The NYCKidSeq randomized controlled trial: Impact of GUÍA digitally enhanced genetic results disclosure in diverse families.

Digital solutions are needed to support rapid increases in the application of genetic/genomic tests (GTs) in diverse clinical settings and patient populations. We developed GUÍA, a bilingual digital application that facilitates disclosure of GT results. The NYCKidSeq randomized controlled trial enrolled diverse children with neurologic, cardiac, and immunologic conditions who underwent GTs. The trial evaluated GUÍA's impact on understanding the GT results by randomizing families to results disclosure genetic counseling with GUÍA (intervention) or standard of care (SOC). Parents/legal guardians (participants) completed surveys at baseline, post-results disclosure, and 6 months later. Survey measures assessed the primary study outcomes of participants' perceived understanding of and confidence in explaining their child's GT results and the secondary outcome of objective understanding. The analysis included 551 diverse participants, 270 in the GUÍA arm and 281 in SOC. Participants in the GUÍA arm had significantly higher perceived understanding post-results (OR = 2.8, CI[1.004, 7.617], p = 0.049) and maintained higher objective understanding over time (OR = 1.1, CI[1.004, 1.127], p = 0.038) compared to SOC. There was no impact on perceived confidence. Hispanic/Latino(a) individuals in the GUÍA arm maintained higher perceived understanding (OR = 3.9, CI[1.603, 9.254], p = 0.003), confidence (OR = 2.7, CI[1.021, 7.277], p = 0.046), and objective understanding (OR = 1.1, CI[1.009, 1.212], p = 0.032) compared to SOC. This trial demonstrates that GUÍA positively impacts understanding of GT results in diverse parents of children with suspected genetic conditions and builds a case for utilizing GUÍA to deliver complex results. Continued development and evaluation of digital applications in diverse populations are critical for equitably scaling GT offerings in specialty clinics.

Expansion and mechanistic insights into de novo DEAF1 variants in DEAF1-associated neurodevelopmental disorders.

De novo deleterious and heritable biallelic mutations in the DNA binding domain (DBD) of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) result in a phenotypic spectrum of disorders termed DEAF1-associated neurodevelopmental disorders (DAND). RNA-sequencing using hippocampal RNA from mice with conditional deletion of Deaf1 in the central nervous system indicate that loss of Deaf1 activity results in the altered expression of genes involved in neuronal function, dendritic spine maintenance, development, and activity, with reduced dendritic spines in hippocampal regions. Since DEAF1 is not a dosage-sensitive gene, we assessed the dominant negative activity of previously identified de novo variants and a heritable recessive DEAF1 variant on selected DEAF1-regulated genes in 2 different cell models. While no altered gene expression was observed in cells over-expressing the recessive heritable variant, the gene expression profiles of cells over-expressing de novo variants resulted in similar gene expression changes as observed in CRISPR-Cas9-mediated DEAF1-deleted cells. Altered expression of DEAF1-regulated genes was rescued by exogenous expression of WT-DEAF1 but not by de novo variants in cells lacking endogenous DEAF1. De novo heterozygous variants within the DBD of DEAF1 were identified in 10 individuals with a phenotypic spectrum including autism spectrum disorder, developmental delays, sleep disturbance, high pain tolerance, and mild dysmorphic features. Functional assays demonstrate these variants alter DEAF1 transcriptional activity. Taken together, this study expands the clinical phenotypic spectrum of individuals with DAND, furthers our understanding of potential roles of DEAF1 on neuronal function, and demonstrates dominant negative activity of identified de novo variants.

Molecular diagnostic yield of genome sequencing versus targeted gene panel testing in racially and ethnically diverse pediatric patients.

PURPOSE: Adoption of genome sequencing (GS) as a first-line test requires evaluation of its diagnostic yield. We evaluated the GS and targeted gene panel (TGP) testing in diverse pediatric patients (probands) with suspected genetic conditions. METHODS: Probands with neurologic, cardiac, or immunologic conditions were offered GS and TGP testing. Diagnostic yield was compared using a fully paired study design. RESULTS: A total of 645 probands (median age 9 years) underwent genetic testing, and 113 (17.5%) received a molecular diagnosis. Among 642 probands with both GS and TGP testing, GS yielded 106 (16.5%) and TGPs yielded 52 (8.1%) diagnoses (P < .001). Yield was greater for GS vs TGPs in Hispanic/Latino(a) (17.2% vs 9.5%, P < .001) and White/European American (19.8% vs 7.9%, P < .001) but not in Black/African American (11.5% vs 7.7%, P = .22) population groups by self-report. A higher rate of inconclusive results was seen in the Black/African American (63.8%) vs White/European American (47.6%; P = .01) population group. Most causal copy number variants (17 of 19) and mosaic variants (6 of 8) were detected only by GS. CONCLUSION: GS may yield up to twice as many diagnoses in pediatric patients compared with TGP testing but not yet across all population groups.

Detection of mosaic variants using genome sequencing in a large pediatric cohort.

The increased use of next-generation sequencing has expanded our understanding of the involvement and prevalence of mosaicism in genetic disorders. We describe a total of eleven cases: nine in which mosaic variants detected by genome sequencing (GS) and/or targeted gene panels (TGPs) were considered to be causative for the proband's phenotype, and two of apparent parental mosaicism. Variants were identified in the following genes: PHACTR1, SCN8A, KCNT1, CDKL5, NEXMIF, CUX1, TSC2, GABRB2, and SMARCB1. In addition, we identified one large duplication including three genes, UBE3A, GABRB3, and MAGEL2, and one large deletion including deletion of ARFGAP1, EEF1A2, CHRNA4, and KCNQ2. All patients were enrolled in the NYCKidSeq study, a research program studying the communication of genomic information in clinical care, as well as the clinical utility and diagnostic yield of GS for children with suspected genetic disorders in diverse populations in New York City. We observed variability in the correlation between reported variant allele fraction and the severity of the patient's phenotype, although we were not able to determine the mosaicism percentage in clinically relevant tissue(s). Although our study was not sufficiently powered to assess differences in mosaicism detection between the two testing modalities, we saw a trend toward better detection by GS as compared with TGP testing. This case series supports the importance of mosaicism in childhood-onset genetic conditions and informs guidelines for laboratory and clinical interpretation of mosaic variants detected by GS.

GenomeDiver: a platform for phenotype-guided medical genomic diagnosis.

PURPOSE: Making a diagnosis from clinical genomic sequencing requires well-structured phenotypic data to guide genotype interpretation. A patient's phenotypic features can be documented using the Human Phenotype Ontology (HPO), generating terms used to prioritize genes potentially causing the patient's disease. We have developed GenomeDiver to provide a user interface for clinicians that allows more effective collaboration with the clinical diagnostic laboratory, with the goal of improving the success of the diagnostic process. METHODS: GenomeDiver uses genomic data to prompt reverse phenotyping of patients undergoing genetic testing, enriching the amount and quality of structured phenotype data for the diagnostic laboratory, and helping clinicians to explore and flag diseases potentially causing their patient's presentation. RESULTS: We show how GenomeDiver communicates the clinician's informed insights to the diagnostic lab in the form of HPO terms for interpretation of genomic sequencing data. We describe our user-driven design process, the engineering of the software for efficiency, security and portability, and examples of the performance of GenomeDiver using genomic testing data. CONCLUSION: GenomeDiver is a first step in a new approach to genomic diagnostics that enhances laboratory-clinician interactions, with the goal of directly engaging clinicians to improve the outcome of genomic diagnostic testing.

Summary report of the 2019 Diversity and Inclusion Task Force of the National Society of Genetic Counselors.

The size and reach of the genetic counseling profession have expanded on a global scale since the 1970s. Despite this growth, the profession of genetic counseling has remained demographically homogenous. Promoting a culture of inclusivity that supports visible and invisible diversity and leveraging that culture not only expands perspectives represented in the field, but also helps foster equity in genetic services. This report summarizes the formation, implementation, and outcomes of the 2019 Diversity and Inclusion Task Force (TF) of the National Society of Genetic Counselors (NSGC), including the group's responses to their allotted charges from the NSGC Board of Directors. The recommendations generated by the TF aim to aid in the (1) establishment of infrastructure for ongoing diversity, inclusion, and equity (DEI) work by collaborating with a DEI organizational expert and forming a DEI advisory group within the NSGC, (2) development of specific short-term DEI initiatives, and (3) identification of seven areas of focus areas that must be addressed in order to create meaningful and measurable DEI improvements. The efficacy of these recommendations will depend on the consistency and creativity of implementation, shared responsibility, sufficient resources allocated to DEI initiatives, and measurable outcomes.

Prospective Comparison of Patient-selected Operative Versus Nonoperative Treatment of Scheuermann Kyphosis.

BACKGROUND: Scheuermann kyphosis (SK) can be managed operatively or nonoperatively. Few studies compare the effect of operative versus nonoperative treatment on patient health-related quality of life. We compare 2-year radiographic and the Scoliosis Research Society-22 questionnaire (SRS-22) results of patients who self-selected either conservative or surgical treatment. METHODS: Single institution review of prospectively collected data for patients presenting with SK from 2006 to 2014. Forty-five of 55 patients returned for 2-year follow-up. Patients were divided into operative (n=27) or nonoperative (n=18) groups based upon their self-selected method of treatment. Radiographic data and SRS-22 scores were collected at initial presentation and 2-year follow-up. RESULTS: Operatively treated patients had larger initial sagittal Cobb angles and lower SRS-22 scores in the pain and appearance domains. Two years postoperatively, surgically treated patients had smaller Cobb angles and improved scores in these SRS-22 domains. Nonoperatively treated patients did not deteriorate over time. CONCLUSIONS: Patients who elect to receive operative treatment for SK have improved radiographic and SRS-22 parameters at 2-year follow-up compared with patients who elect nonoperative treatment. Not surprisingly, patients selecting surgical treatment had greater sagittal Cobb angles and greater levels of pain and dissatisfaction with their appearance. However, at 2-year follow-up, surgical patients experience greater (and significant) change on all parameters; exhibiting smaller Cobb angles, less pain, and greater satisfaction with their outcomes. Nonoperatively treated patients do not deteriorate over 2 years. LEVEL OF EVIDENCE: Level II-prognostic study.

Achievement of Adequate Glycemic Control in Patients With Type 2 Diabetes and Comorbid Mental Health Conditions Treated in a Primary Care Setting.

OBJECTIVE: This study investigated the association between the presence of a mental health condition (MHC) diagnosis and glycemic control in patients with type 2 diabetes in a primary care clinic network. METHODS: This retrospective cross-sectional study compared adequate glycemic control (A1C <8.0%) in patients with type 2 diabetes with and without any MHC, as well as by MHC subtypes of depression or anxiety, bipolar or schizophrenia disorders, and substance use disorder. RESULTS: Of 3,025 patients with type 2 diabetes, 721 (24%) had a diagnosis for one or more MHC. The majority (54.9%) were <65 years of age, female (54.9%), and Caucasian (74.5%). Mean A1C was statistically lower in the MHC cohort at 7.14 ± 1.66% compared to 7.38 ± 1.73% in the group without any MHC (P = 0.001). Furthermore, those with an MHC were more likely to attain adequate glycemic control than those without an MHC (odds ratio 1.27, 95% CI 1.01-1.59). Among patients with MHCs, similar rates of adequate glycemic control were seen between those with depression or anxiety and those with other MHCs. However, fewer patients with substance use disorder had adequate glycemic control compared to those without this condition (66.7 vs. 80.10%, P = 0.004). CONCLUSION: Patients with diabetes and MHCs had slightly better glycemic control than those without any MHC. However, the presence of substance use disorder may present more barriers to adequate glycemic control. Additional research is needed to identify barriers unique to each MHC to optimize diabetes management in this population.

Spectrum of Diagnosis and Disposition of Patients Referred to a Pediatric Orthopaedic Center for a Diagnosis of Intoeing.

BACKGROUND: Orthopaedic surgeons frequently evaluate otherwise healthy children for concern of intoed gait. Intoeing in otherwise healthy young children due to metatarsus adductus, internal tibial torsion, and increased femoral anteversion do not typically require orthopaedic treatment. This study reviewed the actual diagnosis, management, and disposition of patients referred to a pediatric orthopaedic specialty hospital for a diagnosis of intoeing; the efficacy of an Advanced Practice Provider (APP) assessment program to screen and triage patients with a primary complaint of intoeing; and parental satisfaction with that program. METHODS: We established an "Intoeing Clinic" conducted by APPs to conduct initial evaluations of patients referred for a diagnosis of intoeing meeting-specific criteria, including (1) a referring provider's diagnosis of "intoeing"; (2) the patient was under the age of 9 years; and (3) there was no suggestion of comorbidity in the information provided by the referring provider to imply a diagnosis other than "benign" intoeing. Under pediatric orthopaedic surgeon "on-call" supervision, APPs were authorized to perform clinical assessments supplemented by radiographs and laboratory investigations as deemed necessary. We performed an Institutional Review Board-approved, retrospective medical record review of all patients appointed to our Intoeing Clinic over a 30-month period (March 2010 to September 2013). RESULTS: About 95% of 926 patients appointed to APP Intoeing Clinic were confirmed to have a diagnosis of "benign" intoeing or a similar "benign" diagnosis; 5% of these patients requested a reevaluation for the same concern. Approximately 5% were determined to have a nonbenign diagnosis, either known to the family/provider, but not conveyed at the time of referral (4%), or identified at our institution (1%). Two patients (0.2%) were determined at follow-up examination to have a neurological abnormality at the subsequent examination. CONCLUSIONS: An "Intoeing Clinic" staffed by experienced Advanced Pediatric Practitioners or equivalent, with appropriate orthopaedic surgeon availability for consultation can be an effective and efficient method of evaluating patients referred for a diagnosis of "intoeing." LEVEL OF EVIDENCE: Level IV-case series.

Sodium Oxybate for Narcolepsy: Explaining Untoward Effects and Recommending New Approaches in Light of Prevailing Receptor Pharmacology.

Objective: Gamma-hydroxybutyrate (GHB) has been an abused and illicit substance for decades, but the antinarcoleptic medication Xyrem (sodium oxybate), the sodium salt of GHB, was approved just in 2002 for increasing wakefulness. We present a case of coma induced by co-ingestion of prescription GHB and ethanol and describe the response to naloxone treatment, by first responders, without evidence of opiate exposure. The purpose of this report is to bridge updated knowledge on GHB and ethanol pharmacology with the clinical sequence of events in a patient co-ingesting these compounds and to theorize on a potentially better pharmacological approach to narcolepsy. Case Summary: The patient was a 25-year-old woman with a history of narcolepsy. She suddenly collapsed at home but became transiently responsive after being administered naloxone in the ambulance. She presented to the emergency department with apnea, poor responsiveness with a Glasgow Coma Score of 7, and urinary incontinence. While undergoing intubation, the patient spontaneously and abruptly awoke. Labs were unremarkable except a blood alcohol concentration of 0.123%. The dosage of, and adherence to, GHB was unknown in this case. Discussion: The case is described in light of the most recent pharmacological advancements on these co-ingestants. A conceptual dose-response curve is shown to facilitate understanding of the complex pharmacology of GHB. Conclusions: Approved and potential alternatives to GHB, for achieving wakefulness, are discussed. Potential new strategies should bear low to no risk of coma with accidental overdose or co-ingestion of ethanol. In addition, promising antidotes for future consideration are discussed.

Evaluating parental personal utility of pediatric genetic and genomic testing in a diverse, multilingual population.

There is increasing evidence of the clinical utility of genetic and genomic testing (GT); however, factors influencing personal utility of GT, especially in diverse, multilingual populations, remain unclear. We explored these factors in a diverse cohort of parents/guardians (participants) whose children received clinical GT through the NYCKidSeq program. A total of 847 participants completed surveys at baseline, post-results disclosure, and 6 months (6m) post-results. The largest population groups were Hispanic/Latino(a) (48%), White/European American (24%), and Black/African American (16%). Personal utility was assessed using the Personal Utility (PrU) scale, adapted for pediatric populations and included on the surveys. Three PrU subscales were identified using factor analysis: practical, educational, and parental psychological utility. Overall personal utility summary score and the three subscales significantly decreased after receiving results and over time. Hispanic/Latino(a) participants identified greater overall personal utility than European American and African American participants at all time points (p < 0.001) as did participants whose children received positive/likely positive results compared with those with negative and uncertain results (post-results: p < 0.001 and p < 0.001; 6m post-results: p = 0.002 and p < 0.001, respectively). Post-results, higher subscale scores were associated with lower education levels (practical, parental psychological: p ≤ 0.02) and higher levels of trust in the healthcare system (practical, parental psychological: p ≤ 0.04). These findings help to understand the perspectives of diverse parents/guardians, which is critical to tailoring pre- and post-test counseling across a variety of populations and clinical settings.

The effect of experimental pollinator decline on pollinator-mediated selection on floral traits.

Human-mediated environmental change, by reducing mean fitness, is hypothesized to strengthen selection on traits that mediate interactions among species. For example, human-mediated declines in pollinator populations are hypothesized to reduce mean seed production by increasing the magnitude of pollen limitation and thus strengthen pollinator-mediated selection on floral traits that increase pollinator attraction or pollen transfer efficiency. To test this hypothesis, we measured two female fitness components and six floral traits of Lobelia siphilitica plants exposed to supplemental hand-pollination, ambient open-pollination, or reduced open-pollination treatments. The reduced treatment simulated pollinator decline, while the supplemental treatment was used to estimate pollen limitation and pollinator-mediated selection. We found that plants in the reduced pollination treatment were significantly pollen limited, resulting in pollinator-mediated selection for taller inflorescences and more vibrant petals, both traits that could increase pollinator attraction. This contrasts with plants in the ambient pollination treatment, where reproduction was not pollen limited and there was not significant pollinator-mediated selection on any floral trait. Our results support the hypothesis that human-mediated environmental change can strengthen selection on traits of interacting species and suggest that these traits have the potential to evolve in response to changing environments.

Harmful Algal Bloom Exposures Self-reported to Poison Centers in the United States, May-October 2019.

The National Poison Data System (NPDS) comprises self-reported information from people who call US poison center hotlines. NPDS data have proven to be important in identifying emerging public health threats. We used NPDS to examine records of people who had self-reported exposure to harmful algal blooms (HABs). Participating poison centers then contacted people who had called their centers from May through October 2019 about their HAB exposure to ask about exposure route, symptoms, health care follow-up, and awareness of possible risks of exposure. Of 55 callers who agreed to participate, 47 (85%) reported exposure to HABs while swimming or bathing in HAB-contaminated water. Nine callers reported health symptoms from being near waters contaminated with HABs, suggesting potential exposure via aerosolized toxins. Symptoms varied by the reported routes of exposure; the most commonly reported symptoms were gastrointestinal and respiratory. More public and health care provider education and outreach are needed to improve the understanding of HAB-related risks, to address ways to prevent HAB-related illnesses, and to describe appropriate support when exposures occur.

Monitoring trends in lacrimator exposures using the National Poison Data System: 2000-2021.

CONTEXT: Lacrimators are used by individuals for personal defense and by police for crowd control during periods of civil unrest. Increased public awareness about their use has raised concerns about their application and safety. OBJECTIVE: To characterize patterns of lacrimator exposures in the United States, we describe temporal trends of calls to poison centers by demographics, substances, medical outcomes, exposure sites, and scenarios. METHODS: A retrospective data analysis was performed for all single-substance lacrimator exposures in the United States reported to the National Poison Data System between 2000 and 2021. Descriptive analyses were performed to examine demographic characteristics, geographic distribution, product types and medical outcomes associated with lacrimator exposures. RESULTS: A total of 107,149 lacrimator exposure calls were identified. There was an overall decrease in calls per year, from 6,521 calls in 2000 to 2,520 in 2020, followed by an increase to 3,311 calls in 2021. A declining trend was observed independent of total poison center call volume. Oleoresin capsicum was the most commonly reported substance (81,990, 76.5%). Individuals ages 19 years and younger accounted for 62% of calls, but adults ages 20 and over were more likely to develop major clinical effects (odds ratio 3.03; 95% confidence interval 1.91-4.81; P < 0.0001). The most common exposure site was "own residence," followed by schools. School exposures accounted for 15.8% of exposures in children ages 6-12 years and 37.7% in adolescents. Among calls with documented scenarios, 19.7% involved unintentional exposures due to children accessing lacrimators. CONCLUSION: Lacrimator exposure calls to United States poison centers decreased from 2000 to 2021. Most calls pertain to oleoresin capsicum and individuals ages 19 and younger. Improper storage allowing children to have access to these chemicals, is a common scenario. Public safety interventions such as education about safe storage and use of lacrimators, improved product design, or regulatory changes may prevent unintentional exposures.

2022 Annual Report of the National Poison Data System® (NPDS) from America's Poison Centers®: 40th Annual Report.

INTRODUCTION: This is the 40th Annual Report of America's Poison Centers National Poison Data System (NPDS). As of 1 January, 2022, all 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 4.72 [4.40, 9.27] (median [25%, 75%]) minutes, effectuating a near real-time national exposure and information database and surveillance system. METHODS: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure. RESULTS: In 2022, 2,483,183 closed encounters were logged by NPDS: 2,064,875 human exposures, 50,381 animal exposures, 363,099 information requests, 4,790 human confirmed nonexposures, and 38 animal confirmed nonexposures. Total encounters showed a 12.9% decrease from 2021, and human exposure cases decreased by 0.771%, while health care facility (HCF) human exposure cases increased by 0.214%. All information requests decreased by 48.4%, medication identification (Drug ID) requests decreased by 21.2%, and medical information requests showed a 76.92% decrease, although these remain twice the median number before the COVID-19 pandemic. Drug Information requests showed a 52.4% decrease, due to declining COVID-19 vaccine calls to PCs but still comprised 5.55% of all information contacts. Human exposures with less serious outcomes have decreased 1.70% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.41% per year since 2000.Consistent with the previous year, the top 4 substance classes most frequently involved in all human exposures were analgesics (11.5%), household cleaning substances (7.23%), antidepressants (5.61%), and cosmetics/personal care products (5.23%). Antihistamines (4.81%) replaced sedatives/hypnotics/antipsychotics as the 5th substance class. As a class, analgesic exposures increased most rapidly, by 1,514 cases/year (3.26%/year) over the past 10 years for cases with more serious outcomes.The top 5 most common exposures in children age 5 years or less were household cleaning substances (10.3%), analgesics (9.54%), cosmetics/personal care products (9.49%), dietary supplements/herbals/homeopathic (6.65%), and foreign bodies/toys/miscellaneous (6.61%). NPDS documented 3,255 human exposures resulting in death; 2,622 (80.6%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory). CONCLUSIONS: These data support the continued value of PC expertise and the need for specialized medical toxicology information to manage the increasing number of more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information requests. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.

The NYCKidSeq randomized controlled trial: Impact of GUÍA digitally enhanced genetic counseling in racially and ethnically diverse families.

Background: Digital solutions are needed to support rapid increases in the application of genetic and genomic tests (GT) in diverse clinical settings and patient populations. We developed GUÍA, a bi-lingual web-based platform that facilitates disclosure of GT results. The NYCKidSeq randomized controlled trial evaluated GUÍA's impact on understanding of GT results. Methods: NYCKidSeq enrolled diverse children with neurologic, cardiac, and immunologic conditions who underwent GT. Families were randomized to genetic counseling with GUÍA (intervention) or standard of care (SOC) genetic counseling for results disclosure. Parents/legal guardians (participants) completed surveys at baseline, post-results disclosure, and 6-months later. Survey measures assessed the primary study outcomes of perceived understanding of and confidence in explaining their child's GT results and the secondary outcome of objective understanding. We used regression models to evaluate the association between the intervention and the study outcomes. Results: The analysis included 551 participants, 270 in the GUÍA arm and 281 in SOC. Participants' mean age was 41.1 years and 88.6% were mothers. Most participants were Hispanic/Latino(a) (46.3%), White/European American (24.5%), or Black/African American (15.8%). Participants in the GUÍA arm had significantly higher perceived understanding post-results (OR=2.8, CI[1.004,7.617], P=0.049) and maintained higher objective understanding over time (OR=1.1, CI[1.004, 1.127], P=0.038) compared to those in the SOC arm. There was no impact on perceived confidence. Hispanic/Latino(a) individuals in the GUÍA arm maintained higher perceived understanding (OR=3.9, CI[1.6, 9.3], P=0.003), confidence (OR=2.7, CI[1.021, 7.277], P=0.046), and objective understanding (OR=1.1, CI[1.009, 1.212], P=0.032) compared to SOC . Conclusions: This trial demonstrates that GUÍA positively impacts understanding of GT results in diverse parents of children with suspected genetic conditions. These findings build a case for utilizing GUÍA to deliver complex and often ambiguous genetic results. Continued development and evaluation of digital applications in diverse populations are critical for equitably scaling GT offerings in specialty clinics. Trial Registration: Clinicaltrials.gov identifier NCT03738098.

Molecular diagnostic yield of genome sequencing versus targeted gene panel testing in racially and ethnically diverse pediatric patients.

Purpose: Adoption of genome sequencing (GS) as a first-line test requires evaluation of its diagnostic yield. We evaluated the GS and targeted gene panel (TGP) testing in diverse pediatric patients (probands) with suspected genetic conditions. Methods: Probands with neurologic, cardiac, or immunologic conditions were offered GS and TGP testing. Diagnostic yield was compared using a fully paired study design. Results: 645 probands (median age 9 years) underwent genetic testing, and 113 (17.5%) received a molecular diagnosis. Among 642 probands with both GS and TGP testing, GS yielded 106 (16.5%) and TGPs yielded 52 (8.1%) diagnoses ( P < .001). Yield was greater for GS vs . TGPs in Hispanic/Latino(a) (17.2% vs . 9.5%, P < .001) and White/European American (19.8% vs . 7.9%, P < .001), but not in Black/African American (11.5% vs . 7.7%, P = .22) population groups by self-report. A higher rate of inconclusive results was seen in the Black/African American (63.8%) vs . White/European American (47.6%; P = .01) population group. Most causal copy number variants (17 of 19) and mosaic variants (6 of 8) were detected only by GS. Conclusion: GS may yield up to twice as many diagnoses in pediatric patients compared to TGP testing, but not yet across all population groups.

The TeleKidSeq pilot study: incorporating telehealth into clinical care of children from diverse backgrounds undergoing whole genome sequencing.

BACKGROUND: The COVID-19 pandemic forced healthcare institutions and many clinical research programs to adopt telehealth modalities in order to mitigate viral spread. With the expanded use of telehealth, there is the potential to increase access to genomic medicine to medically underserved populations, yet little is known about how best to communicate genomic results via telehealth while also ensuring equitable access. NYCKidSeq, a multi-institutional clinical genomics research program in New York City, launched the TeleKidSeq pilot study to assess alternative forms of genomic communication and telehealth service delivery models with families from medically underserved populations. METHODS: We aim to enroll 496 participants between 0 and 21 years old to receive clinical genome sequencing. These individuals have a neurologic, cardiovascular, and/or immunologic disease. Participants will be English- or Spanish-speaking and predominantly from underrepresented groups who receive care in the New York metropolitan area. Prior to enrollment, participants will be randomized to either genetic counseling via videoconferencing with screen-sharing or genetic counseling via videoconferencing without screen-sharing. Using surveys administered at baseline, results disclosure, and 6-months post-results disclosure, we will evaluate the impact of the use of screen-sharing on participant understanding, satisfaction, and uptake of medical recommendations, as well as the psychological and socioeconomic implications of obtaining genome sequencing. Clinical utility, cost, and diagnostic yield of genome sequencing will also be assessed. DISCUSSION: The TeleKidSeq pilot study will contribute to innovations in communicating genomic test results to diverse populations through telehealth technology. In conjunction with NYCKidSeq, this work will inform best practices for the implementation of genomic medicine in diverse, English- and Spanish-speaking populations.