Neurocognitive profiles of 22q11.2 and 16p11.2 deletions and duplications

Ruben C Gur; Carrie E Bearden; Sebastien Jacquemont; Ann Swillen; Therese van Amelsvoort; Marianne van den Bree; Jacob Vorstman; Jonathan Sebat; Kosha Ruparel; Robert Sean Gallagher; Emily McClellan; Lauren White; Terrence Blaine Crowley; Victoria Giunta; Leila Kushan; Kathleen O'Hora; Jente Verbesselt; Ans Vandensande; Claudia Vingerhoets; Mieke van Haelst; Jessica Hall; Janet Harwood; Samuel J R A Chawner; Nishi Patel; Katrina Palad; Oanh Hong; James Guevara; Charles Olivier Martin; Khadije Jizi; Anne-Marie Bélanger; Stephen W Scherer; Anne S Bassett; Donna M McDonald-McGinn; Raquel E Gur

doi:10.1038/s41380-024-02661-y

Neurocognitive profiles of 22q11.2 and 16p11.2 deletions and duplications

Mol Psychiatry. 2024 Jul 24. doi: 10.1038/s41380-024-02661-y. Online ahead of print.

Authors

Ruben C Gur¹, Carrie E Bearden^{2

3

4}, Sebastien Jacquemont^{5

6}, Ann Swillen⁷, Therese van Amelsvoort⁸, Marianne van den Bree⁹, Jacob Vorstman¹⁰, Jonathan Sebat¹¹, Kosha Ruparel¹², Robert Sean Gallagher¹², Emily McClellan¹², Lauren White¹², Terrence Blaine Crowley¹³, Victoria Giunta¹³, Leila Kushan², Kathleen O'Hora^{2

4}, Jente Verbesselt⁷, Ans Vandensande⁷, Claudia Vingerhoets⁸, Mieke van Haelst⁸, Jessica Hall⁹, Janet Harwood⁹, Samuel J R A Chawner⁹, Nishi Patel¹⁰, Katrina Palad¹⁰, Oanh Hong¹¹, James Guevara¹¹, Charles Olivier Martin⁶, Khadije Jizi⁶, Anne-Marie Bélanger⁶, Stephen W Scherer¹⁰, Anne S Bassett¹⁴, Donna M McDonald-McGinn^{13

15}, Raquel E Gur¹²

Affiliations

¹ Lifespan Brain Institute of the Children's Hospital of Philadelphia (CHOP) and Penn Medicine, University of Pennsylvania, Philadelphia, PA, USA. gur@pennmedicine.upenn.edu.
² Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
³ Department of Psychology, University of California, Los Angeles, CA, USA.
⁴ Neuroscience Interdepartmental Program, University of California, Los Angeles, CA, USA.
⁵ Department of Pediatrics, University of Montreal, Montreal, QC, Canada.
⁶ Sainte Justine Hospital Research Center, Montreal, QC, Canada.
⁷ Centre for Human Genetics, University Hospital Gasthuisberg and Department of Human Genetics, KU Leuven, Leuven, Belgium.
⁸ Department of Psychiatry & Neuropsychology, Maastricht University, Maastricht, The Netherlands.
⁹ Centre for Neuropsychiatric Genetics and Genomics Division of Psychological Medicine and Clinical Neurosciences Cardiff, Cardiff, UK.
¹⁰ Department of Psychiatry, Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
¹² Lifespan Brain Institute of the Children's Hospital of Philadelphia (CHOP) and Penn Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹³ Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania; 22q and You Center, Clinical Genetics Center, and Section of Genetic Counseling, CHOP, Philadelphia, PA, USA.
¹⁴ Dalglish Family 22q Clinic and Toronto General Hospital Research Institute, University Health Network; Clinical Genetics Research Program and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
¹⁵ Department of Human Biology and Medical Genetics, Sapienza University, Rome, Italy.

PMID: 39048645
DOI: 10.1038/s41380-024-02661-y

Abstract

Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are genetic disorders with lifespan risk for neuropsychiatric disorders. Microdeletions and duplications are associated with neurocognitive deficits, yet few studies compared these groups using the same measures to address confounding measurement differences. We report a prospective international collaboration applying the same computerized neurocognitive assessment, the Penn Computerized Neurocognitive Battery (CNB), administered in a multi-site study on rare genomic disorders: 22q11.2 deletions (n = 492); 22q11.2 duplications (n = 106); 16p11.2 deletion (n = 117); and 16p11.2 duplications (n = 46). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and psychomotor speed. Accuracy and speed for each domain were included as dependent measures in a mixed-model repeated measures analysis. Locus (22q11.2, 16p11.2) and Copy number (deletion/duplication) were grouping factors and Measure (accuracy, speed) and neurocognitive domain were repeated measures factors, with Sex and Site as covariates. We also examined correlation with IQ. We found a significant Locus × Copy number × Domain × Measure interaction (p = 0.0004). 22q11.2 deletions were associated with greater performance accuracy deficits than 22q11.2 duplications, while 16p11.2 duplications were associated with greater specific deficits than 16p11.2 deletions. Duplications at both loci were associated with reduced speed compared to deletions. Performance profiles differed among the groups with particularly poor memory performance of the 22q11.2 deletion group while the 16p11.2 duplication group had greatest deficits in complex cognition. Average accuracy on the CNB was moderately correlated with Full Scale IQ. Deletions and duplications of 22q11.2 and 16p11.2 have differential effects on accuracy and speed of neurocognition indicating locus specificity of performance profiles. These profile differences can help inform mechanistic substrates to heterogeneity in presentation and outcome, and can only be established in large-scale international consortia using the same neurocognitive assessment. Future studies could aim to link performance profiles to clinical features and brain function.

Abstract

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