Clinical And Cognitive Phenotyping Of Copy Number Variants Pathogenic For Neurodevelopmental Disorders From A Multi-Ancestry Biobank

BackgroundClinical biobanks linking electronic health records (EHRs) with genotype data are expanding, enabling investigation of genomic risk factors for psychiatric disorders. However, few recall-by-genotype (RbG) studies have been published--particularly for psychiatric risk variants in diverse healthcare systems--indicating a need for further research to inform implementation. Some rare copy number variants (CNVs) confer substantially increased risk for neurodevelopmental disorders (NDDs) and cognitive impairment. We recalled NDD CNV carriers from BioMe, a multi-ancestry biobank within the Mount Sinai Health System, for in-depth phenotyping and empirical insights into the implementation of RbG in psychiatry. MethodsFrom BioMe, 892 adults were recontacted: 335 NDD CNV carriers, 217 with schizophrenia, and 340 neurotypical controls. Of these, 18% responded to recontact, 12% were screened for participation, and 10% began the study. Participants completed structured clinical and cognitive assessments. ResultsSeventy-three participants (8% of those recontacted) completed the study: 30 NDD CNV carriers, 20 schizophrenia cases, and 23 controls. The mean age was 48.8 years, 66% were female, and ancestry was 37% African, 34% Hispanic, and 26% European. Seventy percent of NDD CNV carriers had at least one neuropsychiatric or developmental condition, including 40% with mood or anxiety disorders. Among 22 NDD CNV carriers at loci previously examined for cognitive effects, performance was impaired on digit span backward ({beta}= -1.76, FDR = 0.04) and sequencing ({beta}= -2.01, FDR = 0.04) compared with controls but outperformed schizophrenia cases on verbal learning ({beta}= 4.5, FDR = 0.05). ConclusionsThis proof-of-concept RbG study of rare psychiatric risk variants from a multi-ancestry biobank demonstrates both opportunities and challenges for recontact within healthcare systems. Despite modest enrollment, recalling individuals--including those affected by psychiatric illness and cognitive impairment--yielded a genotypically defined cohort and phenotypes not captured in EHRs, underscoring the potential of RbG to advance precision psychiatry.