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Rare Genetic Syndromes as a Window into the Genetic Architecture of Mental Disorders


Geetha Senthil, Ph.D.
Office of Genomics Research Coordination


This initiative would foster collaborative and coordinated efforts to characterize the underlying genetic architecture of diverse neuropsychiatric phenotypes within and across rare genetic syndromes and identify the shared genetic risk with idiopathic neuropsychiatric disorders.


Subjects with rare genetic lesions of large effect, such as single gene mutations (e.g., MECP2, CHD8, SCN2A) and copy number variants (e.g., 3q29 Del, 16p11.2 Del/Dup, 22q11.2 Del/Dup), are at an elevated risk for developing a variety of neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, anxiety, and attention deficit hyperactivity disorder. The phenotypic presentations in these subjects often parallel those seen in idiopathic cases of neuropsychiatric disease. However, it is not yet understood how the same genetic lesion can lead to a variety of phenotypic outcomes and different genetic lesions can converge on similar phenotypic expressions. A more detailed genetic and dimensional phenotypic characterization of populations with rare genetic syndromes is necessary to better understand the genetic and neurobiological underpinnings of the variability of neuropsychiatric phenotypic expression. Past efforts have been hindered by small sample sizes, deficient integration and standardization of phenotypic measures, and a lack of cutting-edge genomic technologies. A coordinated investigation is therefore needed to amass a sufficient, well-phenotyped patient sample to inform robust genetic analyses. To meet this need, this initiative would encourage such collaborative and coordinated research efforts in areas including, but not limited to, the following:

  • Deeper Genetic Analyses:
    • Analyzing the genome-wide risk contributions of common and rare variation, as well as how such variation influences the risk contribution of the primary lesion.
    • Characterizing the primary lesion and delineating its impacts (e.g., mapping of breakpoints, allelic variation within haplo-insufficient genes, gene regulation).
  • Dimensional Phenotyping:
    • Assessing prospective cohorts using core phenotypic measures that may be applicable across multiple syndromes (e.g., Research Domain Criteria (RDoC), quantitative traits).
    • Harmonizing existing phenotypic data within and across syndromes, including mapping to neuropsychiatric domains, as above.

Investigators under this initiative would form a network to facilitate harmonization efforts across and within syndromes and generate a resource of bio-samples and phenotypic and genetic data for broader dissemination to the scientific community.