NEUROPSYCHOLOGICAL PROFILES AND MULTIMORBIDITY PATTERNS ASSOCIATED WITH 16P11.2 AND 22Q11.2 COPY NUMBER VARIANTS

Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are associated with a lifespan risk for neuropsychiatric disorders. These microdeletions and duplications present 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. We have previously published results of a subsample and are now reporting the final results of the completed study. The sample analyzed includes individuals with completed CNB: 22q11.2 Deletions (N=597, 312 Female, Age 19.9+12.8 yrs.), 22q11.2 Duplications (N=139, 66 Female, Age 19.0+12.8 yrs.), 16p Deletions (N=166, 85 Female, Age 15.5+9.0 yrs.), and 16p Duplications (N=76, 37 Female, Age 15.5+9.1 yrs.). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and psychomotor speed. Accuracy and speed for each domain were entered as dependent measures in a mixed-model repeated measures (MMRM) 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 < 0.001). Overall, 22q11.2del was associated with more severe performance accuracy deficits than 22q11.2dup, while 16p11.2dup was associated with greater specific deficits than 16p11.2del. Duplications at both loci were associated with reduced performance speed compared to deletions. Performance profiles differed among the groups with particularly poor memory performance of the 22q11.2del group while the 16p11.2dup group had greatest deficits in complex cognition. Notably, overall accuracy on the CNB was moderately correlated with Full Scale IQ. We also examined the association between CNB profiles and psychiatric morbidity as measured by C2PS with MMRM. We found a significant effect of psychopathology burden on the 22q11.2del sample (F=7.72, df=2,931.7, p < 0.001), as well as burden group x test interaction (F=3.82, df=18,7575.9, p < 0.001). This interaction indicates that psychopathology burden relates differentially to specific neurocognitive domains. We are implementing the same analyses on the other groups. Thus, deletions and duplications of 22q11.2 and 16p11.2 have differential effects on accuracy and speed of neurocognition demonstrating locus specificity of performance profiles. Furthermore, neuropsychiatric multimorbidity is associated with neurocognition in 22q11.2del. 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 that can parse both accuracy and speed of performance. Future studies could aim to link performance profiles to clinical features and brain function.