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

• Published in: Autism research Vol. 16; no. 12; pp. 2247 - 2262
• Main Authors: O'Hora, Kathleen P., Kushan‐Wells, Leila, Schleifer, Charles H., Cruz, Shayne, Hoftman, Gil D., Jalbrzikowski, Maria, Gur, Raquel E., Gur, Ruben C., Bearden, Carrie E.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.12.2023
• Subjects: 22q.11.2 deletion syndrome; 22q11.2 duplication; Adolescent; Adult; Autism Spectrum Disorder - complications; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - psychology; cognition; copy number variation; DiGeorge Syndrome - complications; DiGeorge Syndrome - genetics; DNA Copy Number Variations - genetics; Female; Humans; intellectual ability; Male; memory; Phenotype; psychopathology; psychosis; Psychotic Disorders - genetics; social function; Velocardiofacial syndrome; Young Adult; 22q11.2 duplication; intellectual ability; memory; cognition; copy number variation; 22q.11.2 deletion syndrome; psychopathology; Velocardiofacial syndrome; psychosis; social function
• ISSN: 1939-3792; 1939-3806
• DOI: 10.1002/aur.3049

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. Lay Summary This study examined reciprocal deletions and duplications at Chromosome 22q11.2, which strongly impact brain development, cognition, and behavior. We found that there are distinct patterns of cognitive performance that characterize these disorders, and that better social cognition was uniquely associated with less severe psychopathology and better psychosocial functioning in individuals with a 22q11.2 Duplication.