BACKGROUND: Past clinical genetic studies have identified rare, copy number variants (CNVs) as risk factors for multiple, neurodevelopmental disorders (NDD), including autism spectrum disorder and schizophrenia. However, the broad, clinical characterization of these NDD-CNVs in large population cohorts, especially of diverse ancestry, is relatively understudied. We characterized the clinical presentation of NDD-CNVs in the BioMe biobank, comprising ~25,000 individuals across diverse ancestry, medical and neuropsychiatric clinical presentation, with a mean age of 50.3 years. METHODS: Individuals within the BioMe biobank harboring NDD-CNVs were identified using a consensus of two CNV calling algorithms, based on whole-exome sequencing and genotype array data, followed by a series of novel, in-silico clinical assessments. RESULTS: The overall prevalence of a set of 64 NDD-CNVs was calculated at ~2.5%, with prevalence varying by locus, corroborating the presence of some relatively, highly-prevalent NDD-CNVs (i.e., 15q11.2 deletion/duplication, 2q13(NPHP1) deletion/duplication). An aggregate set of rare, NDD-CNVs were enriched for congenital disorders (OR=1.8, p-value=0.02) and major depressive disorders (OR=1.3, p-value=0.04) in multi-ancestry analyses, and major depressive-disorder in an African ancestry-stratified group (OR=1.8, p-value=0.01). In a meta-analysis of medical diagnoses (n=195 hierarchically-clustered diagnostic codes), an aggregated set of rare, NDD-CNVs was significantly associated with obstructive sleep apnea (Z-score=3.6 p=3.2x10-4). Further, an aggregated set of rare, NDD-CNVs was associated with increased body mass index (BMI) in a multi-ancestry analysis (Beta=0.14, p-value=0,04), and in Hispanic-stratified analyses (Beta=0.30, p-value=4.2x10-3). For 38 common serum laboratory tests, there was no identified association with the aggregate set of NDD-CNVs. CONCLUSION: The current analyses elucidated clinical features of individuals harboring NDD-CNVs, in a large-scale, multi-ancestry biobank, identifying enrichments for congenital disorders and major depressive disorder, as well as identifying associations with obesity-related phenotypes, obstructive sleep apnea and increased BMI. Future recall of individuals harboring NDD-CNVs will allow for further clinical assessments beyond the electronic health records (EHR) presently analyzed, including neurocognitive and neuroimaging outcomes.
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