NEUROPSYCHIATRIC MULTIMORBIDITY AND ADAPTIVE FUNCTIONING IN 16P11.2 AND 22Q11.2 COPY NUMBER VARIANT CARRIERS

While increased vulnerability to neurodevelopmental and psychiatric conditions in individuals with rare brain-related pathogenic variants is well established, more work is needed to clarify shared and distinct patterns of psychopathology and their impact on adaptive functioning. Here, we report neuropsychiatric phenotypes in 1,292 individuals with 22q11.2 or 16p11.2 deletions/duplications. Methods: As part of a multi-site effort of the Genes to Mental Health (G2MH) Network, we developed and implemented the Core Psychiatric Phenotype Summary (C2PS), a pragmatic harmonization framework capturing evidence for DSM-5–anchored diagnoses and clinically relevant subthreshold symptoms across 9 core domains: psychotic disorders, bipolar disorders, depression, obsessive-compulsive disorder, anxiety, attention-deficit/hyperactivity, oppositional defiant disorder, autism spectrum disorder, and intellectual disability, with source specifiers to accommodate heterogeneous assessment inputs. Results: Neuropsychiatric phenotypes were harmonized for 1,292 G2MH participants (22q11.2del n=729; 22q11.2dup n=219; 16p11.2del n=222; 16p11.2dup n=122; median age 16.0 years [IQR 11.0–27.0]; 52% female). C2PS completion was feasible (mean missingness 4%; range 1%–13%) and reliability was fair-to-excellent across domains (Light’s Kappa 0.48–1.00). Across CNV groups, multi-domain burden was pervasive. At the diagnostic level, multimorbidity (> 2 disorders) affected 56% of participants (median: 3 disorders/individual, IQR 2–5). Including subthreshold symptomatology, only 110 (8.5%) participants had involvement confined to a single domain, and only 43 (3%) were unaffected across all domains, underscoring a broad transdiagnostic phenotype that extends beyond categorical diagnoses and a meaningful contribution of subthreshold psychopathology. We then examined the functional impact of multimorbidity, considering the count of co-existing diagnoses/subthreshold domains, irrespective of their specific classification. We found that the burden of multimorbidity burden showed a strong cumulative association with adaptive functioning: Each additional affected domain was associated with a 5.4-point decrement in Vineland Adaptive Behavior Scales (VABS) (95% CI −7.3 to −3.4; p='1.7 × 10-7; n='275). In contrast, the association with IQ, while significant, was small in its effect (−0.8 IQ points per additional domain; 95% CI −1.5 to −0.2; p=0.014; n=741). Notably, functional impact was also evident in individuals without any formal diagnosis but with subthreshold symptoms (n=295; VABS data in n=98), showing a 5.79 points decrease in VABS per additional impacted domain (95% CI −8.96 to −2.62; p=0.00054). Conclusions: Harmonized phenotyping across heterogeneous international cohorts is feasible and reliable using the C2PS, enabling quantification of transdiagnostic burden at diagnostic and subthreshold levels. In 22q11.2 and 16p11.2 CNV carriers, neuropsychiatric multimorbidity is highly prevalent and associated with reduced adaptive functioning, an effect that remains substantial even among individuals without categorical diagnoses. These findings underscore the importance of assessing across multiple domains while including subthreshold symptomatology in this population. Collectively, they justify further study of both phenotypic and genetic correlations of multimorbidity as a phenotype of interest