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Purpose: Recurrent 15q13.3 deletions are enriched in multiple neurodevelopmental conditions including intellectual disability, autism, epilepsy, and schizophrenia. However, the 15q13.3 microdeletion syndrome remains ill-defined. Methods: We systematically compiled all cases of 15q13.3 deletion published before 2014. We also examined three locally available cohorts to identify new adults with 15q13.3 deletions. Results: We identified a total of 246 cases (133 children, 113 adults) with deletions overlapping or within the 15q13.3 (breakpoint (BP)4–BP5) region, including seven novel adult cases from local cohorts. No BP4–BP5 deletions were identified in 23,838 adult controls. Where known, 15q13.3 deletions were typically inherited (85.4%) and disproportionately of maternal origin ( P < 0.0001). Overall, 198 cases (121 children, 77 adults; 80.5%) had at least one neuropsychiatric diagnosis. Accounting for ascertainment, developmental disability/intellectual disability was present in 57.7%, epilepsy/seizures in 28.0%, speech problems in 15.9%, autism spectrum disorder in 10.9%, schizophrenia in 10.2%, mood disorder in 10.2%, and attention deficit hyperactivity disorder in 6.5%. By contrast, major congenital malformations, including congenital heart disease (2.4%), were uncommon. Placenta previa occurred in the pregnancies of four cases. Conclusion: The 15q13.3 microdeletion syndrome is predominantly characterized by neuropsychiatric expression. There are implications for pre- and postnatal detection, genetic counseling, and anticipatory care. Genet Med 17 2, 149–157.

This study aims to test the association between the place-provider-matrix (PPM) of bystander cardiopulmonary resuscitation (CPR) and outcomes of out-of-hospital cardiac arrest (OHCA). Adult patients with OHCA with a cardiac etiology from 2012 to 2017 in Korea were analyzed, excluding patients who had unknown information on place, type of bystander, or outcome. The PPM was categorized into six groups by two types of places (public versus home) and three types of providers (trained responder (TR), family bystander, and layperson bystander). Outcomes were survival to discharge and good cerebral performance category (CPC) of 1 or 2. Multivariable logistic regression analysis was performed to test the association between PPM group and outcomes with adjustment for potential confounders to calculate adjusted odds ratios (AORs) and 95% confidence intervals (CIs) (reference = Public-TR). A total of 73,057 patients were analyzed and were categorized into Public-TR (0.6%), Home-TR (0.3%), Public-Family (1.8%), Home-Family (79.8%), Public-Layperson (9.9%), and Home-Layperson (7.6%) groups. Compared with the Public-TR group, the AORs (95% CIs) for survival to discharge were 0.61 (0.35-1.05) in the Home-TR group, 0.85 (0.62-1.17) in the Public-Family group, 0.38 (0.29-0.50) in the Home-Family group, 1.12 (0.85-1.49) in the Public-Layperson group, and 0.42 (0.31-0.57) in the Home-Layperson group. The AORs (95% CIs) for good CPC were 0.58 (0.27-1.25) in the Home-TR group, 0.88 (0.61-1.27) in the Public-Family group, 0.38 (0.28-0.52) in the Home-Family group, 1.20 (0.87-1.65) in the Public-Layperson group, and 0.42 (0.30-0.59) in the Home-Layperson group. The OHCA outcomes of the Home-Family and Home-Layperson groups were worse than those of the Public-TR group. This finding suggests that OHCA occurring in private places with family or layperson bystanders requires a new strategy, such as dispatching trained responders to the scene to improve CPR outcomes.

Patient and health care provider access to genetic subspecialists is challenging owing to limited number of genetics experts across the United States. The University of California San Francisco (UCSF) Genetics electronic consultation (e-Consult) service was implemented along with the usual referral pathway to improve access to timely genetic expertise through robust asynchronous provider-to-provider communication. This study examined the impact of the UCSF Genetics e-Consult service on patient access to genetics expertise. A retrospective chart review of 622 e-Consult requests was conducted. Data pertinent to e-Consult completion rates, provider response times, consultation content, and adherence to geneticist recommendations were abstracted. From October 2016 to March 2024, the UCSF Genetics e-Consult service received a total of 622 consultation orders, with yearly volumes increasing from 34 in 2017 to 144 in 2023. A total of 360/622 (57.8%) consultations were completed, of which 197/360 (54.6%) were resolved without requiring a specialty care visit. Of the 262/622 (42.1%) e-Consult orders declined by the geneticist reviewer, 184/262 (70.2%) were scheduled for a synchronous genetics visit due to case complexity precluding an appropriate e-Consult response and 29.8% (78/262) were recommended to be referred to a different and more appropriate specialty. Geneticists responded to 83.9% (522/622) of e-Consults within 3 days, with most spending between 5 and 20 minutes on their e-Consult response. Nearly half of the genetics e-Consult requests (69/144; 47.9%) came from primary care providers and pediatricians. Among the 144 e-Consult requests in 2023, 50.6% (73/144) were about diagnostic queries, 17% (25/144) were on symptom management, and 11% (16/144) were about test interpretation. Provider adherence to geneticists' recommendations was observed in 84% (116/144) of cases. The UCSF Genetics e-Consult service has demonstrated efficiency in providing timely genetic consultations, with a high rate of provider adherence to recommendations. These findings support the potential of e-Consult frameworks as a viable strategy for enhancing access to genetic health care services.

Neurogenetic diseases affect individuals across the lifespan, but accurate diagnosis remains elusive for many patients. Adults with neurogenetic disorders often undergo a long diagnostic odyssey, with multiple specialist evaluations and countless investigations without a satisfactory diagnostic outcome. Reasons for these diagnostic challenges include: (1) clinical features of neurogenetic syndromes are diverse and under-recognized, particularly those of adult-onset, (2) neurogenetic syndromes may manifest with symptoms that span multiple neurological and medical subspecialties, and (3) a positive family history may not be present or readily apparent. Furthermore, there is a large gap in the understanding of how to apply genetic diagnostic tools in adult patients, as most of the published literature focuses on the pediatric population. Despite these challenges, accurate genetic diagnosis is imperative to provide affected individuals and their families guidance on prognosis, recurrence risk, and, for an increasing number of disorders, offer targeted treatment. Here, we provide a framework for recognizing adult neurogenetic syndromes, describe the current diagnostic approach, and highlight studies using next-generation sequencing in different neurological disease cohorts. We also discuss diagnostic pitfalls, barriers to achieving a definitive diagnosis, and emerging technology that may increase the diagnostic yield of testing.

To prepare key stakeholders for the global COVID-19 vaccination rollout, the World Health Organization and partners developed online vaccination training packages. The online course was launched in December 2020 on the OpenWHO learning platform. This paper presents the findings of an evaluation of this course. The aim of this evaluation was to provide insights into user experiences and challenges, measure the impact of the course in terms of knowledge gained, and anticipate potential interest in future online vaccination courses. The primary source of data was the anonymized information on course participants, enrollment, completion, and scores from the OpenWHO platform's statistical data and metric reporting system. Data from the OpenWHO platform were analyzed from the opening of the courses in mid-December 2020 to mid-April 2021. In addition, a learner feedback survey was sent by email to all course participants to complete within a 3-week period (March 19 to April 9, 2021). The survey was designed to determine the perceived strengths and weaknesses of the training packages and to understand barriers to access. During the study period, 53,593 learners enrolled in the course. Of them, 30,034 (56.0%) completed the course, which is substantially higher than the industry benchmark of 5%-10% for a massive open online course (MOOC). Overall, learners averaged 76.5% on the prequiz compared to 85% on the postquiz, resulting in an increase in average score of 9%. A total of 2019 learners from the course participated in the survey. Nearly 98% (n=1647 fully agree, n=308 somewhat agree; N=1986 survey respondents excluding missing values) of respondents fully or somewhat agreed that they had more confidence in their ability to support COVID-19 vaccination following completion of this course. The online vaccine training was well received by the target audience, with a measurable impact on knowledge gained. The key benefits of online training were the convenience, self-paced nature, access to downloadable material, and ability to replay material, as well as an increased ability to concentrate. Online training was identified as a timely, cost-effective way of delivering essential training to a large number of people to prepare for the COVID-19 vaccination rollout.

We have used single-nucleotide polymorphism microarray genotyping and homozygosity-by-descent (HBD) mapping followed by Sanger sequencing or whole-exome sequencing (WES) to identify causative mutations in three consanguineous families with intellectual disability (ID) related to thyroid dyshormonogenesis (TDH). One family was found to have a shared HBD region of 12.1 Mb on 8q24.21-q24.23 containing 36 coding genes, including the thyroglobulin gene, TG. Sanger sequencing of TG identified a homozygous nonsense mutation Arg2336*, which segregated with the phenotype in the family. A second family showed several HBD regions, including 6.0 Mb on 2p25.3-p25.2. WES identified a homozygous nonsense mutation, Glu596*, in the thyroid peroxidase gene, TPO. WES of a mother/father/proband trio from a third family revealed a homozygous missense mutation, Arg412His, in TPO. Mutations in TG and TPO are very rarely associated with ID, mainly because TDH is generally detectable and treatable. However, in populations where resources for screening and detection are limited, and especially where consanguineous marriages are common, mutations in genes involved in thyroid function may also be causes of ID, and as TPO and TG mutations are the most common genetic causes of TDH, these are also likely to be relatively common causes of ID.

In this study, we have performed autozygosity mapping on a large consanguineous Pakistani family segregating with intellectual disability. We identified two large regions of homozygosity-by-descent (HBD) on 16q12.2–q21 and 16q24.1–q24.3. Whole exome sequencing (WES) was performed on an affected individual from the family, but initially, no obvious mutation was detected. However, three genes within the HBD regions that were not fully captured during the WES were Sanger sequenced and we identified a five base pair deletion (actually six base pairs deleted plus one base pair inserted) in exon 7 of the gene FBXO31 . The variant segregated completely in the family, in recessive fashion giving a LOD score of 3.95. This variant leads to a frameshift and a premature stop codon and truncation of the FBXO31 protein, p.(Cys283Asnfs*81). Quantification of mRNA and protein expression suggests that nonsense-mediated mRNA decay also contributes to the loss of FBXO31 protein in affected individuals. FBXO31 functions as a centrosomal E3 ubiquitin ligase, in association with SKP1 and Cullin-1, involved in ubiquitination of proteins targeted for degradation. The FBXO31/SKP1/Cullin1 complex is important for neuronal morphogenesis and axonal identity. FBXO31 also plays a role in dendrite growth and neuronal migration in developing cerebellar cortex. Our finding adds further evidence of the involvement of disruption of the protein ubiquitination pathway in intellectual disability.

Background: The evidence supporting delivery of quality cardiopulmonary resuscitation is growing and significant attention has been focused on improving bystander cardiopulmonary resuscitation education for laypeople. The aim of this randomized trial was to assess the effectiveness of instructor's real-time objective feedback during cardiopulmonary resuscitation training compared to conventional feedback in terms of trainee's cardiopulmonary resuscitation quality. Methods: We performed a cluster-randomized trial of community cardiopulmonary resuscitation training classes at Nowon District Health Community Center in Seoul. Cardiopulmonary resuscitation training classes were randomized into either intervention (instructor's objective real-time feedback based on the QCPR Classroom device) or control (conventional, instructor's judgment-based feedback) group. The primary outcome was total cardiopulmonary resuscitation score, which is an overall measure of chest compression quality. Secondary outcomes were individual cardiopulmonary resuscitation performance parameters, including compression rate, depth, and release. Generalized linear mixed models were used to analyze the outcome data, accounting for both random and fixed effects. Results: A total of 149 training sessions (2613 trainees) were randomized into 70 intervention (1262 trainees) and 79 control (1351 trainees) groups. Trainees in the QCPR feedback group significantly increased overall cardiopulmonary resuscitation score performance compared with those in the conventional feedback group (model-based mean Delta increment from baseline to session 5: 11.2 (95% confidence interval 9.2-13.2) and 8.0 (6.0-9.9), respectively; p = 0.02). Individual parameters of compression depth and release also showed higher improvement among trainees in QCPR group with positive trends (p < 0.08 for both). Conclusion: This randomized trial suggests beneficial effect of instructor's real-time objective feedback on the quality of layperson's cardiopulmonary resuscitation performance.

Background/Objectives: Sudden cardiac death (SCD) poses a significant burden on the modern-day public health system; however, while our understanding of the underlying pathophysiology is still evolving and may not be complete, many insights are known and applied every day. Targeted prevention methods are continually being developed and refined. We conducted a systemic review and meta-analysis to identify a blood nutritional biomarker that can predict and screen population groups at high risk for cardiovascular disease mortality (CVD mortality) or SCD. Methods: The literature search was conducted from November 2023 to 31 January 2024. Based on previous literature research, we studied the association between omega-3 fatty acids (n-3 FA; eicosapentaenoic acid [EPA], docosapentaenoic acid [DPA] and docosahexaenoic acid [DHA]) and SCD and/or CVD mortality individually and in combination. We evaluated and selected 10 prospective cohort studies out of 1789 related publications, with an average follow-up period of 8.7 years. A multivariate adjusted hazard ratio (HR) with 95% confidence interval (CI) was calculated and sub-analyzed to obtain a general trend of reduced risk of SCD in a high n-3 FA intake group from the general population. Results: Finally, we included 10 articles with a total sample size of 310,955 participants. We found an inverse association between circulating n-3 FA levels and SCD. The summary HR of SCD and CVD mortality for high versus low circulating n-3 FA levels (EPA + DHA + DPA) in serum plasma phospholipid was 0.55 (95% CI: 0.37–0.82) and that of EPA + DHA in RBC was 0.67 (95% CI: 0.45–0.99). Based on the sub-analysis, the HR of EPA (%) was 0.79 (95% CI: 0.60–0.82) and that of DHA (%) was 0.72 (95% CI: 0.60–0.87). Conclusions: Our results suggest a potential cardio-protective association between high EPA and DHA levels in blood and a reduced incidence of adverse cardiac events.

Mutations in the transcription factor GLI3, a downstream target of Sonic Hedgehog (SHH) signaling, are responsible for the development of malformation syndromes such as Greig-cephalopolysyndactyly-syndrome (GCPS), or Pallister-Hall-syndrome (PHS). Mutations that lead to loss of function of the protein and to haploinsufficiency cause GCPS, while truncating mutations that result in constitutive repressor function of GLI3 lead to PHS. As an exception, some point mutations in the C-terminal part of GLI3 observed in GCPS patients have so far not been linked to loss of function. We have shown recently that protein phosphatase 2A (PP2A) regulates the nuclear localization and transcriptional activity a of GLI3 function. We have shown recently that protein phosphatase 2A (PP2A) and the ubiquitin ligase MID1 regulate the nuclear localization and transcriptional activity of GLI3. Here we show mapping of the functional interaction between the MID1-alpha4-PP2A complex and GLI3 to a region between amino acid 568-1100 of GLI3. Furthermore we demonstrate that GCPS-associated point mutations, that are located in that region, lead to misregulation of the nuclear GLI3-localization and transcriptional activity. GLI3 phosphorylation itself however appears independent of its localization and remains untouched by either of the point mutations and by PP2A-activity, which suggests involvement of an as yet unknown GLI3 interaction partner, the phosphorylation status of which is regulated by PP2A activity, in the control of GLI3 subcellular localization and activity. The present findings provide an explanation for the pathogenesis of GCPS in patients carrying C-terminal point mutations, and close the gap in our understanding of how GLI3-genotypes give rise to particular phenotypes. Furthermore, they provide a molecular explanation for the phenotypic overlap between Opitz syndrome patients with dysregulated PP2A-activity and syndromes caused by GLI3-mutations.