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 (MAge = 19.2 years, 49.1% male), 30 22qDup carriers (MAge = 17.3 years, 53.3% male), and 41 typically developing (TD) subjects (MAge = 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.

Effects of Gene Dosage and Development on Subcortical Nuclei Volumes in Individuals with 22q11.2 Copy Number Variations

“…Gene dosage also likely does not fully reflect differences in gene transcription and translation in brain tissue, which are likely more closely linked to phenotypes, but cannot be measured in vivo or inferred from less invasively collected tissue such as blood [70,71]. When tested in separate case-control analyses, 22qDel carriers show somewhat stronger effects on subcortical structures relative to TD than do 22qDup, which is consistent with the more severe neurobehavioral/cognitive phenotype in 22qDel [69,72,73]. The smaller 22qDup sample size may partially explain the finding of fewer statistically significant differences between 22qDup and TD compared to 22qDel and TD (Tables S1 and S2).…”