The example of 22q11DS

A relatively common chromosomal CNV, 22q11DS, affects approximately 1 in 4000 live births. It is associated with increased rates of cardiac abnormalities, a range of other physical consequences and intellectual disability. 22q11DS is also associated with markedly high rates of schizophreniform and affective psychosis with peak age at onset in the early 20s. ^{Reference Murphy, Jones and Owen3} Studies of children with 22q11DS also reveal high rates of childhood psychopathology including symptoms of ADHD, autism spectrum disorder and anxiety disorders. ^{Reference Jonas, Montojo and Bearden4,Reference Niarchou, Zammit, van Goozen, Thapar, Tierling and Owen5} Strikingly, 22q11DS has also been shown to be a risk factor for early-onset Parkinson's disease in older individuals. ^{Reference Jonas, Montojo and Bearden4} Overall, therefore, 22q11DS is associated with increased risk for a range of neuropsychiatric and neurodegenerative disorders that present across the lifespan. A similarly wide range of neuropsychiatric outcomes spanning developmental stages is also seen for other CNVs associated with psychiatric risk, ^{Reference Owen1} raising the question as to how individual genetic lesions can increase risk for a range of conditions each with distinct core symptoms.

The effect of neurodevelopmental stage

One possible explanation of the range of outcomes seen following 22q11DS and other genetic risk factors is that the phenotypic effects of the deletion are moderated by the age of penetrance in a given individual. The primary neural mechanisms involved in central brain functions such as learning and prediction are established early in life, but the relative maturation of different brain circuits and the nature of the information being laid down differs at various stages of development. Disruptions of core aspects of brain function at different ages are therefore likely to result in the emergence of different symptoms. For example, in early postnatal life key developmental achievements include the acquisition of motor skills, imitative social behaviours and language. ^{Reference Le Bel, Pinedad and Sharma6} These skills are typically gained in the developmental environment provided by the family and immediate social group. The impact on brain circuitry during these developmental stages is likely to be associated with outcomes associated with altered language development and basic motor and social functions such as are seen in developmental disorders including autism and ADHD. In contrast, after puberty exploration away from the family group increases and learning and prediction must be applied to a different set of circumstances. ^{Reference Konrad, Firk and Uhlhaas7} Disruption of normal brain function at this developmental stage is likely to reflect maturational processes occurring in the post-pubertal brain as it interacts with a wider range of environments, and may be manifest as psychosis and altered motivational states, such as mood disorders. In later life neurodegenerative processes develop in vulnerable populations and may be exacerbated by risk factors that have an impact on the development, maintenance and function of key brain circuitry.

It is not currently known whether the different conditions associated with 22q11DS arise from one primary underlying pathological deficit, or through separate mechanisms. ^{Reference Jonas, Montojo and Bearden4} There are multiple neurally expressed genes within the 22q11DS region, each with differing expression patterns and developmental trajectories and potentially having an impact on multiple different brain circuits/systems at different developmental stages, many of which may contribute to vulnerability to the range of neuropsychiatric outcomes seen in 22q11DS. However, several of the neuropsychiatric conditions associated with 22q11DS show overlap at the resolution not just of loci or even individual genes, but even of mutations with similar functional (loss-of-function) effects. ^{Reference Fromer, Pocklington, Kavanagh, Williams, Dwyer and Gormley8} Thus, it remains possible that deletion of either a single gene or multiple genes within the 22q11DS region might contribute to the diverse neurodevelopmental outcomes seen in 22q11DS.

Notably, many of the neuropsychiatric outcomes seen in 22q11DS have been associated with alterations in the regulation of monoaminergic functioning. Disruption of the regulation of monoaminergic systems such as mesostriatal dopamine involved in learning and reward may therefore represent one common aspect of the vulnerability to neuropsychiatric symptoms seen in 22q11DS that would be expected to produce different outcomes at different developmental stages. However, detailed studies of monoamine levels and regulation in 22q11DS are currently lacking and more needs to be known about the basic pathophysiology in 22q11DS before any specific conclusions can be drawn.

Implications for research and classification

A clear priority for future research will be the longitudinal characterisation of psychopathology in individuals bearing genetic lesions such as CNVs conferring high risk for neuropsychiatric disorders. Only through longitudinal cohort studies of these risk factors will we truly understand the nature and interrelationship of symptom emergence over neurodevelopment. Such studies will also provide an important opportunity to study the development of associated physical comorbidities in these populations, with additional potential benefits in terms of health monitoring and intervention. Interpreting the emergence of symptoms at different developmental stages will also greatly benefit from further study of the normal development and functional maturation of brain systems such as the mesolimbic dopaminergic projections and associated cortico-striatal circuitry. Understanding of the biological effects and differential penetrance of CNVs will also be advanced by the ability to study development in meaningful cellular and animal models of these conditions.

In the longer term these findings will also have major implications for how we view the classification of psychiatric disorders. ^{Reference Owen1} Current classification systems view neurodevelopmental disorders such as autism and adult disorders such as schizophrenia as distinct. However, if individual specific risk factors increase risk for both ‘developmental’ and ‘adult’ conditions dependent on the timing of onset, classifications based on aetiology will eventually need to reflect a matrix of risk including both lesion type and developmental stage. ^{Reference Owen1} As the identification of genetic risk factors such as CNVs becomes more common in children and adults presenting to clinical genetic services, understanding risk across the neurodevelopmental age range and developing classification systems that reflect the true nature of risk will become an increasingly pressing clinical concern.

Funding

This work was supported by a Wellcome Trust Strategic Award (503147), Medical Research Centre (MRC) Centre Grant (G0801418), MRC programme grant (G0800509) and grants from The Waterloo Foundation.