Identification of Neuropsychiatric Copy Number Variants in a Health Care System Population

Abstract

IMPORTANCE Population screening for medically relevant genomic variants that cause diseases such as hereditary cancer and cardiovascular disorders is increasing to facilitate early disease detection or prevention. Neuropsychiatric disorders (NPDs) are common, complex disorders with clear genetic causes; yet, access to genetic diagnosis is limited. We explored whether inclusion of NPD in population-based genomic screening programs is warranted by assessing 3 key factors: prevalence, penetrance, and personal utility. OBJECTIVE To evaluate the suitability of including pathogenic copy number variants (CNVs) associated with NPD in population screening by determining their prevalence and penetrance and exploring the personal utility of disclosing results. DESIGN, SETTING, AND PARTICIPANTS In this cohort study, the frequency of 31 NPD CNVs was determined in patient-participants via exome data. Associated clinical phenotypes were assessed using linked electronic health records. Nine CNVs were selected for disclosure by licensed genetic counselors, and participants' psychosocial reactions were evaluated using a mixed-methods approach. A primarily adult population receiving medical care at Geisinger, a large integrated health care system in the United States with the only population-based genomic screening program approved for medically relevant results disclosure, was included. The cohort was identified from the Geisinger MyCode Community Health Initiative. Exome and linked electronic health record data were available for this cohort, which was recruited

Leveraging population‐based exome screening to impact clinical care: The evolution of variant assessment in the Geisinger MyCode research project

“…Furthermore, EHR access also enables correlation of clinically relevant results with personal and family history of disease leading to more informed clinical care. Lastly, implementation of population genomic screening in an integrated, learning healthcare system allows longitudinal analyses of outcomes data and can inform future guidance on the personal, medical, and financial utility of such programs (Buchanan et al, 2020; Haggerty et al, 2017; Hao et al, 2020; Jones et al, 2018; Patel et al, 2019; Savatt et al, 2020) and facilitate expansion beyond what most programs are reporting at this time (Martin et al, 2020; Savatt et al, 2020).…”

Copy Number Variation: Methods and Clinical Applications

“…CNVs can be analyzed from different biological sources, offering various valuable information, so there are plenty of biomedical applications where CNV detection may be useful. CNVs have been studied in neuropsychiatric [72,73], developmental [74], and cardiovascular diseases [75]. Several studies have identified the role of CNVs in common diseases such as coronary artery disease or in rarer events such as sudden cardiac death.…”

Population Genomic Screening for Genetic Etiologies of Neurodevelopmental/Psychiatric Disorders Demonstrates Personal Utility and Positive Participant Responses

“…Recordings were transcribed verbatim. A grounded theory approach with two independent coders (KW and KT) was used to develop an initial codebook using the first 14 transcripts [15,23]. The remaining 13 transcripts were similarly coded independently and discussed to assess for thematic saturation and to refine the final codebook.…”

“…NPD represent an etiologically heterogenous group of clinically defined disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, bipolar disorder, and others [ 14 , 15 ]. These disorders are collectively common, affecting at least 14–18% of children and adults in the United States [ 16 , 17 ].…”

“…These disorders are collectively common, affecting at least 14–18% of children and adults in the United States [ 16 , 17 ]. NPD are defined individually by clinical assessment and observation, yet they represent variable manifestations of underlying developmental brain dysfunction and share common genetic etiologies, including high-impact, pathogenic genetic variants that are amenable to identification via population genomic screening, such as recurrent, pathogenic copy number variants (CNV) and sequence-level variants [ 14 , 15 ]. Clinical genetic testing for patients with NPD has been embraced in pediatric settings where combined diagnostic yields for sequence variants and CNVs approach 40% in certain cohorts [ 1 , 7 , 18 , 19 , 20 , 21 , 22 ].…”