Study protocol for The Emory 3q29 Project: evaluation of neurodevelopmental, psychiatric, and medical symptoms in 3q29 deletion syndrome

Abstract

Background3q29 deletion syndrome is caused by a recurrent hemizygous 1.6 Mb deletion on the long arm of chromosome 3. The syndrome is rare (1 in 30,000 individuals) and is associated with mild to moderate intellectual disability, increased risk for autism and anxiety, and a 40-fold increased risk for schizophrenia, along with a host of physical manifestations. However, the disorder is poorly characterized, the range of manifestations is not well described, and the underlying molecular mechanism is not understood. We designed the Emory 3q29 Project to document the range of neurodevelopmental and psychiatric manifestations associated with 3q29 deletion syndrome. We will also create a biobank of samples from our 3q29 deletion carriers for mechanistic studies, which will be a publicly-available resource for qualified investigators. The ultimate goals of our study are three-fold: first, to improve management and treatment of 3q29 deletion syndrome. Second, to uncover the molecular mechanism of the disorder. Third, to enable cross-disorder comparison with other rare genetic syndromes associated with neuropsychiatric phenotypes.MethodsWe will ascertain study subjects, age 6 and older, from our existing registry (3q29deletion.org). Participants and their families will travel to Atlanta, GA for phenotypic assessments, with particular emphasis on evaluation of anxiety, cognitive ability, autism symptomatology, and risk for psychosis via prodromal symptoms and syndromes. Evaluations will be performed using standardized instruments. Structural, diffusion, and resting-state functional MRI data will be collected from eligible study participants. We will also collect blood from the 3q29 deletion carrier and participating family members, to be banked at the NIMH Repository and Genomics Resource (NRGR).DiscussionThe study of 3q29 deletion has the potential to transform our understanding of complex disease. Study of individuals with the deletion may provide insights into long term care and management of the disorder. Our project describes the protocol for a prospective study of the behavioral and clinical phenotype associated with 3q29 deletion syndrome. The paradigm described here could easily be adapted to study additional CNV or single gene disorders with high risk for neuropsychiatric phenotypes, and/or transferred to other study sites, providing a means for data harmonization and cross-disorder analysis.

New phenotypes associated with 3q29 duplication syndrome: Results from the 3q29 registry

“…If our study sample is taken from the extreme end of 3q29dup phenotypes, scores on the SRS and CBCL/ABCL and reported health problems and diagnoses are likely to be inflated as compared to the true prevalence in the 3q29dup population. Direct assessment of individuals with 3q29dup by the Emory 3q29 Project (http://genome.emory.edu/3q29/) (Murphy et al, ) aim to address some of the weakness of this work by performing comprehensive gold‐standard evaluations by expert clinicians.…”

Convergent and distributed effects of the schizophrenia-associated 3q29 deletion on the human neural transcriptome

“…Participants and their families traveled to Atlanta, GA, where phenotypic assessments were conducted using gold-standard diagnostic instruments administered by expert clinicians as part of a comprehensive and systematic phenotyping protocol developed by the Emory 3q29 Project [95]. This study has been approved by the Emory University Institutional Review Board and all participants (or legal guardians) provided informed consent.…”

Behavioral changes and growth deficits in a CRISPR engineered mouse model of the schizophrenia-associated 3q29 deletion

“…The B6.Del16 +/Bdh1-Tfrc mouse provides an entry point for such genetic dissection and ultimately, understanding of the circuitry and molecular mechanisms underlying these phenotypes. Towards this goal, the behavioral deficits provide clues to which brain regions may be most affected by the 3q29 deletion: the MWM is a hippocampaldependent task (33,34), social interaction is a striatum-dependent task, (35), and startle response is dependent on the caudal pontine reticular nucleus (36 (37). Phenotypic data from the B6.Del16 +/Bdh1-Tfrc mice can inform human phenotyping protocols and downstream analyses.…”