Dimensional, Sleep, and Genomic Analyses of Down Syndrome to Elucidate Phenotypic Variability

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The present work falls under an administrative supplement to study Down syndrome (DS) within the existing grant, “Dimensional Analysis of
Developmental Brain Disorders using an Online, Genome First Approach” (R01-MH107431). The study aims to build validated, quantitative measures of psychopathology for DS.

Principal Investigators

Martin, Christa, PhD, FACMG Morse, Anne Marie, MD


Developmental brain disorders (DBD) include a wide range of developmental and psychiatric disorders that are etiologically heterogeneous with variable impacts on neurodevelopmental functioning. Down syndrome (DS) is the most common genetic cause of DBD that historically has been described as having a relatively homogeneous phenotype. However, with increasing life expectancies in individuals with DS, distinct cognitive, behavioral and genetic differences are becoming apparent. To investigate this inter-individual variability, we will use the Research Domain Criteria (RDoC) framework to elucidate risk and resilience to comorbid diagnoses and examine genomic contributors that influence neurodevelopmental functioning. We will add a Down syndrome cohort to our existing grant, Dimensional Analysis of Developmental Brain Disorders, using an Online, Genome- Genomefirst approach to build validated, quantitative measures of psychopathology for DS through the following specific aims:

Aim 1: Onsite and online phenotyping across RDoC domains and constructs of patients with DS and their unaffected family members.

Aim 2: Examination of sleep-wake dysfunction as a contributor to variable expressivity

Aim 3: Identification of quantitative genomic contributors to variable expressivity

The clinical features observed in Down syndrome can be quite variable. Our project will examine the impact that genetic variants and sleep-wake characteristics have on clinical features in individuals with Down syndrome compared to their unaffected family members to determine why there are differences. The results from these analyses will help researchers, families, and clinicians understand the various presentations of Down syndrome, and pave the way towards targeted behavioral and medical interventions.