The genome sequence of the Dracula fish, Danionella dracula (Britz, Conway & Rüber, 2009).

We present a genome assembly from an individual Danionella dracula (the Dracula fish; Chordata; Actinopterygii; Cypriniformes; Danionidae; Danioninae). The genome sequence is 665.21 megabases in span. This is a scaffold-level assembly, with a scaffold N50 of 10.29 Mb.

Transitioning an implementation research intervention to a sustained clinical service: Telehealth primary care mental health integration implementation in Veterans Health Administration.

Often in implementation science efforts, an intervention originated by research funding does not continue in clinical practice after funding ends, or if it does, the process by which it was sustained remains known only to the implementation research or clinical teams. From 2018 to 2020, we implemented a complex telehealth interdisciplinary behavioral health program supported by research funding. The intervention was Primary Care Mental Health Integration (PCMHI) delivered via televideo from a large parent medical facility to rural satellite clinics (tele-PCMHI) within the Veterans Health Administration. Two implementation facilitators worked closely with clinical leaders and staff to plan, launch, and sustain tele-PCMHI across four sites. The intervention is still maintained by the clinical service and has spread to eight sites. Based on ethnographic and qualitative data collected weekly over 2 years, we categorized sustainment strategies across distinct time periods for this complex program, theoretically grounded in the Dynamic Sustainability Framework, emphasizing changes to adapt intervention fit to rapidly changing context. To contextualize, we identified barriers and strengths, such as difficulty training staff to use new equipment, restructuring clinic workflow, and determining suicide risk management remotely. New barriers arose, and, thus, new strategies were needed to continue implementing at the onset of the COVID-19 pandemic in 2020. Different strategies at different stages of implementation allowed sustainment to be a dynamic and evolving process. Plus, proactive and persistent planning for sustainment early in the effort, along with alignment with performance metrics and national policy, supported continued delivery in real-world organized care. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike-Wave Activation in Sleep (D/EE-SWAS).

OBJECTIVE: To understand the etiological landscape and phenotypic differences between 2 developmental and epileptic encephalopathy (DEE) syndromes: DEE with spike-wave activation in sleep (DEE-SWAS) and epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS). METHODS: All patients fulfilled International League Against Epilepsy (ILAE) DEE-SWAS or EE-SWAS criteria with a Core cohort (n = 91) drawn from our Epilepsy Genetics research program, together with 10 etiologically solved patients referred by collaborators in the Expanded cohort (n = 101). Detailed phenotyping and analysis of molecular genetic results were performed. We compared the phenotypic features of individuals with DEE-SWAS and EE-SWAS. Brain-specific gene co-expression analysis was performed for D/EE-SWAS genes. RESULTS: We identified the etiology in 42/91 (46%) patients in our Core cohort, including 29/44 (66%) with DEE-SWAS and 13/47 (28%) with EE-SWAS. A genetic etiology was identified in 31/91 (34%). D/EE-SWAS genes were highly co-expressed in brain, highlighting the importance of channelopathies and transcriptional regulators. Structural etiologies were found in 12/91 (13%) individuals. We identified 10 novel D/EE-SWAS genes with a range of functions: ATP1A2, CACNA1A, FOXP1, GRIN1, KCNMA1, KCNQ3, PPFIA3, PUF60, SETD1B, and ZBTB18, and 2 novel copy number variants, 17p11.2 duplication and 5q22 deletion. Although developmental regression patterns were similar in both syndromes, DEE-SWAS was associated with a longer duration of epilepsy and poorer intellectual outcome than EE-SWAS. INTERPRETATION: DEE-SWAS and EE-SWAS have highly heterogeneous genetic and structural etiologies. Phenotypic analysis highlights valuable clinical differences between DEE-SWAS and EE-SWAS which inform clinical care and prognostic counseling. Our etiological findings pave the way for the development of precision therapies. ANN NEUROL 2024.

Inflation of polygenic risk scores caused by sample overlap and relatedness: Examples of a major risk of bias.

Polygenic risk scores (PRSs) are an important tool for understanding the role of common genetic variants in human disease. Standard best practices recommend that PRSs be analyzed in cohorts that are independent of the genome-wide association study (GWAS) used to derive the scores without sample overlap or relatedness between the two cohorts. However, identifying sample overlap and relatedness can be challenging in an era of GWASs performed by large biobanks and international research consortia. Although most genomics researchers are aware of best practices and theoretical concerns about sample overlap and relatedness between GWAS and PRS cohorts, the prevailing assumption is that the risk of bias is small for very large GWASs. Here, we present two real-world examples demonstrating that sample overlap and relatedness is not a minor or theoretical concern but an important potential source of bias in PRS studies. Using a recently developed statistical adjustment tool, we found that excluding overlapping and related samples was equal to or more powerful than adjusting for overlap bias. Our goal is to make genomics researchers aware of the magnitude of risk of bias from sample overlap and relatedness and to highlight the need for mitigation tools, including independent validation cohorts in PRS studies, continued development of statistical adjustment methods, and tools for researchers to test their cohorts for overlap and relatedness with GWAS cohorts without sharing individual-level data.

Shared Medical Appointments in Heart Failure for Post Acute Care Follow-Up: A Randomized Controlled Trial.

BACKGROUND: Shared medical appointments (SMAs) in heart failure (HF) are medical visits where several patients with HF meet with multidisciplinary providers at the same time for efficient and comprehensive care. It is unknown whether HF-SMAs can improve overall and cardiac health status for high-risk patients with HF discharged from acute care. METHODS AND RESULTS: A 3-site, open-label, randomized-controlled-trial was conducted. Participants within 12 weeks of HF acute care (emergency-room/hospitalization) requiring intravenous diuretic therapy were randomized to receive either HF-SMA or usual HF clinical care (usual-care) on a 1:1 ratio. The HF-SMA team, which consisted of a nurse, nutritionist, psychologist, nurse practitioner and/or a clinical pharmacist, provided four 2-hour session HF-SMAs that met every other week for 8 weeks. Primary outcomes were the overall health status measured by European Quality of Life Visual Analog Scale and cardiac health status by Kansas City Cardiomyopathy Questionnaire, 180 days postrandomization. Of the 242 patients enrolled (HF-SMA n=117, usual-care n=125, mean age 69.3±9.4 years, 71.5% White patients, 94.6% male), 84% of participants completed the study (n=8 HF-SMA and n=9 usual-care patients died). After 180 days, both HF-SMA and usual-care participants had significant improvements from baseline in Kansas City Cardiomyopathy Questionnaire that were not statistically different. Only HF-SMA participants had significant improvements in European Quality of Life Visual Analog Scale (mean change = 7.2±15.8 in HF-SMA versus -0.4±19.0 points in usual-care, P < 0.001). CONCLUSIONS: Both HF-SMA and usual-care in participants with HF achieved significant improvements in cardiac health status, but only a team approach through HF-SMA achieved significant improvements in overall health status. Future larger studies are needed to evaluate hospitalization and death outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02481921.

Provider perspectives on the impact of COVID-19 on treatment of substance use and opioid use disorders among American Indian and Alaska Native adults.

Introduction: American Indian/Alaska Native (AI/AN) communities are more likely to suffer negative consequences related to substance misuse. The COVID-19 pandemic exacerbated the opioid poisoning crisis, in combination with ongoing treatment barriers resulting from settler-colonialism, systemic oppression and racial discrimination. AI/AN adults are at greatest risk of COVID-19 related serious illness and death. In collaboration with an Indigenous community advisory board and Tribal leadership, this study explored AI/AN treatment provider perceptions of client-relatives' (i.e., SUD treatment recipients) experiences during the pandemic from 2020 to 2022. Methods: Providers who underwent screening and were eligible to participate (N = 25) represented 6 programs and organizations serving rural and urban areas in Washington, Utah, and Minnesota. Participants engaged in audio-recorded 60-90 min semi-structured individual interviews conducted virtually via Zoom. The interview guide included 15 questions covering regulatory changes, guidance for telemedicine, policy and procedures, staff communication, and client-relatives' reactions to implemented changes, service utilization, changes in treatment modality, and perceptions of impact on their roles and practice. Interview recordings were transcribed and de-identified. Members of the research team independently reviewed transcripts before reaching consensus. Coding was completed in Dedoose, followed by analyses informed by a qualitative descriptive approach. Results: Five main domains were identified related to client-relative experiences during the COVID-19 pandemic, as observed by providers: (1) accessibility, (2) co-occurring mental health, (3) social determinants of health, (4) substance use, coping, and harm reduction strategies, and (5) community strengths. Providers reported the distinctive experiences of AI/AN communities, highlighting the impact on client-relatives, who faced challenges such as reduced income, heightened grief and loss, and elevated rates of substance use and opioid-related poisonings. Community and culturally informed programming promoting resilience and healing are outlined. Conclusion: Findings underscore the impact on SUD among AI/AN communities during the COVID-19 pandemic. Identifying treatment barriers and mental health impacts on client-relatives during a global pandemic can inform ongoing and future culturally responsive SUD prevention and treatment strategies. Elevating collective voice to strengthen Indigenous informed systems of care to address the gap in culturally-and community-based services, can bolster holistic approaches and long-term service needs to promote SUD prevention efforts beyond emergency response efforts.

The Bioinformatic Applications of Hi-C and Linked Reads.

Long-range sequencing grants insight into additional genetic information beyond that which can be accessed by both short reads and modern long-read technology. Several new sequencing technologies are available for long-range datasets such as "Hi-C" and "Linked Reads" with high-throughput and high-resolution genome analysis, and are rapidly advancing the field of genome assembly, genome scaffolding, and more comprehensive variant identification. In this article, we focused on five major long-range sequencing technologies: high-throughput chromosome conformation capture (Hi-C), 10x Genomics Linked Reads, haplotagging, transposase enzyme linked long-read sequencing (TELL-seq), and single tube long fragment read (stLFR). We detailed the mechanisms and data products of the five platforms, introduced several of the most important applications, evaluated the quality of sequencing data from different platforms, and discussed the currently available bioinformatics tools. We hope this work will benefit the selection of appropriate long-range technology for specific biological studies.

Familial aggregation of seizure outcomes in four familial epilepsy cohorts.

OBJECTIVE: To assess the possible effects of genetics on seizure outcome by estimating the familial aggregation of three outcome measures: seizure remission, history of ≥4 tonic-clonic seizures, and seizure control for individuals taking antiseizure medication. METHODS: We analyzed families containing multiple persons with epilepsy in four previously collected retrospective cohorts. Seizure remission was defined as being 5 and 10 years seizure-free at last observation. Total number of tonic-clonic seizures was dichotomized at <4 and ≥4 seizures. Seizure control in patients taking antiseizure medication was defined as no seizures for 1, 2, and 3 years. We used Bayesian generalized linear mixed-effects model (GLMM) to estimate the intraclass correlation coefficient (ICC) of the family-specific random effect, controlling for epilepsy type, age at epilepsy onset, and age at last data collection as fixed effects. We analyzed each cohort separately and performed meta-analysis using GLMMs. RESULTS: The combined cohorts included 3644 individuals with epilepsy from 1463 families. A history of ≥4 tonic-clonic seizures showed strong familial aggregation in three separate cohorts and meta-analysis (ICC .28, 95% confidence interval [CI] .21-.35, Bayes factor 8 × 1016). Meta-analyses did not reveal significant familial aggregation of seizure remission (ICC .08, 95% CI .01-.17, Bayes factor 1.46) or seizure control for individuals taking antiseizure medication (ICC .13, 95% CI 0-.35, Bayes factor 0.94), with heterogeneity among cohorts. SIGNIFICANCE: A history of ≥4 tonic-clonic seizures aggregated strongly in families, suggesting a genetic influence, whereas seizure remission and seizure control for individuals taking antiseizure medications did not aggregate consistently in families. Different seizure outcomes may have different underlying biology and risk factors. These findings should inform the future molecular genetic studies of seizure outcomes.

Coming together for something good: recommendations from a scoping review for dissemination and implementation science to improve indigenous substance use disorder treatment.

Introduction: Dissemination and Implementation (D&I) science is growing among Indigenous communities. Indigenous communities are adapting and implementing evidence-based treatments for substance use disorders (SUD) to fit the needs of their communities. D&I science offers frameworks, models, and theories to increase implementation success, but research is needed to center Indigenous knowledge, enhancing D&I so that it is more applicable within Indigenous contexts. In this scoping review, we examined the current state of D&I science for SUD interventions among Indigenous communities and identified best-practice SUD implementation approaches. Methods: PubMed and PsycINFO databases were queried for articles written in English, published in the United States, Canada, Australia, and New Zealand. We included key search terms for Indigenous populations and 35 content keywords. We categorized the data using the adapted and extended Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework that emphasizes equity and sustainability. RE-AIM has also been used as a primary model to consistently identify implementation outcomes. Results: Twenty articles were identified from the original unduplicated count of over 24,000. Over half the articles discussed processes related to Reach, Adoption, and Implementation. Effectiveness was discussed by 50% of the studies (n = 10), with 25% of the articles discussing Maintenance/sustainability (n = 4). Findings also highlighted the importance of the application of each RE-AIM domain for meaningful, well-defined community-engaged approaches. Conclusion: Finding indicated a need to prioritize Indigenous methods to culturally center, re-align and adapt Western treatments and frameworks to increase health equity and improve SUD treatment outcomes. Utility in the use of the modified RE-AIM and the continued modification for Indigenous communities was also noted.

Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture.

OBJECTIVE: Familial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome; its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippocampal sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in individuals with FMTLE. METHODS: We studied 134 families with ≥ 2 first or second-degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one individual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls. RESULTS: The age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13-28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug-resistance and/or hippocampal sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007); in contrast, no enrichment for the febrile seizure PRS was observed. INTERPRETATION: FMTLE is a generally mild drug-responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub-genome-wide significant focal epilepsy genome-wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023;94:825-835.

Developing and testing a COVID-19 vaccination acceptance intervention: A pragmatic trial comparing vaccine acceptance intervention vs usual care - Rationale, methods, and implementation.

BACKGROUND: COVID-19 has resulted in significant disability and loss of life. COVID-19 vaccines effectively prevent severe illness, hospitalization, and death. Nevertheless, many people remain hesitant to accept vaccination. Veterans perceive healthcare providers (HCP) and staff as trusted vaccine information sources and thereby are well suited to initiate vaccine discussions. The overall objective of this study is to implement and test a virtual COVID-19 Vaccine Acceptance Intervention (VAI) training that is informed by motivational interviewing (MI) techniques. METHODS: The VAI training is being delivered to VA HCPs and staff within a Hybrid Type 2 pragmatic implementation-effectiveness trial using Implementation Facilitation as the implementation strategy. The implementation team includes external facilitators paired with VA Healthcare System (VAHCS)-level internal facilitators. The trial has three aims: 1) Examine the effectiveness of the VAI versus usual care on unvaccinated veterans' vaccination rates in a one-year cluster randomized controlled trial, with randomization at the level of VAHCS. 2) Determine factors associated with veterans' decisions to accept or decline primary COVID-19 vaccination, and better understand how these factors influence vaccination decisions, through survey and qualitative data; and 3) Use qualitative interviews with HCPs and staff from clinics with high and low vaccination rates to learn what was helpful and not helpful about the VAI and implementation strategies. CONCLUSION: This is the first multisite randomized controlled trial to test an MI-informed vaccine acceptance intervention to improve COVID-19 vaccine acceptance. Information gained can be used to inform healthcare systems' approaches to improve future vaccination and other public health campaigns. CLINICALTRIALS: gov Identifier: NCT05027464.

Genomics of cold adaptations in the Antarctic notothenioid fish radiation.

Numerous novel adaptations characterise the radiation of notothenioids, the dominant fish group in the freezing seas of the Southern Ocean. To improve understanding of the evolution of this iconic fish group, here we generate and analyse new genome assemblies for 24 species covering all major subgroups of the radiation, including five long-read assemblies. We present a new estimate for the onset of the radiation at 10.7 million years ago, based on a time-calibrated phylogeny derived from genome-wide sequence data. We identify a two-fold variation in genome size, driven by expansion of multiple transposable element families, and use the long-read data to reconstruct two evolutionarily important, highly repetitive gene family loci. First, we present the most complete reconstruction to date of the antifreeze glycoprotein gene family, whose emergence enabled survival in sub-zero temperatures, showing the expansion of the antifreeze gene locus from the ancestral to the derived state. Second, we trace the loss of haemoglobin genes in icefishes, the only vertebrates lacking functional haemoglobins, through complete reconstruction of the two haemoglobin gene clusters across notothenioid families. Both the haemoglobin and antifreeze genomic loci are characterised by multiple transposon expansions that may have driven the evolutionary history of these genes.

Caecilian Genomes Reveal the Molecular Basis of Adaptation and Convergent Evolution of Limblessness in Snakes and Caecilians.

We present genome sequences for the caecilians Geotrypetes seraphini (3.8 Gb) and Microcaecilia unicolor (4.7 Gb), representatives of a limbless, mostly soil-dwelling amphibian clade with reduced eyes, and unique putatively chemosensory tentacles. More than 69% of both genomes are composed of repeats, with retrotransposons being the most abundant. We identify 1,150 orthogroups that are unique to caecilians and enriched for functions in olfaction and detection of chemical signals. There are 379 orthogroups with signatures of positive selection on caecilian lineages with roles in organ development and morphogenesis, sensory perception, and immunity amongst others. We discover that caecilian genomes are missing the zone of polarizing activity regulatorysequence (ZRS) enhancer of Sonic Hedgehog which is also mutated in snakes. In vivo deletions have shown ZRS is required for limb development in mice, thus, revealing a shared molecular target implicated in the independent evolution of limblessness in snakes and caecilians.

NCTC3000: a century of bacterial strain collecting leads to a rich genomic data resource.

The National Collection of Type Cultures (NCTC) was founded on 1 January 1920 in order to fulfil a recognized need for a centralized repository for bacterial and fungal strains within the UK. It is among the longest-established collections of its kind anywhere in the world and today holds approximately 6000 type and reference bacterial strains - many of medical, scientific and veterinary importance - available to academic, health, food and veterinary institutions worldwide. Recently, a collaboration between NCTC, Pacific Biosciences and the Wellcome Sanger Institute established the NCTC3000 project to long-read sequence and assemble the genomes of up to 3000 NCTC strains. Here, at the beginning of the collection's second century, we introduce the resulting NCTC3000 sequence read datasets, genome assemblies and annotations as a unique, historically and scientifically relevant resource for the benefit of the international bacterial research community.

Recognition and epileptology of protracted CLN3 disease.

OBJECTIVE: This study was undertaken to analyze phenotypic features of a cohort of patients with protracted CLN3 disease to improve recognition of the disorder. METHODS: We analyzed phenotypic data of 10 patients from six families with protracted CLN3 disease. Haplotype analysis was performed in three reportedly unrelated families. RESULTS: Visual impairment was the initial symptom, with onset at 5-9 years, similar to classic CLN3 disease. Mean time from onset of visual impairment to seizures was 12 years (range = 6-41 years). Various seizure types were reported, most commonly generalized tonic-clonic seizures; focal seizures were present in four patients. Progressive myoclonus epilepsy was not seen. Interictal electroencephalogram revealed mild background slowing and 2.5-3.5-Hz spontaneous generalized spike-wave discharges. Additional interictal focal epileptiform discharges were noted in some patients. Age at death for the three deceased patients was 31, 31, and 52 years. Molecular testing revealed five individuals were homozygous for c.461-280_677 + 382del966, the "common 1-kb" CLN3 deletion. The remaining individuals were compound heterozygous for various combinations of recurrent pathogenic CLN3 variants. Haplotype analysis demonstrated evidence of a common founder for the common 1-kb deletion. Dating analysis suggested the deletion arose approximately 1500 years ago and thus did not represent cryptic familial relationship in this Australian cohort. SIGNIFICANCE: We highlight the protracted phenotype of a disease generally associated with death in adolescence, which is a combined focal and generalized epilepsy syndrome with progressive neurological deterioration. The disorder should be suspected in an adolescent or adult patient presenting with generalized or focal seizures preceded by progressive visual loss. The common 1-kb deletion has been typically associated with classic CLN3 disease, and the protracted phenotype has not previously been reported with this genotype. This suggests that modifying genetic factors may be important in determining this somewhat milder phenotype and identification of these factors should be the subject of future research.

IRF2BPL: A new genotype for progressive myoclonus epilepsies.

The progressive myoclonus epilepsies (PMEs) are a heterogeneous group of neurodegenerative disorders, typically presenting in late childhood. An etiologic diagnosis is achieved in about 80% of patients with PME, and genome-wide molecular studies on remaining, well-selected, undiagnosed cases can further dissect the underlying genetic heterogeneity. Through whole-exome sequencing (WES), we identified pathogenic truncating variants in the IRF2BPL gene in two, unrelated patients presenting with PME. IRF2BPL belongs to the transcriptional regulators family and it is expressed in multiple human tissues, including the brain. Recently missense and nonsense mutations in IRF2BPL were found in patients presenting with developmental delay and epileptic encephalopathy, ataxia, and movement disorders, but none with clear PME. We identified 13 other patients in the literature with myoclonic seizures and IRF2BPL variants. There was no clear genotype-phenotype correlation. With the description of these cases, the IRF2BPL gene should be considered in the list of genes to be tested in the presence of PME, in addition to patients with neurodevelopmental or movement disorders.

WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk.

OBJECTIVE: WWOX is an autosomal recessive cause of early infantile developmental and epileptic encephalopathy (WWOX-DEE), also known as WOREE (WWOX-related epileptic encephalopathy). We analyzed the epileptology and imaging features of WWOX-DEE, and investigated genotype-phenotype correlations, particularly with regard to survival. METHODS: We studied 13 patients from 12 families with WWOX-DEE. Information regarding seizure semiology, comorbidities, facial dysmorphisms, and disease outcome were collected. Electroencephalographic (EEG) and brain magnetic resonance imaging (MRI) data were analyzed. Pathogenic WWOX variants from our cohort and the literature were coded as either null or missense, allowing individuals to be classified into one of three genotype classes: (1) null/null, (2) null/missense, (3) missense/missense. Differences in survival outcome were estimated using the Kaplan-Meier method. RESULTS: All patients experienced multiple seizure types (median onset = 5 weeks, range = 1 day-10 months), the most frequent being focal (85%), epileptic spasms (77%), and tonic seizures (69%). Ictal EEG recordings in six of 13 patients showed tonic (n = 5), myoclonic (n = 2), epileptic spasms (n = 2), focal (n = 1), and migrating focal (n = 1) seizures. Interictal EEGs demonstrated slow background activity with multifocal discharges, predominantly over frontal or temporo-occipital regions. Eleven of 13 patients had a movement disorder, most frequently dystonia. Brain MRIs revealed severe frontotemporal, hippocampal, and optic atrophy, thin corpus callosum, and white matter signal abnormalities. Pathogenic variants were located throughout WWOX and comprised both missense and null changes including five copy number variants (four deletions, one duplication). Survival analyses showed that patients with two null variants are at higher mortality risk (p-value = .0085, log-rank test). SIGNIFICANCE: Biallelic WWOX pathogenic variants cause an early infantile developmental and epileptic encephalopathy syndrome. The most common seizure types are focal seizures and epileptic spasms. Mortality risk is associated with mutation type; patients with biallelic null WWOX pathogenic variants have significantly lower survival probability compared to those carrying at least one presumed hypomorphic missense pathogenic variant.

Genes4Epilepsy: An epilepsy gene resource.

OBJECTIVE: "How many epilepsy genes are there?" is a frequently asked question. We sought to (1) provide a curated list of genes that cause monogenic epilepsies, and (2) compare and contrast epilepsy gene panels from multiple sources. METHODS: We compared genes included on the epilepsy panels (as of July 29, 2022) of four clinical diagnostic providers: Invitae, GeneDx, Fulgent Genetics, and Blueprint Genetics; and two research resources: PanelApp Australia and ClinGen. A master list of all unique genes was supplemented by additional genes identified via PubMed searches up until August 15, 2022, using the search terms "genetics" AND/OR "epilepsy" AND/OR "seizures". Evidence supporting a monogenic role for all genes was manually reviewed; those with limited or disputed evidence were excluded. All genes were annotated according to inheritance pattern and broad epilepsy phenotype. RESULTS: The comparison of genes included on epilepsy clinical panels revealed high heterogeneity in both number of genes (range: 144-511) and content. Just 111 genes (15.5%) were included on all four clinical panels. Subsequent manual curation of all "epilepsy genes" identified >900 monogenic etiologies. Almost 90% of genes were associated with developmental and epileptic encephalopathies. By comparison only 5% of genes were associated with monogenic causes of "common epilepsies" (i.e., generalized and focal epilepsy syndromes). Autosomal recessive genes were most frequent (56% of genes); however, this varied according to the associated epilepsy phenotype(s). Genes associated with common epilepsy syndromes were more likely to be dominantly inherited and associated with multiple epilepsy types. SIGNIFICANCE: Our curated list of monogenic epilepsy genes is publicly available: github.com/bahlolab/genes4epilepsy and will be regularly updated. This gene resource can be utilized to target genes beyond those included on clinical gene panels, for gene enrichment methods and candidate gene prioritization. We invite ongoing feedback and contributions from the scientific community via genes4-epilepsy@unimelb.edu.au.

Centering culture in the treatment of opioid use disorder with American Indian and Alaska Native Communities: Contributions from a National Collaborative Board.

American Indian/Alaska Native (AI/AN) communities are disproportionally impacted by the opioid overdose epidemic. There remains a dearth of research evaluating methods for effectively implementing treatments for opioid use disorder (OUD) within these communities. We describe proceedings from a 2-day Collaborative Board (CB) meeting tasked with developing an implementation intervention for AI/AN clinical programs to improve the delivery of medications to treat OUD (MOUD). The CB was comprised of Elders, cultural leaders, providers, individuals with lived experience with OUD, and researchers from over 25 communities, organizations, and academic institutions. Conversations were audio-recorded, transcribed, and coded by two academic researchers with interpretation oversight provided by the CB. These proceedings provided a foundation for ongoing CB work and a frame for developing the program-level implementation intervention using a strength-based and holistic model of OUD recovery and wellbeing. Topics of discussion posed to the CB included engagement and recovery strategies, integration of extended family traditions, and addressing stigma and building trust with providers and clients. Integration of traditional healing practices, ceremonies, and other cultural practices was recommended. The importance of centering AI/AN culture and involving family were highlighted as priorities for the intervention.

Comparing saliva and blood for the detection of mosaic genomic abnormalities that cause syndromic intellectual disability.

We aimed to determine whether SNP-microarray genomic testing of saliva had a greater diagnostic yield than blood for pathogenic copy number variants (CNVs). We selected patients who underwent CMA testing of both blood and saliva from 23,289 blood and 21,857 saliva samples. Our cohort comprised 370 individuals who had testing of both, 224 with syndromic intellectual disability (ID) and 146 with isolated ID. Mosaic pathogenic CNVs or aneuploidy were detected in saliva but not in blood in 20/370 (4.4%). All 20 individuals had syndromic ID, accounting for 9.1% of the syndromic ID sub-cohort. Pathogenic CNVs were large in size (median of 46 Mb), and terminal in nature, with median mosaicism of 27.5% (not exceeding 40%). By contrast, non-mosaic pathogenic CNVs were 100% concordant between blood and saliva, considerably smaller in size (median of 0.65 Mb), and predominantly interstitial in location. Given that salivary microarray testing has increased diagnostic utility over blood in individuals with syndromic ID, we recommend it as a first-tier testing in this group.