Distinct neurocognitive profiles and clinical phenotypes associated with copy number variation at the 22q11.2 locus

Abstract

Rare genetic variants that confer large effects on neurodevelopment and behavioral phenotypes can reveal novel gene-brain-behavior relationships relevant to autism. Copy number variation at the 22q11.2 locus offer one compelling example, as both the 22q11.2 deletion (22qDel) and duplication (22qDup) confer increased likelihood of autism spectrum disorders (ASD) and cognitive deficits, but only 22qDel confers increased psychosis risk. Here, we used the Penn Computerized Neurocognitive Battery (Penn-CNB) to characterized neurocognitive profiles of 126 individuals: 55 22qDel carriers (M_Age = 19.2 years, 49.1% male), 30 22qDup carriers (M_Age = 17.3 years, 53.3% male), and 41 typically developing (TD) subjects (M_Age = 17.3 years, 39.0% male). We performed linear mixed models to assess group differences in overall neurocognitive profiles, domain scores, and individual test scores. We found all three groups exhibited distinct overall neurocognitive profiles. 22qDel and 22qDup carriers showed significant accuracy deficits across all domains relative to controls (episodic memory, executive function, complex cognition, social cognition, and sensorimotor speed), with 22qDel carriers exhibiting more severe accuracy deficits, particularly in episodic memory. However, 22qDup carriers generally showed greater slowing than 22qDel carriers. Notably, slower social cognition speed was uniquely associated with increased global psychopathology and poorer psychosocial functioning in 22qDup. Compared to TD, 22q11.2 copy number variants (CNV) carriers failed to show age-associated improvements in multiple cognitive domains. Exploratory analyses revealed 22q11.2 CNV carriers with ASD exhibited differential neurocognitive profiles, based on 22q11.2 copy number. These results suggest that there are distinct neurocognitive profiles associated with either a loss or gain of genomic material at the 22q11.2 locus.

Keywords: 22q.11.2 deletion syndrome; 22q11.2 duplication; Velocardiofacial syndrome; cognition; copy number variation; intellectual ability; memory; psychopathology; psychosis; social function.

Figure 1.

Changes in Penn-CNB Speed Scores across the age range for all subtests with a significant subject group-by-age interaction. Both CNV groups failed to show the same degree of age-related performance increases for Emotion Differentiation, Mental Flexibility, and Age Differentiation while only 22qDel carriers failed to show age-related increases for Verbal Reasoning. For Sensorimotor Speed, 22qDel carriers showed significantly less age-related increases than 22qDup carriers.

Figure 2.

Profile of neurocognitive performance across all Penn-CNB tests in 22qDel carriers (green line), 22qDup carriers (purple line), and TD controls (orange line). Accuracy (a) and speed (b) scores are presented for mental flexibility (ABF), attention (ATT), working memory (WM), verbal memory (VMEM), face memory (FMEM), spatial memory (SMEM), verbal reasoning (VR), nonverbal reasoning (NVR), spatial processing (SPA), emotion identification (EI), emotion differentiation (ED), and age differentiation (AD). Additional speed scores are presented for motor praxis (MOT) and sensorimotor speed (SM). Both 22q CNV groups were less accurate than the TD group across all tests, with the 22qDel carriers exhibiting worse overall accuracy than 22qDup carriers. Contrastingly, 22qDup carriers exhibited worse overall speed performance than 22qDel carriers.

Figure 3.

Beta coefficients and 95% confidence intervals for linear mixed models testing the association between Penn-CNB domains and clinical outcomes (Psychopathology, Social Function, Global Function, and Positive symptoms) in 22qDel carriers (green) and 22qDup carriers (purple). Worse Social Cognition speed performance was associated with increased psychopathology and worse global and social functioning in 22qDup carriers. Worse Social Functioning was also associated with worse speed performance on episodic memory, complex cognition, and sensorimotor speed domains. *q<0.05, **q<0.01, ***q<0.001

Figure 4.

Neurocognitive Profiles of 22qDelASD− (red), 22qDelASD+ (orange), 22qDupASD− (blue), 22qASD+ (purple). Accuracy (a) and speed (b) scores are presented for mental flexibility (ABF), attention (ATT), working memory (WM), verbal memory (VMEM), face memory (FMEM), spatial memory (SMEM), verbal reasoning (VR), nonverbal reasoning (NVR), spatial processing (SPA), emotion identification (EI), emotion differentiation (ED), and age differentiation (AD). Additional speed scores are presented for motor praxis (MOT) and sensorimotor speed (SM). LMMs revealed that distinct neurocognitive profiles exist between groups for speed (b) but not accuracy (a).