Beyond IQ: Executive function deficits and their relation to functional, clinical, and neuroimaging outcomes in 3q29 deletion syndrome

Background 3q29 deletion syndrome (3q29del) is a rare (∼1:30,000) genomic disorder associated with a wide array of neurodevelopmental and psychiatric phenotypes. Prior work by our team identified clinically significant executive function deficits in 47% of individuals with 3q29del; however, the nuances of executive function in this population have not been described. Methods We used the Behavior Rating Inventory of Executive Function (BRIEF) to perform the first in-depth assessment of real-world executive functioning in a cohort of 32 individuals with 3q29del (62.50% male, mean age=14.50±8.26 years). High-resolution structural magnetic resonance imaging was performed on a subset of participants (n=24). Results We found global deficits in executive function; individuals with 3q29del scored significantly higher than the population mean on the BRIEF Global Executive Composite (GEC) and all subscales. 81.25% of study subjects (n=26) scored in the clinical range on at least one BRIEF subscale. BRIEF GEC T scores were significantly higher among 3q29del participants with a diagnosis of ADHD, and BRIEF GEC T scores were significantly associated with schizophrenia spectrum symptoms as measured by the SIPS. The BRIEF-2 ADHD Form accurately (sensitivity=86.70%) classified individuals with 3q29del based on ADHD diagnosis status, highlighting its potential use as a screener for ADHD in this population. BRIEF GEC T scores were significantly correlated with cerebellar white matter and subregional cerebellar cortex volumes. Conclusions Together, these data expand our understanding of the phenotypic spectrum of 3q29del and identify executive function as a core feature linked to both psychiatric and neuroanatomical features of the syndrome. ### Competing Interest Statement CAS reports receiving royalties from Pearson Assessments for the Vineland-3. The remaining authors have no competing interests to disclose. ### Funding Statement This work was supported by the National Institute of Mental Health grant R01 MH110701 (PI Mulle) and R01 MH118534 (MPI Schultz/Mulle). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of Emory University gave ethical approval for this work. IRB of Rutgers University gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.