what accounts for the observed variable penetrance and pleiotropy of neuropsychiatric phenotypes in individuals with the same pathogenic variant?

In this review, we focus on findings of clinical and preclinical studies of the 22q11.2 deletion syndrome (22q11DS). This particular variant is not only one of the most common among the increasing list of known rare pathogenic variants, but also one that benefits from a relatively long research history. Consequently, 22q11DS is an appealing model as it allows us to: (1) elucidate specific genotype-phenotype associations, (2) prospectively study behaviorally defined classifications, such as ASD or SSD, in the context of a known, well-characterized genetic basis, and (3) elucidate mechanisms underpinning variable penetrance and pleiotropy, phenomena with far-reaching ramifications for research and clinical practice. We discuss how findings from animal and in vitro studies relate to observations in human studies and can help elucidate factors, including genetic, environmental, and stochastic, that impact the expression of neuropsychiatric phenotypes in 22q11DS, and how this may inform mechanisms underlying neurodevelopmental expression in the general population.

We conclude with research priorities for the field, which may pave the way for novel therapeutics.