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

Abstract

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 (EF) deficits in 47% of individuals with 3q29del; however, the nuances of EF 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 EF in a cohort of 32 individuals with 3q29del (62.5% male, mean age = 14.5 ± 8.3 years). All participants were also evaluated with gold-standard neuropsychiatric and cognitive assessments. High-resolution structural magnetic resonance imaging was performed on a subset of participants (n = 24).

Results: We found global deficits in EF; individuals with 3q29del scored higher than the population mean on the BRIEF global executive composite (GEC) and all subscales. In total, 81.3% of study subjects (n = 26) scored in the clinical range on at least one BRIEF subscale. BRIEF GEC T scores were higher among 3q29del participants with a diagnosis of attention deficit/hyperactivity disorder (ADHD), and BRIEF GEC T scores were associated with schizophrenia spectrum symptoms as measured by the Structured Interview for Psychosis-Risk Syndromes. BRIEF GEC T scores were not associated with cognitive ability. The BRIEF-2 ADHD form accurately (sensitivity = 86.7%) classified individuals with 3q29del based on ADHD diagnosis status. BRIEF GEC T scores were 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 EF as a core feature linked to both psychiatric and neuroanatomical features of the syndrome.

Keywords: 3q29 deletion; BRIEF; cognition; copy number variant; executive function; schizophrenia.

Figure 1.

(a) Distribution of T scores on the BRIEF GEC and BRIEF subscales for study participants with 3q29del (n = 32). The black dashed line indicates the population mean; the red dashed line indicates the clinical cutoff. Subscales are ordered left to right by decreasing mean severity. (b) Pie chart showing the proportion of study participants with 3q29del (n = 32) scoring in the clinical range (T scores ⩾ 70) on one or more BRIEF scales, expanded to show the proportion of participants scoring in the clinical range on 1 to 9 BRIEF scales. 3q29del, 3q29 deletion syndrome; BRIEF, Behavior Rating Inventory of Executive Function; GEC, global executive composite.

Figure 2.

(a) Correlation between BRIEF GEC T scores and composite IQ for study participants with 3q29del (n = 32). (b) Correlation between BRIEF GEC T scores and non-verbal IQ for study participants with 3q29del (n = 32). (c) Correlation between BRIEF GEC T scores and verbal IQ for study participants with 3q29del (n = 32). (d) Correlation between BRIEF GEC T scores and SIPS Positive Symptom Ratings for study participants with 3q29del (n = 23). (e) Correlation between BRIEF GEC T scores and SIPS Negative Symptom Ratings for study participants with 3q29del (n = 23). (f) Correlation between BRIEF GEC T scores and SIPS Disorganization Symptom Ratings for study participants with 3q29del (n = 23). 3q29del, 3q29 deletion syndrome; BRIEF, Behavior Rating Inventory of Executive Function; GEC, global executive composite; SIPS, Structured Interview for Psychosis-Risk Syndromes.

Figure 3.

(a) Distribution of BRIEF GEC T scores for study participants with 3q29del (n = 32) with and without specific neurodevelopmental or psychiatric diagnoses. (b) Distribution of BRIEF GEC T scores for study participants with 3q29del (n = 32) with an increasing number of multimorbid neurodevelopmental and psychiatric diagnoses. (c) Receiver operating characteristic curve showing the ability of the BRIEF-2 ADHD form to correctly classify study participants with 3q29del (n = 26) with and without a diagnosis of ADHD. 3q29del, 3q29 deletion syndrome; BRIEF, Behavior Rating Inventory of Executive Function; GEC, global executive composite; ADHD, attention-deficit/hyperactivity disorder.

Figure 4.

(a) Diagram illustrating the cerebellum with a representative coronal image from a T1-weighted MRI showing cerebellar white matter and cerebellar cortex. (b) Correlation between BRIEF GEC T scores and total cerebellar volume for study participants with 3q29del (n = 23). (c) Correlation between BRIEF GEC T scores and cerebellar white matter volume for study participants with 3q29del (n = 23). (d) Correlation between BRIEF GEC T scores and cerebellar cortical (grey matter) volume for study participants with 3q29del (n = 23). 3q29del, 3q29 deletion syndrome; BRIEF, Behavior Rating Inventory of Executive Function; GEC, global executive composite.