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

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.

An integrated clinical approach to children at genetic risk for neurodevelopmental and psychiatric conditions: interdisciplinary collaboration and research infrastructure.

BACKGROUND: A sizeable proportion of pathogenic genetic variants identified in young children tested for congenital differences are associated with neurodevelopmental psychiatric disorders (NPD). In this growing group, a genetic diagnosis often precedes the emergence of diagnosable developmental concerns. Here, we describe DAGSY (Developmental Assessment of Genetically Susceptible Youth), a novel interdisciplinary 'genetic-diagnosis-first' clinic integrating psychiatric, psychological and genetic expertise, and report our first observations and feedback from families and referring clinicians. METHODS: We retrieved data on referral sources and indications, genetic and NPD diagnoses and recommendations for children seen at DAGSY between 2018 and 2022. Through a survey, we obtained feedback from twenty families and eleven referring clinicians. RESULTS: 159 children (mean age 10.2 years, 57.2% males) completed an interdisciplinary (psychiatry, psychology, genetic counselling) DAGSY assessment during this period. Of these, 69.8% had a pathogenic microdeletion or microduplication, 21.5% a sequence-level variant, 4.4% a chromosomal disorder, and 4.4% a variant of unknown significance with emerging evidence of pathogenicity. One in four children did not have a prior NPD diagnosis, and referral to DAGSY was motivated by their genetic vulnerability alone. Following assessment, 76.7% received at least one new NPD diagnosis, most frequently intellectual disability (24.5%), anxiety (20.7%), autism spectrum (18.9%) and specific learning (16.4%) disorder. Both families and clinicians responding to our survey expressed satisfaction, but also highlighted some areas for potential improvement. CONCLUSIONS: DAGSY addresses an unmet clinical need for children identified with genetic variants that confer increased vulnerability for NPD and provides a crucial platform for research in this area. DAGSY can serve as a model for interdisciplinary clinics integrating child psychiatry, psychology and genetics, addressing both clinical and research needs for this emerging population.

Neurocognitive Profiles of 22q11.2 and 16p11.2 Deletions and Duplications.

Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are among the most common rare genetic disorders associated with significant risk for neuropsychiatric disorders across the lifespan. Microdeletions and duplications in these loci are associated with neurocognitive deficits, yet there are few studies comparing these groups using the same measures. We address this gap in a prospective international collaboration applying the same computerized neurocognitive assessment. The Penn Computerized Neurocognitive Battery (CNB) was administered in a multi-site study on rare genomic disorders: 22q11.2 deletion (n = 397); 22q11.2 duplication (n = 77); 16p11.2 deletion (n = 94); and 16p11.2 duplication (n = 26). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and sensori-motor speed. Accuracy and speed for each neurocognitive domain were included as dependent measures in a mixed-model repeated measures analysis, with locus (22q11.2, 16p11.2) and copy number (deletion/duplication) as grouping factors and neurocognitive domain as a repeated measures factor, with age and sex as covariates. We also examined correlation with IQ and site effects. We found that 22q11.2 deletions were associated with greater deficits in overall performance accuracy than 22q11.2 duplications, while 16p11.2 duplications were associated with greater deficits than 16p11.2 deletions. Duplications at both loci were associated with reduced speed. Performance profiles differed among the groups with particularly poor performance of 16p11.2 duplication on non-verbal reasoning and social cognition. Average accuracy on the CNB was moderately correlated with Full Scale IQ. No site effects were observed. Deletions and duplications of 22q11.2 and 16p11.2 have varied effects on neurocognition indicating locus specificity, with performance profiles differing among the groups. These profile differences can help inform mechanistic substrates to heterogeneity in presentation and outcome. Future studies could aim to link performance profiles to clinical features and brain function.