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Asthma is the most common chronic condition in children and the third leading cause of hospitalization in pediatrics. The genome-wide association study catalog reports 140 studies with genome-wide significance. A polygenic risk score (PRS) with predictive value across ancestries has not been evaluated for this important trait.This study aimed to train and validate a PRS relying on genetic determinants for asthma to provide predictions for disease occurrence in pediatric cohorts of diverse ancestries.This study applied a Bayesian regression framework method using the Trans-National Asthma Genetic Consortium genome-wide association study summary statistics to derive a multiancestral PRS score, used one Electronic Medical Records and Genomics (eMERGE) cohort as a training set, used a second independent eMERGE cohort to validate the score, and used the UK Biobank data to replicate the findings. A phenome-wide association study was performed using the PRS to identify shared genetic etiology with other phenotypes.The multiancestral asthma PRS was associated with asthma in the 2 pediatric validation datasets. Overall, the multiancestral asthma PRS has an area under the curve (AUC) of 0.70 (95% CI, 0.69-0.72) in the pediatric validation 1 and AUC of 0.66 (0.65-0.66) in the pediatric validation 2 datasets. We found significant discrimination across pediatric subcohorts of European (AUC, 95% CI, 0.60 and 0.66), African (AUC, 95% CI, 0.61 and 0.66), admixed American (AUC, 0.64 and 0.70), Southeast Asian (AUC, 0.65), and East Asian (AUC, 0.73) ancestry. Pediatric participants with the top 5% PRS had 2.80 to 5.82 increased odds of asthma compared to the bottom 5% across the training, validation 1, and validation 2 cohorts when adjusted for ancestry. Phenome-wide association study analysis confirmed the strong association of the identified PRS with asthma (odds ratio, 2.71, PsubFDR/sub = 3.71 × 10sup-65/sup) and related phenotypes.A multiancestral PRS for asthma based on Bayesian posterior genomic effect sizes identifies increased odds of pediatric asthma.

Adjunctive l-methylfolate is commonly prescribed for children and adolescents with treatment-resistant mood disorders; however, the relationship between l-methylfolate augmentation across methylenetetrahydrofolate reductase (MTHFR) genotypes in youths with depressive symptoms is unclear.We retrospectively examined the electronic health records of patients (N = 412) with depressive symptoms associated with unipolar depressive disorders and their MTHFR C677T genotypes from 2013 to 2019. Patients were ≤18 years of age at the time of MTHFR pharmacogenetic testing. Treatment response was assessed with Clinical Global Impression-Improvement (CGI-I) score reported in the medical record.Patients with an MTHFR C677T C/T or T/T genotype were more likely to be prescribed l-methylfolate when the clinician knew their MTHFR genotype (p 0.0001, OR: 15.1, 95 % CI: [5.1, 44.2]), but not when the clinician did not know their genotype (p = 0.4, OR: 2.1, 95 % CI: [0.4, 11.4]). Change in baseline and endpoint CGI-I scores between patients with an MTHFR C677T variant who were prescribed and not prescribed l-methylfolate did not significantly differ (p = 0.39). Response rate was not associated with l-methylfolate prescription (p = 0.17) or l-methylfolate dose (p = 0.69).This was a retrospective study, which yielded a heterogeneous patient population and limited data availability (e.g., adherence). Patients are severely ill and may have a refractory illness that limits response to adjunctive l-methylfolate.Clinicians prescribe l-methylfolate to children and adolescents with depressive symptoms associated with unipolar depressive disorders who have an MTHFR C677T variant, although augmentation may not be associated with treatment response, regardless of MTHFR genotype or dose.

The clinical genomics knowledgebase is dynamic with variant classifications changing as newly identified cases, additional population data, and other evidence become available. This is a challenge for the clinical laboratory because of limited resource availability for variant reassessment.Throughout the Electronic Medical Records and Genomics phase III program, clinical sites associated with the Mass General Brigham/Broad sequencing center received automated, real-time notifications when reported variants were reclassified. In this study, we summarized the nature of these reclassifications and described the proactive reassessment framework we used for the Electronic Medical Records and Genomics program data set to identify variants most likely to undergo reclassification.Reanalysis of 1855 variants led to the reclassification of 2% (n = 45) of variants, affecting 0.6% (n = 67) of participants. Of these reclassifications, 78% (n = 35) were high-impact changes affecting reportability, with 8 variants downgraded from likely pathogenic/pathogenic to variants of uncertain significance (VUS) and 27 variants upgraded from VUS to likely pathogenic/pathogenic. Most upgraded variants (67%) were initially classified as VUS-Favor Pathogenic, highlighting the benefit of VUS subcategorization. The most common reason for reclassification was new published case data and/or functional evidence.Our results highlight the importance of periodic sequence variant reevaluation and the need for automated approaches to advance routine implementation of variant reevaluations in clinical practice.

Contains fulltext : 291896.pdf (Publisher’s version ) (Closed access) AMOTL1 encodes angiomotin-like protein 1, an actin-binding protein that regulates cell polarity, adhesion, and migration. The role of AMOTL1 in human disease is equivocal. We report a large cohort of individuals harboring heterozygous AMOTL1 variants and define a core phenotype of orofacial clefting, congenital heart disease, tall stature, auricular anomalies, and gastrointestinal manifestations in individuals with variants in AMOTL1 affecting amino acids 157-161, a functionally undefined but highly conserved region. Three individuals with AMOTL1 variants outside this region are also described who had variable presentations with orofacial clefting and multi-organ disease. Our case cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157-161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.

Genomic medicine holds great promise for improving health care, but integrating searchable and actionable genetic data into electronic health records (EHRs) remains a challenge. Here we describe Neptune, a system for managing the interaction between a clinical laboratory and an EHR system during the clinical reporting process. We developed Neptune and applied it to two clinical sequencing projects that required report customization, variant reanalysis, and EHR integration. Neptune has been applied for the generation and delivery of over 15,000 clinical genomic reports. This work spans two clinical tests based on targeted gene panels that contain 68 and 153 genes respectively. These projects demanded customizable clinical reports that contained a variety of genetic data types including single-nucleotide variants (SNVs), copy-number variants (CNVs), pharmacogenomics, and polygenic risk scores. Two variant reanalysis activities were also supported, highlighting this important workflow. Methods are needed for delivering structured genetic data to EHRs. This need extends beyond developing data formats to providing infrastructure that manages the reporting process itself. Neptune was successfully applied on two high-throughput clinical sequencing projects to build and deliver clinical reports to EHR systems. The software is open source and available at https://gitlab.com/bcm-hgsc/neptune .

Purpose: The electronic Medical Records and Genomics (eMERGE) Phase III study was undertaken to assess clinical utility of returning medically actionable genomic screening results. We assessed pediatric clinical outcomes following return of pathogenic/likely pathogenic (P/LP) variants in autosomal dominant conditions with available effective interventions. Methods: The two eMERGE III pediatric sites collected outcome data and assessed changes in medical management at 6 and 12 months. Results: We returned P/LP results to 29 participants with outcome data. For 23 of the 29 participants, the P/LP results were previously unknown. Five of the 23 participants were already followed for conditions related to the P/LP variant. Of those receiving novel results and not being followed for the condition related to the P/LP result (n = 18), 14 (77.8%) had a change in healthcare after return of results (RoR). Following RoR, cascade testing of family members occurred for 10 of 23 (43.5%). Conclusions: The most common outcomes post-RoR included imaging/laboratory testing and health behavior recommendations. A change in healthcare was documented in 77.8% of those receiving results by 6 months. Our findings demonstrate how return of genomic screening results impacts healthcare in pediatric populations.

This editorial provides context for a series of published case reports in ACI Open by summarizing activities and outputs of joint electronic health record integration and pharmacogenomics workgroups in the NIH-funded electronic Medical Records and Genomics (eMERGE) Network. A case report is a useful tool to describe the range of capabilities that an IT infrastructure or a particular technology must support. The activities we describe have informed infrastructure requirements used during eMERGE phase III, provided a venue to share experiences and ask questions among other eMERGE sites, summarized potential hazards that might be encountered for specific clinical decision support (CDS) implementation scenarios, and provided a simple framework that captured progress toward implementing CDS at eMERGE sites in a consistent format.

Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk.To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores (PRS), monogenic risks, family history, and clinical risk assessments via a Genome Informed Risk Assessment (GIRA) report and will assess uptake of care recommendations after return of results.GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022.Return of a novel report for communicating monogenic, polygenic, and family history based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.

Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone, and methadone). Polymorphisms in CYP2D6 have been studied for an association with the clinical effect and safety of these drugs. Other genes that have been studied for their association with opioid clinical effect or adverse events include OPRM1 (mu receptor) and COMT (catechol-O-methyltransferase). This guideline updates and expands the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and codeine therapy and includes a summation of the evidence describing the impact of CYP2D6, OPRM1, and COMT on opioid analgesia and adverse events. We provide therapeutic recommendations for the use of CYP2D6 genotype results for prescribing codeine and tramadol and describe the limited and/or weak data for CYP2D6 and hydrocodone, oxycodone, and methadone, and for OPRM1 and COMT for clinical use.

Population-based genomic screening has the potential to improve health outcomes by identifying genetic causes of disease before they occur. While much attention has been paid to supporting the needs of the small percentage of patients who will receive a life-altering positive genomic screening result that requires medical attention, little attention has been given to the communication of negative screening results. As there are currently no best practices for returning negative genomic screening results, we drew on experiences across the electronic medical records and genomics (eMERGE) III Network to highlight the diversity of reporting methods employed, challenges encountered in reporting negative test results, and "lessons learned" across institutions. A 60-item survey that consisted of both multiple choice and open-ended questions was created to gather data across institutions. Even though institutions independently developed procedures for reporting negative results, and had very different study populations, we identified several similarities of approach, including but not limited to: returning results by mail, placing results in the electronic health record via an automated process, reporting results to participants' primary care provider, and providing genetic counseling to interested patients at no cost. Differences in procedures for reporting negative results included: differences in terminology used to describe negative results, definitions of negative results, guidance regarding the meaning of negative results for participants and their family members, and recommendations for clinical follow up. Our findings highlight emerging practices for reporting negative genomic screening results and highlight the need to create patient education and clinical support tools for reporting negative screening results.

Background We offered adolescents personalized choices about the type of genetic results they wanted to learn during a research study and created a workflow to filter and transfer the results to the electronic health record (EHR). Methods We describe adaptations needed to ensure that adolescents' results documented in the EHR and returned to adolescent/parent dyads matched their choices. A web application enabled manual modification of the underlying laboratory report data based on adolescents' choices. The final PDF format of the laboratory reports was not viewable through the EHR patient portal, so an EHR form was created to support the manual entry of discrete results that could be viewed in the portal. Results Enabling adolescents' choices about genetic results was a labor-intensive process. More than 350 hours was required for development of the application and EHR form, as well as over 50 hours of a study professional's time to enter choices into the application and EHR. Adolescents and their parents who learned genetic results through the patient portal indicated that they were satisfied with the method of return and would make their choices again if given the option. Conclusion Although future EHR upgrades are expected to enable patient portal access to PDFs, additional improvements are needed to allow the results to be partitioned and filtered based on patient preferences. Furthermore, separating these results into more discrete components will allow them to be stored separately in the EHR, supporting the use of these data in clinical decision support or artificial intelligence applications.

Discovering an incidental finding (IF) or secondary finding (SF) is a potential result of genomic testing, but few data exist describing types and frequencies of SFs likely to appear in broader clinical populations.The Electronic Medical Records and Genomics Network Phase III (eMERGE III) developed a CLIA-compliant sequencing panel of 109 genes and 1551 variants of clinical relevance or research interest and deployed this panel at ten clinical sites. We evaluated medically actionable SFs across 67 genes and 14 single-nucleotide variants (SNVs) in a diverse cohort of 21,915 participants drawn from a variety of settings (e.g., primary care, biobanks, specialty clinics).Correcting for testing indication, we found a 3.02% overall frequency of SFs; 2.54% from 59 genes the American College of Medical Genetics and Genomics recommends for SF return, and 0.48% in other genes, primarily HFE and PALB2. SFs associated with cancer susceptibility were most frequent (1.38%), followed by cardiovascular diseases (0.87%), and lipid disorders (0.50%). After removing HFE, the frequency of SFs and proportion of pathogenic versus likely pathogenic SFs did not differ in those self-identifying as White versus others.Here we present frequencies and types of medically actionable secondary findings to support informed decision making by patients, participants, and practitioners engaged in genomic medicine.

PURPOSE: The goal of Electronic Medical Records and Genomics (eMERGE) Phase III Network was to return actionable sequence variants to 25,084 consenting participants from 10 different health care institutions across the United States. The purpose of this study was to evaluate system-based issues relating to the return of results (RoR) disclosure process for clinical grade research genomic tests to eMERGE3 participants. METHODS: RoR processes were developed and approved by each eMERGE institution’s internal review board. Investigators at each eMERGE3 site were surveyed for RoR processes related to the participant’s disclosure of pathogenic or likely pathogenic variants and engagement with genetic counseling. Standard statistical analysis was performed. RESULTS: Of the 25,084 eMERGE participants, 1444 had a pathogenic or likely pathogenic variant identified on the eMERGEseq panel of 67 genes and 14 single nucleotide variants. Of these, 1077 (74.6%) participants had results disclosed, with 562 (38.9%) participants provided with variant-specific genetic counseling. Site-specific processes that either offered or required genetic counseling in their RoR process had an effect on whether a participant ultimately engaged with genetic counseling (P = .0052). CONCLUSION: The real-life experience of the multiarm eMERGE3 RoR study for returning actionable genomic results to consented research participants showed the impact of consent, method of disclosure, and genetic counseling on RoR.

There has been considerable debate over whether adolescents should have the opportunity to learn genetic information about adult-onset disease risk and carrier status without a clinical indication. Adolescents face increasing opportunities to learn more about such genetic risks through the return of secondary findings from clinical genomic testing, direct-to-consumer genetic testing, and research opportunities. However, little is known about the perspectives of adolescents who have received genomic screening results. We conducted separate qualitative interviews with 15 adolescents and their parents who enrolled in a research protocol where they decided which genomic screening results to receive for the adolescent for up to 32 conditions informed by 84 genes. The goal of these interviews was to explore the impact of adolescents learning genomic results without a clinical indication for screening. Of the participating dyads, four received positive results for a pathogenic/likely pathogenic (P/LP) variant for an autosomal dominant (AD) condition, five received carrier results for a heterozygous P/LP variant for an autosomal recessive (AR) condition, and six received negative results. An interpretive descriptive qualitative approach was used. Interview transcripts were coded using a guide developed by the study team based on themes that emerged from the interviews. Degree of recall and description of results, actionability, and emotional responses differed according to the types of results received. However, all participants were satisfied with their decision to learn results, and most did not report any lasting psychological harms. Participants adapted to genomic information about themselves, even after learning about unexpected increased risk for future health problems. Our findings support the position that, whenever possible, perspectives and wishes of adolescents should be strongly considered and respected in the decision-making process regarding genetic testing.

Chemotherapy-induced nausea and vomiting (CINV) is commonly experienced by patients receiving antineoplastic agents prior to hemopoietic stem cell transplant (HSCT). Ondansetron, a 5-HT3 antagonist metabolized by CYP2D6, is an antiemetic prescribed to treat short-term CINV, but some patients still experience uncontrolled nausea and vomiting while taking ondansetron. Adult CYP2D6 ultrarapid metabolizers (UMs) are at higher risk for CINV due to rapid ondansetron clearance, but similar studies have not been performed in pediatric patients. We performed a retrospective chart review of 128 pediatric HSCT recipients who received ondansetron for CINV prevention and had CYP2D6 genotyping for 20 alleles and duplication detection. The number of emetic episodes for each patient was collected from the start of chemotherapy through 7 days after HSCT. The average age of the cohort was 6.6 years (range: 0.2-16.7) and included three UMs, 72 normal metabolizers, 47 intermediate metabolizers, and six poor metabolizers. Because UMs are the population at risk for inefficacy, we describe the course of treatment for these three patients, as well as the factors influencing emesis: chemotherapy emetogenicity, diagnosis, and duration of ondansetron administration. The cases described support guidelines recommending non-CYP2D6 metabolized antiemetics (e.g., granisetron) when a patient is a known CYP2D6 UM, but pediatric studies with a larger sample of CYP2D6 UMs are needed to validate our findings.

Historically, medical geneticists and genetic counselors have provided the majority of genetic services. Advances in technology, reduction in testing costs, and increased public awareness have led to a growing demand for genetic services in both clinical and direct-to-consumer spaces. Recent and anticipated changes in the workforce of genetic counselors and medical geneticists require a reexamination of the way we educate health-care providers and the means by which we provide access to genetic services. The time is ripe for rapid growth of genetic and genomic services, but to capitalize on these opportunities, we need to consider a variety of educational mechanisms to reach providers both within and beyond the traditional genetic counseling and medical genetics sectors, including nurses, physician assistants, and nongenetics physicians. This article summarizes the educational efforts underway in each of these professions.

Purpose: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers. Methods: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned. Results: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy number variation and 9 common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability. Conclusion: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.

The advancement of precision medicine requires new methods to coordinate and deliver genetic data from heterogeneous sources to physicians and patients. The eMERGE III Network enrolled >25,000 participants from biobank and prospective cohorts of predominantly healthy individuals for clinical genetic testing to determine clinically actionable findings. The network developed protocols linking together the 11 participant collection sites and 2 clinical genetic testing laboratories. DNA capture panels targeting 109 genes were used for testing of DNA and sample collection, data generation, interpretation, reporting, delivery, and storage were each harmonized. A compliant and secure network enabled ongoing review and reconciliation of clinical interpretations, while maintaining communication and data sharing between clinicians and investigators. A total of 202 individuals had positive diagnostic findings relevant to the indication for testing and 1,294 had additional/secondary findings of medical significance deemed to be returnable, establishing data return rates for other testing endeavors. This study accomplished integration of structured genomic results into multiple electronic health record (EHR) systems, setting the stage for clinical decision support to enable genomic medicine. Further, the established processes enable different sequencing sites to harmonize technical and interpretive aspects of sequencing tests, a critical achievement toward global standardization of genomic testing. The eMERGE protocols and tools are available for widespread dissemination.

The American College of Medical Genetics and Genomics supports parents’ opting in or out of secondary analysis of 59 genes when their child has clinical exome/genome sequencing. We explored the reasons adolescents choose to learn certain types of results and the reasons they want to involve or not involve parents in decision-making. Adolescents recruited without clinical indication were offered independent, followed by joint choices with a parent to learn genomic results. After making independent choices, adolescent/parent dyads were interviewed to explore the reasons for their choices. Interviews were audio-recorded and transcribed. The constant comparative method was used to analyze 64 purposefully selected transcripts that included 31 from adolescents who excluded some or all potential results. Three major themes informed adolescents’ choices: (1) actionability of information, (2) knowledge seeking, and (3) psychological impact. Of adolescents who independently excluded some conditions (n=31), 58% changed their initial choices during the joint interview due to parental influence or improved understanding. Nearly all adolescents (98%) wanted to be involved in the decision-making process, and 53% wanted to make choices independently. Our findings contribute empirical evidence to support the refinement of professional guidelines for adolescents’ engagement and preferences in genetic testing decisions.

A challenge in returning genomic test results to research participants is how best to communicate complex and clinically nuanced findings to participants in a manner that is scalable to the large numbers of participants enrolled. The purpose of this study was to examine the features of genetic results letters produced at each Electronic Medical Records and Genomics (eMERGE3) Network site to assess their readability and content. Letters were collected from each site, and a qualitative analysis of letter content and a quantitative analysis of readability statistics were performed. Because letters were produced independently at each eMERGE site, significant heterogeneity in readability and content was found. The content of letters varied widely from a baseline of notifying participants that results existed to more detailed information about positive or negative results, as well as materials for sharing with family members. Most letters were significantly above the Centers for Disease Control-suggested reading level for health communication. While continued effort should be applied to make letters easier to understand, the ongoing challenge of explaining complex genomic information, the implications of negative test results, and the uncertainty that comes with some types of test and result makes simplifying letter text challenging.

PURPOSE: Secondary findings are typically offered in an all or none fashion when sequencing is used for clinical purposes. This study aims to describe the process of offering categorical and granular choices for results in a large research consortium. METHODS: Within the third phase of the electronic MEdical Records and GEnomics (eMERGE) Network, several sites implemented studies that allowed participants to choose the type of results they wanted to receive from a multigene sequencing panel. Sites were surveyed to capture the details of the implementation protocols and results of these choices. RESULTS: Across the ten eMERGE sites, 4664 participants including adolescents and adults were offered some type of choice. Categories of choices offered and methods for selecting categories varied. Most participants (94.5%) chose to learn all genetic results, while 5.5% chose subsets of results. Several sites allowed participants to change their choices at various time points, and 0.5% of participants made changes. CONCLUSION: Offering choices that include learning some results is important and should be a dynamic process to allow for changes in scientific knowledge, participant age group, and individual preference.

Significant inter-individual variability in medication response can result in adverse drug reactions (ADRs) and increased health care costs. Based on ADR prevalence and mounting evidence linking genetics and pharmacokinetic variability, Cincinnati Children’s Hospital Medical Center (CCHMC) launched the Genetic Pharmacology Service (GPS) in 2004 and has since performed >25,000 tests. Herein, we describe how the service developed, launched, and has been updated along with how it is currently utilized, and key lessons learned.

Opportunities to participate in genomic sequencing studies, as well as recommendations to screen for variants in 59 medically actionable genes anytime clinical genomic sequencing is performed, indicate adolescents will increasingly be involved in decisions about learning secondary findings from genome sequencing. However, how adolescents want to be involved in such decisions is unknown. We conducted five focus groups with adolescents (2) and parents (3) to learn their decisional preferences about return of genomic research results to adolescents. Discussions about decisional preferences centered around three themes: feelings about receiving genomic risk information, adolescent involvement and capacity to participate in decision-making, and recommendations for parental versus collaborative decision-making. We address the contested space between parental duties to act in their children’s best interests when choosing which results to return and adolescents’ desires to make autonomous decisions. A collaborative decision-making approach is recommended for obtaining consent from adolescents and their parents for genome sequencing research.

Primary microcephaly is a congenital brain malformation characterized by a head circumference less than three standard deviations below the mean for age and sex and results in moderate to severe mental deficiencies and decreased lifespan. We recently studied two children with primary microcephaly in an otherwise unaffected family. Exome sequencing identified an autosomal recessive mutation leading to an amino acid substitution in a WD40 domain of the highly conserved Coatomer Protein Complex, Subunit Beta 2 (COPB2). To study the role of Copb2 in neural development, we utilized genome editing technology to generate an allelic series in the mouse. Two independent null alleles revealed that Copb2 is essential for early stages of embryogenesis. Mice homozygous for the patient variant (Copb2R254C/R254C) appear to have a grossly normal phenotype, likely due to differences in corticogenesis between the two species. Strikingly, mice heterozygous for the patient mutation and a null allele (Copb2R254C/Znf) show a severe perinatal phenotype including low neonatal weight, significantly increased apoptosis in the brain, and death within the first week of life. Immunostaining of the Copb2R254C/Znf brain revealed a reduction in layer V (CTIP2+) neurons, while the overall cell density of the cortex is unchanged. Moreover, disruption of Copb2 in mouse neurospheres resulted in reduced proliferation. These results identify a general requirement for COPB2 in embryogenesis and a specific role in corticogenesis. We further demonstrate the utility of CRISPR-Cas9 generated mouse models in the study of potential pathogenicity of variants of potential clinical interest.

There has been extensive debate about both the necessity of orthogonal confirmation of next-generation sequencing (NGS) results in Clinical Laboratory Improvement Amendments-approved laboratories and return of research NGS results to participants enrolled in research studies. In eMERGE-PGx, subjects underwent research NGS using PGRNseq and orthogonal targeted genotyping in clinical laboratories, which prompted a comparison of genotyping results between platforms. Concordance (percentage agreement) was reported for 4077 samples tested across nine combinations of research and clinical laboratories. Retesting was possible on a subset of 1792 samples, and local laboratory directors determined sources of genotype discrepancy. Research NGS and orthogonal clinical genotyping had an overall per sample concordance rate of 0.972 and per variant concordance rate of 0.997. Genotype discrepancies attributed to research NGS were because of sample switching (preanalytical errors), whereas the majority of genotype discrepancies (92.3%) attributed to clinical genotyping were because of allele dropout as a result of rare variants interfering with primer hybridization (analytical errors). These results highlight the analytical quality of clinically significant pharmacogenetic variants derived from NGS and reveal important areas for research and clinical laboratories to address with quality management programs.

Genomic testing of adolescents is increasing yet engaging them in decision-making is not routine. We assessed decisional conflict in adolescents and a parent making independent decisions about actual genomic testing results and factors that influenced their choices. We enrolled 163 dyads consisting of an adolescent (13-17 years) not selected based on a specific clinical indication and one parent. After independently choosing categories of conditions to learn for the adolescent, participants completed the validated Decisional Conflict Scale and a survey assessing factors influencing their respective choices. Adolescents had higher decisional conflict scores than parents (15.6 [IQR:4.7-25.6] vs 9.4 [IQR:1.6-21.9]; P = .0007). Adolescents with clinically significant decisional conflict were less likely to choose to learn all results than adolescents with lower decisional conflict (19.6% vs 80.4%; P < .0001) and less likely to report their choices were influenced by actionability of results (33.3% vs 18.9%; P = .044) and feeling confident they can deal with the results (71.2% vs 91.9%; P = .0005). Our findings suggest higher decisional conflict in adolescents may influence the type and amount of genomic results they wish to learn. Additional research assessing decisional conflict and factors influencing testing choices among adolescents in clinical settings are required.

Genomic knowledge is being translated into clinical care. To fully realize the value, it is critical to place credible information in the hands of clinicians in time to support clinical decision-making. The electronic health record is an essential component of clinician workflow. Utilizing the electronic health record to present information to support the use of genomic medicine in clinical care to improve outcomes represents a tremendous opportunity. However, there are numerous barriers that prevent the effective use of the electronic health record for this purpose. The electronic health record working groups of the electronic MEdical Records and GEnomics network (eMERGE) and the Clinical Genome Resource (ClinGen) project, along with other groups, have been defining these barriers, to allow the development of solutions that can be tested using implementation pilots. In this paper, we present ‘lessons learned’ from these efforts to inform future efforts leading to the development of effective and sustainable solutions that will support the realization of genomic medicine.

Purpose Adolescents will increasingly be involved in decisions about the return of genomic results. We examined adolescents' and parents' decisions about learning actual genomic research results for the adolescent and whether choices were associated with participants' demographic factors. Methods Adolescents aged between 13 and 17 years and a parent (dyads) were recruited through flyers, social media, employee emails, and clinic visits at a pediatric hospital. Dyads used a decision tool to independently choose the categories of conditions they wanted to learn about the adolescent. They then came together to discuss their independent decisions and make final joint decisions. Conditions were categorized by preventability, treatability, adult-onset conditions, and carrier status. Participants could make granular choices by including or excluding conditions in each category. Categorical choices were collapsed into the “aggregate choice” to learn all or not all results. Results Study visits were completed by 163 dyads. Adolescents were less likely than their parents to independently choose to learn all results (64.4% vs. 76.1%; p = .0056). Parents were less likely to independently choose to learn all results for their daughters than their sons (odds ratio = .41, 95% confidence interval .18–.96; p = .032). Black adolescents were less likely to independently choose to learn all results than white adolescents (odds ratio = .22; 95% confidence interval .08–.55; p = .0015). After making joint decisions, 70.6% of dyads chose to learn all results. Conclusions Adolescents independently wanted to learn less genomic information than their parents. Although adolescents cannot legally make genomic testing decisions without parental permission, adolescents' should be engaged in decisions about the return of genomic results.

Concerns about the ethical and social implications of genetics persist as more applications of genetic and genomic technology have become available. Pediatric testing for genetic influences on response to opioids like codeine is one area of application. We interviewed parents of children enrolled in a mixed-methods study following the communication of actual or hypothetical results for CYP2D6, which impacts opioid response. Forty-one parents of children naive to opioids and 42 parents of children previously exposed to opioids participated in qualitative interviews. Findings did not differ by the child's opioid exposure or by actual versus hypothetical results. Parents' responses centered on the experience of the parent(s) and the potential impact of that information on the parent, rather than the result's impact on the child. Parents also emphasized that the results did not impact their perceptions of the child, reaffirming that the child was still "normal" regardless of test result. When asked about the impact of receiving secondary results, parents' responses emphasized how the results would impact their ability to advocate for the child or impact their state of mind. While the answers reflect parents' role as surrogate decision maker for their child, they also reinforced concerns that health care decisions might be influenced by secondary parental concerns as much as by the best interests of the child. Emphasis on the child's "normality" challenges concerns about the impact of genetic essentialism, but further research is required to see whether the type of testing done or the way results were communicated shaped this response.

Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE‐PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of “precision medicine.” The February 2015 eMERGE‐PGx data release includes sequence‐derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation‐Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.

A goal of the 3rd phase of the Electronic Medical Records and Genomics (eMERGE3) Network was to examine the return of results (RoR) of actionable variants in more than 100 genes to consenting participants and their healthcare providers. Each of the 10 eMERGE sites developed plans for three essential elements of the RoR process: Disclosure to the participant, notification of the health care provider, and integration of results into the electronic health record (EHR). Procedures and protocols around these three elements were adapted as appropriate to individual site requirements and limitations. Detailed information about the RoR procedures at each site was obtained through structured telephone interviews and follow-up surveys with the clinical investigator leading or participating in the RoR process at each eMERGE3 institution. Because RoR processes at each of the 10 sites allowed for taking into account differences in population, disease focus and institutional requirements, significant heterogeneity of process was identified, including variability in the order in which patients and clinicians were notified and results were placed in the EHR. This heterogeneity in the process flow for eMERGE3 RoR reflects the &ldquo, real world&rdquo, of genomic medicine in which RoR procedures must be shaped by the needs of the patients and institutional environments.

A recent convergence of technological innovations has re-energized the ability to apply genetics to research in human craniofacial development. Next-generation exome and whole genome sequencing have significantly dropped in price, making it relatively trivial to sequence and analyze patients and families with congenital craniofacial anomalies. A concurrent revolution in genome editing with the use of the CRISPR-Cas9 system enables the rapid generation of animal models, including mouse, which can precisely recapitulate human variants. Here, we summarize the choices currently available to the research community. We illustrate this approach with the study of a family with a novel craniofacial syndrome with dominant inheritance pattern. The genomic analysis suggested a causal variant in AMOTL1 which we modeled in mice. We also made a novel deletion allele of Amotl1. Our results indicate that Amotl1 is not required in the mouse for survival to weaning. Mice carrying the variant identified in the human sequencing studies, however, do not survive to weaning in normal ratios. The cause of death is not understood for these mice complicating our conclusions about the pathogenicity in the index patient. Thus, we highlight some of the powerful opportunities and confounding factors confronting current craniofacial genetic research.

OBJECTIVE To determine the prevalence of abnormal thyroid-stimulating hormone (TSH) measures in youth with severe mood and anxiety disorders and to examine clinical and demographic predictors of abnormal TSH measures. METHODS We retrospectively examined screening TSH concentrations in psychiatrically hospitalized children and adolescents (3-19 years) with mood/anxiety disorders (DSM-IV and DSM-5 criteria) at a large, urban, pediatric hospital between September 2013 and April 2017. Symptoms were extracted from the medical record using adaptive natural language processing algorithms, and the utility of demographic, clinical, and treatment variables as predictors of abnormal TSH measures was evaluated using logistic regression. RESULTS In this sample (N = 1,017, mean ± SD age = 14.7 ± 2.24 years), 62 patients had a TSH concentration > 3.74 μIU/mL (5.3% [n = 6] of patients < 12 years of age and 6.2% [n = 56] of patients ≥ 12 years of age), and 7 patients had a TSH concentration < 0.36 μIU/mL. Elevated TSH concentrations were associated with a recent weight gain (odds ratio [OR] = 3.60; 95% CI, 1.13-9.61; P = .017), a history of thyroid disease (OR = 6.88; 95% CI, 2.37-10.7; P ≤ .0001), abnormal menstrual bleeding/menometrorrhagia (OR = 2.03; CI, 1.04-3.63; P = .024), and benzodiazepine treatment (OR = 2.29; 95% CI, 1.07-4.52; P = .02). No association was observed for sex, age, or body mass index z score. Among patients with elevated TSH measures, 12.9% (n = 8, mean ± SD age = 16.5 ± 1.5 years, 87.5% female) had an abnormal free/total thyroxine (T₄) level or other biochemical findings consistent with thyroid disease. Patients with thyroid disease (compared to those patients with elevated TSH and normal active thyroid hormone concentrations) were older (16.5 ± 1.5 vs 14.6 ± 2.3 years, P = .020) but did not differ in sex distribution (87.5% vs 63.6% female, P = .444). CONCLUSIONS TSH concentrations are abnormal in approximately 6% of psychiatrically hospitalized youth, although thyroid disease was present in < 1% of the total sample. Targeted screening should focus on patients with recent weight gain, those treated with benzodiazepines, and girls with a history of abnormal uterine bleeding/menometrorrhagia.

A recent convergence of technological innovations has re-energized the ability to apply genetics to research in human craniofacial development. Next-generation exome and whole genome sequencing have dropped in price significantly making it relatively trivial to sequence and analyze patients and families with congenital craniofacial anomalies. A concurrent revolution in genome editing with the use of the CRISPR-Cas9 system enables the rapid generation of animal models, including mouse, which can precisely recapitulate human variants. Here we summarize the choices currently available to the research community. We illustrate this approach with the study of a family with a novel craniofacial syndrome with dominant inheritance pattern. The genomic analysis suggest a causal variant in AMOTL1 which we modeled in mice. We also made a novel deletion allele of Amotl1. Our results indicate that Amotl1 is not required in the mouse for survival to weaning. Mice carrying the variant identified in the human sequencing studies, however, do not survive to weaning in normal ratios. The cause of death is not understood for these mice complicating our conclusions about the pathogenicity in the index patient. Thus, we highlight some of the powerful opportunities and confounding factors confronting current craniofacial genetic research.

Dominant optic atrophy (DOA) and axonal peripheral neuropathy (Charcot-Marie-Tooth type 2, or CMT2) are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively. In yeast, homologs of OPA1 (Mgm1) and MFN2 (Fzo1) work in concert with Ugo1, for which no human equivalent has been identified thus far. By whole-exome sequencing of patients with optic atrophy and CMT2, we identified four families with recessive mutations in SLC25A46. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1). Loss of function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of SLC25A46 strengthens the genetic overlap between optic atrophy and CMT2 while exemplifying a new class of modified solute transporters linked to mitochondrial dynamics.

Objective Unpredictable interindividual variability in response to opioids results in inadequate analgesia and opioid-related adverse effects. The effects of the child's sex on opioid response have not been well studied. The aim of this study is to determine the effects of sex on opioid-related adverse effects in children undergoing tonsillectomy. Design Prospective observational clinical study. Setting Outpatient pediatric surgery. Subjects Two hundred and seventy five children between 6 and 15 years of age undergoing outpatient tonsillectomy. Methods All children received standard perioperative care with a standard intraoperative dose of morphine. Opioid-related analgesia and safety outcomes included incidences of respiratory depression (RD), postoperative nausea and vomiting (PONV) and incidence of prolonged stay in the, post-anesthesia recovery unit (PACU) due to opioid related adverse effects. Results Given the small sample of minority population, we focused our study on 219 white children. Significant morphine effect was observed in girls but not boys for PONV (P = 0.001) and prolonged PACU stay due to PONV (P = 0.010). Although the overall incidence of RD is not statistically different between boys and girls, the incidence of RD (52% vs 32%) and PONV (43% vs 4%) tended to be more in white girls than boys as the total perioperative morphine dose increased to 0.3 mg/kg or more. Conclusions This study demonstrates that child's sex influences morphine's dose response and adverse effects. White girls have an unequal burden with higher incidences of PONV, RD, and prolonged PACU stays following tonsillectomy from PONV and RD as total morphine doses are increased.

Autosomal dominant omodysplasia is a rare skeletal dysplasia characterized by short humeri, radial head dislocation, short first metacarpals, facial dysmorphism and genitourinary anomalies. We performed next-generation whole-exome sequencing and comparative analysis of a proband with omodysplasia, her unaffected parents and her affected daughter. We identified a de novo mutation in FRIZZLED2 (FZD2) in the proband and her daughter that was not found in unaffected family members. The FZD2 mutation (c.1644G>A) changes a tryptophan residue at amino acid 548 to a premature stop (p.Trp548*). This altered protein is still produced in vitro, but we show reduced ability of this mutant form of FZD2 to interact with its downstream target DISHEVELLED. Furthermore, expressing the mutant form of FZD2 in vitro is not able to facilitate the cellular response to canonical Wnt signaling like wild-type FZD2. We therefore conclude that the FRIZZLED2 mutation is a de novo, novel cause for autosomal dominant omodysplasia.

Aim: To determine parents’ use of their children's CYP2D6 research result. We hypothesized that perceived utility, likelihood of sharing and actual sharing of results would differ between parents with children previously exposed (cases) or unexposed (controls) to opioids. Methods: We returned results by phone (baseline). We surveyed parents about perceived utility and likelihood of sharing their child's research result at baseline, and actual sharing at 3 and 12 months. Results: Cases were more likely than controls to agree that they (p = 0.022) and the doctors (p = 0.041) could use the results to care for their child, to report higher likelihood of sharing (p = 0.042) and to actually share results with the child's doctor (p = 0.026). Conclusion: Prior opioid exposure influenced perceived clinical utility and sharing behaviors.

Ten organizations within the Electronic Medical Records and Genomics Network developed programs to implement pharmacogenomic sequencing and clinical decision support into clinical settings. Recognizing the importance of informed prescribers, a variety of strategies were used to incorporate provider education to support implementation. Education experiences with pharmacogenomics are described within the context of each organization's prior involvement, including the scope and scale of implementation specific to their Electronic Medical Records and Genomics projects. We describe common and distinct education strategies, provide exemplars and share challenges. Lessons learned inform future perspectives. Future pharmacogenomics clinical implementation initiatives need to include funding toward implementing provider education and evaluating outcomes.

ObjectiveHaving failed to achieve adequate influenza vaccination rates among employees through voluntary programmes, healthcare organisations have adopted mandatory ones. Some programmes permit religious exemptions, but little is known about who requests religious objections or why.MethodsContent analysis of applications for religious exemptions from influenza vaccination at a free-standing children’s hospital in Cincinnati, Ohio, USA during the 2014–2015 influenza season.ResultsTwelve of 15 260 (0.08%) employees submitted applications requesting religious exemptions. Requestors included both clinical and non-clinical employees. All requestors voluntarily identified their religious affiliation, and most were Christian (n=9). Content analysis identified six categories of reasons used to justify an exemption: risks/benefits, ethical/political, lack of direct patient contact, providence, purity and sanctity of life. Individuals articulated reasons in 1–5 (mean 2.6) categories. The most frequently cited category (n=9) was purity; the vaccine and/or its mode of administration were impure, or receiving the vaccine would make the individual impure. Two individuals asserted that the vaccine contained cells derived from aborted human fetuses. Individuals (n=6) also volunteered information supporting the sincerity of their beliefs including distress over previous vaccination and examples of behaviour consistent with their specific objection or their general religious commitment. All requests were approved.ConclusionsLess than 0.1% of employees requested religious exemptions. Partnering with religious leaders and carefully correcting erroneous information may help address requestors’ concerns.