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Genomic variants that cause neurodevelopmental/psychiatric disorders (NPD) are relatively prevalent and highly penetrant. This study aimed to understand adults' immediate responses to receiving NPD-related results to inform inclusion in population-based genomic screening programs. Nine recurrent, pathogenic copy number variants (CNVs) were identified from research exome data, clinically confirmed, and disclosed to adult participants of the Geisinger MyCode Community Health Initiative DiscovEHR cohort by experienced genetic counselors. A subset of in-person genetic counseling sessions (n = 27) were audio-recorded, transcribed, and coded using a grounded theory approach. Participant reactions were overwhelmingly positive and indicated that an NPD genetic etiology was highly valuable and personally useful. Participants frequently reported learning disabilities or other NPD that were not documented in their electronic health records and noted difficulties obtaining support for NPD needs. Most intended to share their genetic result with family members and health care providers and were interested in how their result could improve their healthcare. This study indicates that results from population-based NPD genomic screening can provide personal value for adults with NPD, were viewed positively by participants, and could improve clinical outcomes by informing symptom monitoring for NPD and co-morbidities, promoting improved health behaviors, and enhancing psychotherapeutic approaches. [ABSTRACT FROM AUTHOR]

Uncertainty is prevalent in various health contexts. It is imperative to understand how health-related uncertainty can impact individuals' healthcare experiences and health decision making. The purpose of the present paper is to provide five overarching recommendations from an interdisciplinary team of experts to address gaps in the literature on health-related uncertainty. We present a case study of health-related uncertainty within the specific context of alcohol use to demonstrate these gaps and provide context for the recommendations. The five recommendations concerning health-related uncertainty include: (1) use common, consistent terminology to discuss uncertainty, (2) clarify measures of individual differences in response to uncertainty, (3) increase research on uncertainty and affect, (4) investigate the impact of the channel through which uncertainty is communicated, and (5) develop theory-driven interventions to improve uncertainty management. We conclude by reviewing health contexts in which health-related uncertainty exists and note how our recommendations complement existing reviews and data. [ABSTRACT FROM AUTHOR]

Autism, schizophrenia, and other clinically distinct neurodevelopmental psychiatric disorders (NPDs) have shared genetic etiologies, including single-gene and multigenic copy number variants (CNVs). Because rare variants are primarily investigated in clinical cohorts, population-based estimates of their prevalence and penetrance are lacking. The authors determined the prevalence, penetrance, and NPD risk of pathogenic single-gene variants in a large health care system population. The authors analyzed linked genomic and electronic health record (EHR) data in a subset of 90,595 participants from Geisinger's MyCode Community Health Initiative, known as the DiscovEHR cohort. Loss-of-function pathogenic variants in 94 high-confidence NPD genes were identified through exome sequencing, and NPD penetrance was calculated using preselected EHR diagnosis codes. NPD risk was estimated using a case-control comparison of DiscovEHR participants with and without NPD diagnoses. Results from single-gene variant analyses were also compared with those from 31 previously reported pathogenic NPD CNVs. Pathogenic variants were identified in 0.34% of the DiscovEHR cohort and demonstrated a 34.3% penetrance for NPDs. Similar to CNVs, sequence variants collectively conferred a substantial risk for several NPD diagnoses, including autism, schizophrenia, and bipolar disorder. Significant NPD risk remained after participants with intellectual disability were excluded from the analysis, confirming the association with major psychiatric disorders in individuals without severe cognitive deficits. Collectively, rare single-gene variants and CNVs were found in >1% of individuals in a large health care system population and play an important contributory role in mental health disorders. Diagnostic genetic testing for pathogenic variants among symptomatic individuals with NPDs could improve clinical outcomes through early intervention and anticipatory therapeutic support. [ABSTRACT FROM AUTHOR]

Importance: Cerebral palsy is a common neurodevelopmental disorder affecting movement and posture that often co-occurs with other neurodevelopmental disorders. Individual cases of cerebral palsy are often attributed to birth asphyxia; however, recent studies indicate that asphyxia accounts for less than 10% of cerebral palsy cases.Objective: To determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy.Design, Setting, and Participants: A retrospective cohort study of patients with cerebral palsy that included a clinical laboratory referral cohort with data accrued between 2012 and 2018 and a health care-based cohort with data accrued between 2007 and 2017.Exposures: Exome sequencing with copy number variant detection.Main Outcomes and Measures: The primary outcome was the molecular diagnostic yield of exome sequencing.Results: Among 1345 patients from the clinical laboratory referral cohort, the median age was 8.8 years (interquartile range, 4.4-14.7 years; range, 0.1-66 years) and 601 (45%) were female. Among 181 patients in the health care-based cohort, the median age was 41.9 years (interquartile range, 28.0-59.6 years; range, 4.8-89 years) and 96 (53%) were female. The molecular diagnostic yield of exome sequencing was 32.7% (95% CI, 30.2%-35.2%) in the clinical laboratory referral cohort and 10.5% (95% CI, 6.0%-15.0%) in the health care-based cohort. The molecular diagnostic yield ranged from 11.2% (95% CI, 6.4%-16.2%) for patients without intellectual disability, epilepsy, or autism spectrum disorder to 32.9% (95% CI, 25.7%-40.1%) for patients with all 3 comorbidities. Pathogenic and likely pathogenic variants were identified in 229 genes (29.5% of 1526 patients); 86 genes were mutated in 2 or more patients (20.1% of 1526 patients) and 10 genes with mutations were independently identified in both cohorts (2.9% of 1526 patients).Conclusions and Relevance: Among 2 cohorts of patients with cerebral palsy who underwent exome sequencing, the prevalence of pathogenic and likely pathogenic variants was 32.7% in a cohort that predominantly consisted of pediatric patients and 10.5% in a cohort that predominantly consisted of adult patients. Further research is needed to understand the clinical implications of these findings. [ABSTRACT FROM AUTHOR]

Purpose: Informed consent for genetic testing has historically been acquired during pretest genetic counseling, without specific guidance defining which core concepts are required. Methods: The Clinical Genome Resource (ClinGen) Consent and Disclosure Recommendations Workgroup (CADRe) used an expert consensus process to identify the core concepts essential to consent for clinical genetic testing. A literature review identified 77 concepts that are included in informed consent for genetic tests. Twenty-five experts (9 medical geneticists, 8 genetic counselors, and 9 bioethicists) completed two rounds of surveys ranking concepts' importance to informed consent. Results: The most highly ranked concepts included: (1) genetic testing is voluntary; (2) why is the test recommended and what does it test for?; (3) what results will be returned and to whom?; (4) are there other types of potential results, and what choices exist?; (5) how will the prognosis and management be impacted by results?; (6) what is the potential family impact?; (7) what are the test limitations and next steps?; and (8) potential risk of genetic discrimination and legal protections. Conclusion: Defining the core concepts necessary for informed consent for genetic testing provides a foundation for quality patient care across a variety of healthcare providers and clinical indications. [ABSTRACT FROM AUTHOR]