A genomic approach to autism and schizophrenia risk through 17q12 CNVs

Although rare genetic abnormalities can collectively explain up to 35% of cases of autism and strongly contribute towards schizophrenia risk, the study of individual rare genetic variants is often hampered by their low frequency in the population and the absence of standardized remote assessments that can uncover and characterize the pleiotropy that is often a hallmark of these rare genetic variants. This proposal will study individuals with copy number variants in 17q12 (deletions and duplications) as a model of a rare genetic variant that confers high neuropsychiatric risk using mobile based platforms for categorical and dimensional neuropsychiatric and somatic assessments, and to evaluate the contribution of common genetic variation towards the expression of somatic and psychiatric phenotypes, setting the grounds for a strategy that can be expanded to other rare genetic variants that confer high risk for neuropsychiatric disorders.

Assessing the effect of rare and common variants on phenotypic variability associated with 16p12.1 deletion

This project primarily investigates the 16p12.1 deletion as a paradigm for understanding these complex neurodevelopmental disorders. This deletion is enriched in children with a variety of neurodevelopmental disorders, including developmental delay, epilepsy, and schizophrenia, and is inherited in >95% of cases from a mildly affected parent (Girirajan et al, Nature Genetics, 2010; Pizzo et al, Genet Med, 2019). Thus, it confers varying disease risk even among carriers within the same family. The 16p12.1 deletion also contributes to increased risk for schizophrenia and cognitive defects in the general population (Rees et al, HMG, 2014; Stefansson et al, Nature, 2014). Affected children with the deletion have an increase in “second-hits” (rare variants outside of the 16p12.1 region) compared to their carrier parents, a finding that can be generalizable for other variably-expressive CNVs (Girirajan et al, NEJM, 2012). This finding suggests that the 16p12.1 deletion and other variably-expressive CNVs sensitize the genome for a range of neurodevelopmental outcomes, while second-hits modulate the ultimate disease trajectory. However, the genetic basis of this increased sensitivity is not completely understood. This study analyzes more than 150 families with 16p12.1 deletion using whole genome sequencing and quantitative assessments for developmental, cognitive, psychiatric, and behavioral features. The results obtained from this analysis will be used to perform genotype-phenotype correlations to identify specific effects of second hits towards variability of phenotypes associated with the deletion. Harmonization and integration of this data with those from other CNVs studied as part of the G2MH consortium will suggest common genetic underpinnings for neuropsychiatric disorders.

The 3q29 project

The 3q29 Project, led by Dr. Jennifer Mulle at the Robert Wood Johnson School of Medicine at Rutgers University, is focused on understanding the phenotypic spectrum, molecular mechanism, and natural history of the 3q29 deletion and 3q29 duplication syndromes.

To meet these goals, we pursue scientific investigation across the research spectrum, from basic science to clinical translational work. In collaboration with the G2MH Network, our latest studies will accomplish the following:

Aim 1: To determine and quantify the behavioral and clinical phenotype in 200 probands with 3q29 deletion syndrome.

Using our validated remote phenotyping protocol, we will characterize 200 new study subjects, and identify the full phenotypic spectrum, sex-dependent phenotypic risks and significant comorbid relationships in 3q29 deletion syndrome. We will also quantify parental phenotypes along four dimensions: cognitive ability, social behavior, executive function, and symptoms of psychosis including sub-threshold psychosis. We will contextualize the burden of illness in 3q29 deletion syndrome relative to departure from mid-parental phenotype, to clarify the range of phenotypic heterogeneity in 3q29 deletion syndrome.

Aim 2: To test the hypothesis that genetic background influences the 3q29 deletion phenotype.

We will assess the contribution of polygenic background to key phenotypes including cognitive ability, executive function, and psychosis. We will also perform whole genome sequencing to identify the contribution of second-site rare variants to phenotypic heterogeneity.

Aim 3: To compare phenotypes and risk modifiers between 3q29 deletion syndrome and >2,000 samples from other genomic disorders through a large collaborative network.

In collaboration with the NIMH-sponsored Genes 2 Mental Health Network, we will compare the phenotypic spectrum and risk modifiers of 3q29 deletion syndrome with other genomic disorders associated with neurodevelopmental and neuropsychiatric disorders, including 22q11.2 deletion and duplication, 16p11 deletion and duplication, 1q21 deletion, and others.

Impact: Upon completing this project, we will have a rich and nuanced understanding of 3q29 deletion phenotypes; we will articulate and quantify factors contributing to the variance in phenotypic severity; and we will produce a side-by-side comparison of the 3q29 deletion with other CNV disorders. These data will pave the way toward our long-term goal: harmonized studies of convergent biology among rare genetic disorders.