Identification Of Neuropsychiatric Copy Number Variants In A Health Care System Population (Vol 77, Pg 1, 2020)

This cohort study evaluates the suitability of including pathogenic copy number variants associated with neuropsychiatric disorders in population screening by determining their prevalence and penetrance and exploring the personal utility of disclosing results.Key PointsQuestionAre neuropsychiatric disorders that are associated with pathogenic copy number variants suitable for inclusion in population-based genomic screening programs? FindingsIn this health care system population of more than 90595 participants, copy number variants associated with neuropsychiatric disorders were prevalent and penetrant. Participant responses to receiving these genomic results were overall positive, suggesting personal utility. MeaningNeuropsychiatric disorders associated with genetic variants should be considered in the design of population-based genomic screening programs.ImportancePopulation 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. ObjectiveTo 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 ParticipantsIn 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 from February 2007 to April 2017. Data were collected for the qualitative analysis April 2017 through February 2018. Analysis began February 2018 and ended December 2019. Main Outcomes and MeasuresThe planned outcomes of this study include (1) prevalence estimate of NPD-associated CNVs in an unselected health care system population; (2) penetrance estimate of NPD diagnoses in CNV-positive individuals; and (3) qualitative themes that describe participants' responses to receiving NPD-associated genomic results. ResultsOf 90595 participants with CNV data, a pathogenic CNV was identified in 708 (0.8%; 436 women [61.6%]; mean [SD] age, 50.04 [18.74] years). Seventy percent (n=494) had at least 1 associated clinical symptom. Of these, 28.8% (204) of CNV-positive individuals had an NPD code in their electronic health record, compared with 13.3% (11 835 of 89 887) of CNV-negative individuals (odds ratio, 2.21; 95% CI, 1.86-2.61; P < .001); 66.4% (470) of CNV-positive individuals had a history of depression and anxiety compared with 54.6% (49 118 of 89 887) of CNV-negative individuals (odds ratio, 1.53; 95% CI, 1.31-1.80; P < .001). 16p13.11 (71 [0.078%]) and 22q11.2 (108 [0.119%]) were the most prevalent deletions and duplications, respectively. Only 5.8% of individuals (41 of 708) had a previously known genetic diagnosis. Results disclosure was completed for 141 individuals. Positive participant responses included poignant reactions to learning a medical reason for lifelong cognitive and psychiatric disabilities. Conclusions and RelevanceThis study informs critical factors central to the development of population-based genomic screening programs and supports the inclusion of NPD in future designs to promote equitable access to clinically useful genomic information.