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

Abstract

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.

Fig. 1. One challenge of biomarker research in a clinical population, such as patients with a specific neurodevelopmental diagnosis (e.g., ASD or schizophrenia), is the underlying etiological heterogeneity (different colored circles).

Theoretically, extracting a subset of patients based on a shared genetic origin (red circles only) such as 22q11DS, could reduce heterogeneity, thereby improving the ability to detect meaningful biomarker signals. Notable examples include the highly reproducible neuroanatomic signature of 22q11DS-associated psychosis [169, 156, 159], and emerging evidence for distinguishable ASD profiles in subgroups of individuals with ASD according to genetic etiology [–173]. Examples of reduced heterogeneity in genetically selected subsets of patients are also observed in other genetic conditions; for example, distinctive electrophysiological brain wave patterns observed in children with ASD related to the 15q11.2-q13.2 duplication compared to children with idiopathic ASD [174], and macrocephaly and gastrointestinal problems in children with ASD related to mutations in CHD8 [175].

Fig. 2. Select neurobiological alterations may underlie psychiatric heterogeneity in 22q11.2 deletion syndrome.

To reduce complexity, one model animal system and imaging modality are shown to demonstrate neurobiological correlates of psychiatric phenotypes in 22q11.2 deletion syndrome. A Left panel shows a recent elegant molecular study in a 22q11.2 mouse model. Superficial (layer 2/3) pyramidal and GABA neurons are shown in focus in red-orange and green colors, respectively. These neurons had widespread alterations that were not seen in the deeper layer neurons (faded colors). Alterations in green may underlie, at least in part, cortical thickness increases in 22q11DS human subjects observed on structural MRI (right panel). Blue colors indicate greater cortical thickness (CT) in 22q11DS versus controls. Alterations in red may index, at least in part, surface area (SA) decreases in 22q11DS human subjects on structural MRI (right panel). Red colors indicate lower SA in 22q11DS versus controls. The dashed arrow indicates that these are hypothesized contributors across modalities and species, and that further studies are needed to elucidate many unanswered questions linking these associations mechanistically. B Distributed alterations in cortical structure and function in humans are hypothesized to contribute to a range of brain-related phenotypes and psychiatric disorders in 22q11DS, resulting in pleiotropy of diagnostic labels and intermediate traits, as well as a continuum of severity for each of these. ADHD attention-deficit/hyperactivity disorder, INs interneurons (GABA neurons), MGE medial ganglionic eminences, PNs projection (pyramidal) neurons, Adapted from [77, 156]).

Fig. 3. High-impact genetic variants such as the 22q11.2 deletion are thought to alter brain developmental programs.

The resulting (range of) phenotypic outcomes in carriers of such variants are probabilistic due to the stochastic trajectories of developmental programs, analogous to the course of water flowing down a hilly landscape; trajectories of brain development are further influenced by additional genetic and environmental factors. The result of the interplay of these factors leads to variable phenotypic manifestations associated with the primary genetic variant, as represented by the color spectrum.

Fig. 4. Symptom overlap between ASD and SSD.

While the developmental timecourse of these diagnostic groups differs, specific symptoms and traits (indicated by the overlapping circles) are common to both. For some symptoms (e.g., blunted affect), it is difficult to determine whether they reflect a deficit in nonverbal communication vs. negative symptoms. Others (e.g., delusions) are unique to SSD vs. ASD.