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Phenotypic Manifestations of Rare Variations Associated with Neurodevelopmental Disorders


Anjené M. Addington, Ph.D., M.P.H.
Division of Neuroscience and Basic Behavioral Science


The goal of this initiative is to estimate population prevalence of rare variants associated with neurodevelopmental disorders using very large, unselected populations (epidemiologic cohorts), and conduct in-depth clinical assessments of variant carriers to determine penetrance, range of associated phenotypes, and genotype-by-environment interactions.


Recent studies have confirmed the association of many genetic variants and neurodevelopmental disorders. In addition to hundreds of common variants with small individual effects, rare genetic variants, especially long stretches of DNA that have been either duplicated or deleted in particular regions of the genome (i.e., copy number variants (CNVs)), have been identified as prominent risk factors with moderate to large effect sizes. While CNVs are now broadly accepted as major components of neurological and non-neurological disease, their prevalence in the general population remains unknown. Where CNVs have been identified, they were found to be highly pleiotropic; that is, the same duplications/deletions have been implicated in a range of seemingly disparate neuropsychiatric disorders. These findings challenge existing classification criteria, but also provide opportunities to understand the etiology and inter-relatedness of psychiatric categories.

For the majority of disorders, the role of CNVs as causal factors is unknown, though studies of autism spectrum disorder, schizophrenia, and intellectual disability suggest that CNVs are implicated as major causal factors in neurodevelopmental disorders and account for approximately 7-10% of cases. Intriguingly, the same CNVs have been associated with these and other disorders—including both cardiovascular and metabolic disorders—indicating a shared pathogenesis. In order to make sense of this phenomenon, diagnosis-based genomic studies need to be supplemented by variant-based large population studies. Only a large population study, for which detailed phenotypic data are available, can approximate overall variant prevalence and penetrance, and delineate the extent to which gene networks cross disease boundaries. Enhancing neurodevelopmental data with longitudinal medical records will further facilitate our understanding of the role of recurrent rare variants in more than one organ system.

An important next step in understanding rare variants on both a clinical and mechanistic level is to utilize a variant-led approach (genotype-to-phenotype) in a very large population-based sample, for which substantial health related phenotypic and environmental data are available and patient re-contact is possible. Such availability would permit the best estimate of the prevalence of these risks factors and their overall clinical burden.

This initiative would accomplish the following goals:

  • Estimate prevalence of rare variants that are associated with neurodevelopmental disorders in diverse populations;
  • Characterize genotype-to-phenotype relationships through in-depth clinical assessments of rare-variant carriers:
    • Structured diagnostic psychiatric interviews;
    • Neurocognitive testing measuring: valence systems, cognition and memory, social processing, and arousal;
    • Brain structure/function measures;
    • Gene-environment interaction effects; and,
    • Overall medical status.
  • Estimate penetrance of disease-related rare variants, using the range of identified phenotypes both within and beyond the neuropsychiatric domain.

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