Greater than the sum of its parts: A novel psychiatric multimorbidity metric applied to rare disease

Importance: Rare genetic syndromes are often drivers of complex multimorbidity. However, current methods consider multimorbidity as the sum of chronic diagnoses, which does not account for subthreshold impairment. Objective: To develop a quantitative multimorbidity score (MMS) for rare genetic syndromes that summarizes the neurodevelopmental and psychiatric multimorbidity landscape, including subthreshold symptoms, using 3q29 deletion and 3q29 duplication syndromes as hallmark examples. Design: We developed a multimorbidity metric and applied it to cross-sectional data. Remote phenotyping from 2023-2026. In-person phenotyping from 2017-2020. Setting: Remote phenotyping conducted at Rutgers University. In-person phenotyping conducted at Emory University. Participants: Participants were 6 years of age and older. 3q29del and 3q29dup recruited from the 3q29 registry and direct referrals and contacts. Syndrome status confirmed by genetic report review. Typically developing controls recruited from community sources and ResearchMatch. Main Outcomes and Measures: We developed a quantitative MMS across five distinct domains of functioning, operationalized as the sum of z-scores across six standardized assessments. The MMS was calculated for each study participant and compared across groups. Within 3q29del, we evaluated the relationship between MMSs and Vineland-3 adaptive behavior. Results: 96 individuals with 3q29del (52.08% male, 18.01+/-11.47 years old), 28 individuals with 3q29dup (50.00% male, 20.82+/-13.64 years old), and 53 controls (41.51% male, 17.77+/-10.74 years old) were included. 3q29del and 3q29dup participants had significantly lower MMS scores compared to controls (3q29del mean=-8.22+/-4.67, 3q29dup mean=-6.47+/-4.66, control mean=1.36+/-2.35, 3q29del p<2E-16, 3q29dup p=4.89E-16). Within 3q29del, subjects with more severe multimorbidity had greater impairment in adaptive behavior (R2=0.589, p<2E-16). The quantitative MMS is more highly correlated with adaptive behavior than traditional diagnosis-based multimorbidity metrics (quantitative MMS R2=0.589, diagnosis-based multimorbidity R2=0.447). In a subset of 24 3q29del participants with longitudinal data (58.33% male, 13.17+/-9.08 years old at first evaluation, average time to follow up=5.17+/-0.87 years), the MMS is stable over time (R2=0.858, p=8.34E-8). Conclusions and Relevance: Our novel quantitative MMS is an improved metric for measuring psychiatric multimorbidity in high-risk populations, and accounts for the impact of subthreshold impairments. When applied to 3q29del and 3q29dup, it quantifies the individual burden of multimorbidity, is stable over time, and is associated with clinical outcome measures.