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The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1-a pivotal component of the epigenetic machinery. We have recruited 209 individuals with a rare EHMT1 variant and performed comprehensive molecular in silico and in vitro testing alongside DNA methylation (DNAm) signature analysis for the identified variants. We (re)classified the variants as likely pathogenic/pathogenic (molecularly confirming Kleefstra syndrome) in 191 individuals. We provide an updated and broader clinical and molecular spectrum of Kleefstra syndrome, including individuals with normal intelligence and familial occurrence. Analysis of the EHMT1 variants reveals a broad range of molecular effects and their associated phenotypes, including distinct genotype-phenotype associations. Notably, we showed that disruption of the "reader" function of the ankyrin repeat domain by a protein altering variant (PAV) results in a KLEFS1-specific DNAm signature and milder phenotype, while disruption of only "writer" methyltransferase activity of the SET domain does not result in KLEFS1 DNAm signature or typical KLEFS1 phenotype. Similarly, N-terminal truncating variants result in a mild phenotype without the DNAm signature. We demonstrate how comprehensive variant analysis can provide insights into pathogenesis of the disorder and DNAm signature. In summary, this study presents a comprehensive overview of KLEFS1 and EHMT1, revealing its broader spectrum and deepening our understanding of its molecular mechanisms, thereby informing accurate variant interpretation, counseling, and clinical management., Competing Interests: Declaration of interests A.M.M. is an employee of GeneDx, LLC. B.S. is a shareholder in EpiSign Inc., a biotechnology company involved in commercialization of EpiSign technology., (Copyright © 2024 American Society of Human Genetics. All rights reserved.)

The North American Great Lakes have been experiencing dramatic change during the past half-century, highlighting the need for holistic, ecosystem-based approaches to management. To assess interest in ecosystem-based management (EBM), including the value of a comprehensive public database that could serve as a repository for the numerous physical, chemical, and biological monitoring Great Lakes datasets that exist, a two-day workshop was organized, which was attended by 40+ Great Lakes researchers, managers, and stakeholders. While we learned during the workshop that EBM is not an explicit mission of many of the participating research, monitoring, and management agencies, most have been conducting research or monitoring activities that can support EBM. These contributions have ranged from single-resource (-sector) management to considering the ecosystem holistically in a decision-making framework. Workshop participants also identified impediments to implementing EBM, including: 1) high anticipated costs; 2) a lack of EBM success stories to garner agency buy-in; and 3) difficulty in establishing common objectives among groups with different mandates (e.g., water quality vs. fisheries production). We discussed as a group solutions to overcome these impediments, including construction of a comprehensive, research-ready database, a prototype of which was presented at the workshop. We collectively felt that such a database would offer a cost-effective means to support EBM approaches by facilitating research that could help identify useful ecosystem indicators and management targets and allow for management strategy evaluations that account for risk and uncertainty when contemplating future decision-making.

There is a well-recognized, yet nuanced, positive relationship between acute physical activity and cognitive function. However, the precise impact of exercise intensity remains ambiguous. We tested learning and memory, working memory and processing speed, and motor speed and accuracy across three distinct exercise intensities. A sample of 207 participants (100 female) between 18 and 44 years (mean age: 22.5±3.7years) completed all study procedures. Utilizing a within-subjects, cross-over design, participants completed moderate (35% VO 2 Max), vigorous (70% VO 2 Max), and sedentary (no exercise) conditions. Cognitive and motor assessments, including the Paced Auditory Serial Addition Test (PASAT), Rey Auditory Verbal Learning Test (RAVLT), Typing Speed Test, and Ten Key Data Entry Task, were conducted approximately 60min post-exercise. There were no significant differences in primary cognitive or motor outcome measures across the three exercise intensities, even with the study being strongly powered. There was, however, a small difference on the fastest trial of the PASAT, where vigorous-intensity exercise yielded slightly better performance compared to both sedentary and moderate-intensity exercise. This effect was no longer significant when including VO 2 Max or maximum heart rate as indicators of fitness. There were no interactions on outcome variables by exercise intensity when including biological sex in the models. Thus, a single bout of acute exercise, regardless of its intensity, did not alter cognitive and motor performance when measured approximately 1h post-exercise. Findings highlight the importance of large samples and suggest that the temporal dynamics post-exercise might play a pivotal role in cognitive outcomes., Competing Interests: Disclosures There are no disclosures or conflicts of interest to report for this paper., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Resting state functional magnetic resonance imaging (rsfMRI) provides researchers and clinicians with a powerful tool to examine functional connectivity across large-scale brain networks, with ever-increasing applications to the study of neurological disorders, such as traumatic brain injury (TBI). While rsfMRI holds unparalleled promise in systems neurosciences, its acquisition and analytical methodology across research groups is variable, resulting in a literature that is challenging to integrate and interpret. The focus of this narrative review is to address the primary methodological issues including investigator decision points in the application of rsfMRI to study the consequences of TBI. As part of the ENIGMA Brain Injury working group, we have collaborated to identify a minimum set of recommendations that are designed to produce results that are reliable, harmonizable, and reproducible for the TBI imaging research community. Part one of this review provides the results of a literature search of current rsfMRI studies of TBI, highlighting key design considerations and data processing pipelines. Part two outlines seven data acquisition, processing, and analysis recommendations with the goal of maximizing study reliability and between-site comparability, while preserving investigator autonomy. Part three summarizes new directions and opportunities for future rsfMRI studies in TBI patients. The goal is to galvanize the TBI community to gain consensus for a set of rigorous and reproducible methods, and to increase analytical transparency and data sharing to address the reproducibility crisis in the field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: Concussion in children and adolescents is a public health concern with higher concussion incidence than adults and increased susceptibility to axonal injury. The corpus callosum is a vulnerable location of concussion-related white matter damage that can be associated with short- and long-term effects of concussion. Interhemispheric transfer time (IHTT) of visual information across the corpus callosum can be used as a direct measure of corpus callosum functioning that may be impacted by adolescent concussion with slower IHTT relative to matched controls. Longitudinal studies and studies testing physiological measures of IHTT following concussion in adolescents are lacking., Methods: We used the N1 and P1 components of the scalp-recorded brain event-related potential (ERP) to measure IHTT in 20 adolescents (ages 12-19 years old) with confirmed concussion and 16 neurologically-healthy control participants within 3 weeks of concussion (subacute stage) and approximately 10 months after injury (longitudinal)., Results: Separate two-group (concussion, control) by two-time (3 weeks, 10 months) repeated measures ANOVAs on difference response times and IHTT latencies of the P1 and N1 components showed no significant differences by group ( p s ≥ 0.25) nor by time ( p s ≥ 0.64), with no significant interactions ( p s ≥ 0.15)., Discussion: Results from the current sample suggest that measures of IHTT may not be strongly influenced at 3 weeks or longitudinally following adolescent concussion using the current IHTT paradigm., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Christensen, Clark, Muir, Allen, Corbin, Jaggi, Alder, Clawson, Farrer, Bigler and Larson.)

Natural resource governance is inherently complex owing to the socio-ecological systems in which it is embedded. Working arrangements have been fundamentally transformed throughout the COVID-19 pandemic with potential negative impacts on trust-based social networks foundational to resource management and transboundary governance. To inform development of a post-pandemic new-normal in resource management, we examined trust relationships using the Laurentian Great Lakes of North America as a case study. 82.9% (n = 97/117) of Great Lakes fishery managers and scientists surveyed indicated that virtual engagement was effective for maintaining well-established relationships during the pandemic; however, 76.7% (n = 89/116) of respondents indicated in-person engagement to be more effective than virtual engagement for building and maintaining trust. Despite some shortcomings, virtual or remote engagement presents opportunities, such as: (1) care and nurturing of well-established long-term relationships; (2) short-term (1-3 years) trust maintenance; (3) peer-peer or mentor-mentee coordination; (4) supplemental communications; (5) producer-push knowledge dissemination; and, if done thoughtfully, (6) enhancing diversity, equity, and inclusion. Without change, pre-pandemic trust-based relationships foundational to cooperative, multinational, resource management are under threat., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20., Methods: Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed., Results: We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type β-propeller domain of the KLHL20 protein, which shapes the substrate binding surface., Conclusion: Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity., Competing Interests: Conflict of Interest M.M.M. and R.E.S. are employees of GeneDx, Inc. All other authors declare no conflict interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: Supraphysiologic serum estradiol levels may negatively impact the likelihood of conception and live birth following IVF. The purpose of this study is to determine if there is an association between serum estradiol level on the day of progesterone start and clinical outcomes following programmed frozen blastocyst transfer cycles utilizing oral estradiol., Methods: This is a retrospective cohort study at an academic fertility center analyzing 363 patients who underwent their first autologous single (SET) or double frozen embryo transfer (DET) utilizing oral estradiol and resulting in blastocyst transfer from June 1, 2012, to June 30, 2018. Main outcome measures included implantation, clinical pregnancy, live birth, and miscarriage rates. Cycles were stratified by quartile of serum estradiol on the day of progesterone start and separately analyzed for SET cycles only. Poisson and Log binomial regression were used to calculate relative risks (RR) with 95% confidence intervals (CI) for implantation, clinical pregnancy, live birth, and miscarriage with adjustments made for age and BMI., Results: Cycles with the highest quartile of estradiol (mean 528 pg/mL) were associated with lower risks of implantation (RR 0.66, CI 0.50-0.86), ongoing pregnancy (RR 0.66, CI 0.49-0.88), and live birth (RR 0.70, CI 0.52-0.94) compared with those with the lowest estradiol quartile (mean 212 pg/mL). Similar findings were seen for analyses limited to SETs. There was no significant difference in miscarriage rate or endometrial thickness between groups., Conclusion: High levels of serum estradiol on the day of progesterone start may be detrimental to implantation, pregnancy, and live birth following frozen blastocyst transfer., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Dupilumab has been approved to treat atopic dermatitis, asthma, and nasal polyps and is in active clinical trials for the treatment of eosinophilic esophagitis (EoE). Given its shared immunopathology, we hypothesized that EoE symptoms and inflammation would improve when dupilumab therapy was used for other allergic indications., Objective: To measure the clinical and histologic response in EoE to dupilumab when treating other atopic diseases., Methods: We completed a retrospective chart review of all patients at Children's Hospital of Philadelphia and Rady Children Hospital who were prescribed dupilumab for atopic dermatitis, asthma, or nasal polyps and had a concomitant clinical diagnosis of EoE. Demographic information along with histology, symptom scores, medications, and diet information were collected. Response to dupilumab was evaluated., Results: A total of 45 patients were identified. Of which, 11 patients were prescribed dupilumab for asthma, 27 for atopic dermatitis, 3 for nasal polyps, and 4 for compassionate use for EoE. There was no follow-up data for 8 patients. Follow-up histology was available for 26 patients: 22 of 26 had less than 6 eosinophils per high power field after the initiation of dupilumab with significant improvement (pre: 52.9 + 35.1 to post: 4.5 + 10.9 eosinophils/high power field, P < .005). A total of 28 patients had improvement of symptoms, with 24 patients reporting complete resolution of symptoms after dupilumab initiation. Reductions in EoE treatment medications (swallowed steroids, proton pump inhibitors) or expansion of diet occurred in 29 patients treated with dupilumab., Conclusion: Dupilumab therapy initiated for atopic disease effectively induces symptomatic and histologic remission of esophageal disease and reduces the need for EoE-directed therapy in patients with concomitant EoE., (Copyright © 2022 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7., Competing Interests: Declaration of interests I.E.S. has served on scientific advisory boards for UCB, Eisai, GlaxoSmithKline, BioMarin, Nutricia, Rogcon, Chiesi, Encoded Therapeutics, Xenon Pharmaceuticals, and Knopp Biosciences; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin and Eisai; has served as an investigator for Zogenix, Zynerba, Ultragenyx, GW Pharma, UCB, Eisai, Anavex Life Sciences, Ovid Therapeutics, Epygenyx, Encoded Therapeutics and Marinus; and has consulted for Zynerba Pharmaceuticals, Atheneum Partners, Ovid Therapeutics, Care Beyond Diagnosis, Epilepsy Consortium and UCB. She may accrue future revenue on pending patent WO2009/086591; her patent for SCN1A testing is held by Bionomics and is licensed to various diagnostic companies; and she has a patent for a molecular diagnostic/therapeutic target for benign familial infantile epilepsy (BFIE) (PRRT2), WO/2013/059884. She receives and/or has received research support from the National Health and Medical Research Council of Australia, Medical Research Future Fund, Health Research Council of New Zealand, CURE, Australian Epilepsy Research Fund, and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. J.P. is co-chief scientific officer for Global Gene Corp. All other authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Here, we present an annotated, chromosome-anchored, genome assembly for Lake Trout (Salvelinus namaycush) - a highly diverse salmonid species of notable conservation concern and an excellent model for research on adaptation and speciation. We leveraged Pacific Biosciences long-read sequencing, paired-end Illumina sequencing, proximity ligation (Hi-C) sequencing, and a previously published linkage map to produce a highly contiguous assembly composed of 7378 contigs (contig N50 = 1.8 Mb) assigned to 4120 scaffolds (scaffold N50 = 44.975 Mb). Long read sequencing data were generated using DNA from a female double haploid individual. 84.7% of the genome was assigned to 42 chromosome-sized scaffolds and 93.2% of Benchmarking Universal Single Copy Orthologues were recovered, putting this assembly on par with the best currently available salmonid genomes. Estimates of genome size based on k-mer frequency analysis were highly similar to the total size of the finished genome, suggesting that the entirety of the genome was recovered. A mitochondrial genome assembly was also produced. Self-versus-self synteny analysis allowed us to identify homeologs resulting from the salmonid specific autotetraploid event (Ss4R) as well as regions exhibiting delayed rediploidization. Alignment with three other salmonid genomes and the Northern Pike (Esox lucius) genome also allowed us to identify homologous chromosomes in related taxa. We also generated multiple resources useful for future genomic research on Lake Trout, including a repeat library and a sex-averaged recombination map. A novel RNA sequencing data set for liver tissue was also generated in order to produce a publicly available set of annotations for 49,668 genes and pseudogenes. Potential applications of these resources to population genetics and the conservation of native populations are discussed., (© 2021 The Authors. Molecular Ecology Resources published by John Wiley & Sons Ltd.)

Mitochondrial disease diagnosis requires interrogation of both nuclear and mitochondrial (mtDNA) genomes for single-nucleotide variants (SNVs) and copy number alterations, both in the proband and often maternal relatives, together with careful phenotype correlation. We developed a comprehensive mtDNA sequencing test ('MitoGenome') using long-range PCR (LR-PCR) to amplify the full length of the mtDNA genome followed by next generation sequencing (NGS) to accurately detect SNVs and large-scale mtDNA deletions (LSMD), combined with droplet digital PCR (ddPCR) for LSMD heteroplasmy quantification. Overall, MitoGenome tests were performed on 428 samples from 394 patients with suspected or confirmed mitochondrial disease. The positive yield was 11% (43/394), including 34 patients with pathogenic or likely pathogenic SNVs (the most common being m.3243A > G in 8/34 (24%) patients), 8 patients with single LSMD, and 3 patients with multiple LSMD exceeding 10% heteroplasmy levels. Two patients with both LSMD and pathogenic SNV were detected. Overall, this LR-PCR/NGS assay provides a highly accurate and comprehensive diagnostic method for simultaneous mtDNA SNV detection at heteroplasmy levels as low as 1% and LSMD detection at heteroplasmy levels below 10%. Inclusion of maternal samples for variant classification and ddPCR to quantify LSMD heteroplasmy levels further enables accurate pathogenicity assessment and clinical correlation interpretation of mtDNA genome sequence variants and copy number alterations., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A comprehensive characterization of the brain's white matter is critical for improving our understanding of healthy and diseased aging. Here we used diffusion-weighted magnetic resonance imaging (dMRI) to estimate age and sex effects on white matter microstructure in a cross-sectional sample of 15,628 adults aged 45-80 years old (47.6% male, 52.4% female). Microstructure was assessed using the following four models: a conventional single-shell model, diffusion tensor imaging (DTI); a more advanced single-shell model, the tensor distribution function (TDF); an advanced multi-shell model, neurite orientation dispersion and density imaging (NODDI); and another advanced multi-shell model, mean apparent propagator MRI (MAPMRI). Age was modeled using a data-driven statistical approach, and normative centile curves were created to provide sex-stratified white matter reference charts. Participant age and sex substantially impacted many aspects of white matter microstructure across the brain, with the advanced dMRI models TDF and NODDI detecting such effects the most sensitively. These findings and the normative reference curves provide an important foundation for the study of healthy and diseased brain aging., (© 2021. The Author(s).)

We report seven affected individuals from six families with a recurrent, de novo variant in the ARPC4 gene (c.472C>T [p.Arg158Cys (GenBank: NM&#95;005718.4)]). Core features in affected individuals include microcephaly, mild motor delays, and significant speech impairment. ARPC4 is a core subunit of the actin-related protein (ARP2/3) complex, which catalyzes the formation of F-actin networks. We show that the recurrent ARPC4 missense change is associated with a decreased amount of F-actin in cells from two affected individuals. Taken together, our results implicate heterozygous ARPC4 missense variants as a cause of neurodevelopmental disorders and microcephaly., Competing Interests: K.G.M., T.S.S., and I.M.W. are employees of GeneDx, Inc. All other authors declare no competing interests., (© 2021 The Authors.)

Purpose: Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear., Methods: We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF., Results: Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10 -11 )., Conclusion: Rare KDR variants, in particular PTVs, strongly associate with TOF, likely in the setting of different inheritance patterns. Supported by genetic and in vivo and in vitro functional analysis, we propose loss-of-function of VEGFR2 as one of the mechanisms involved in the pathogenesis of TOF., (© 2021. The Author(s).)

Food-related inhibitory control, the ability to withhold a dominant response towards highly palatable foods, influences dietary decisions. Food-related inhibitory control abilities may increase following a bout of aerobic exercise; however, the impact of exercise intensity on both food-related inhibitory control and broader cognitive control processes is currently unclear. We used a high-powered, within-subjects, crossover design to test how relative intensity of aerobic exercise influenced behavioral (response time, accuracy) and neural (N2 and P3 components of the scalp-recorded event-related potential [ERP]) measures of food-related inhibitory and cognitive control. Two hundred and ten participants completed three separate conditions separated by approximately one week in randomized order: two exercise conditions (35% VO 2max or 70% VO 2max ) and seated rest. Directly following exercise or rest, participants completed a food-based go/no-go task and a flanker task while electroencephalogram data were recorded. Linear mixed models showed generally faster response times (RT) and improved accuracy following 70% VO 2max exercise compared to rest, but not 35% VO 2max ; RTs and accuracy did not differ between 35% VO 2max exercise and rest conditions. N2 and P3 amplitudes were larger following 70% VO 2max exercise for the food-based go/no-go task compared to rest and 35% VO 2max exercise. There were no differences between exercise conditions for N2 amplitude during the flanker task; however, P3 amplitude was more positive following 70% VO 2max compared to rest, but not 35% VO 2max exercise. Biological sex did not moderate exercise outcomes. Results suggest improved and more efficient food-related recruitment of later inhibitory control and cognitive control processes following 70% VO 2max exercise., Competing Interests: Declaration of Competing Interest There are no disclosures or conflicts of interest to report in regards to this paper., (Copyright © 2021. Published by Elsevier Inc.)

Objective: The MAST family of microtubule-associated serine-threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum., Methods: Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells., Results: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wild-type. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally., Interpretation: In summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex. ANN NEUROL 2021;90:274-284., (© 2021 American Neurological Association.)

Accurate reward predictions include forecasting both what a reward will be and when a reward will occur. We tested how variations in the certainty of reward outcome and certainty in timing of feedback presentation modulate neural indices of reward prediction errors using the reward positivity (RewP) component of the scalp-recorded brain event-related potential (ERP). In a within-subjects design, seventy-three healthy individuals completed two versions of a cued doors task; one cued the probability of a reward outcome while the other cued the probability of a delay before feedback. Replicating previous results, RewP amplitude was larger for uncertain feedback compared to certain feedback. Additionally, RewP amplitude was differentially associated with uncertainty of presence/absence of reward, but not uncertainty of feedback timing. Findings suggest a dissociation in that RewP amplitude is modulated by reward prediction certainty but is less affected by certainty surrounding timing of feedback., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene., Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual., Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy., Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.

Pathways through which phenotypic variation among individuals arise can be complex. One assumption often made in relation to intraspecific diversity is that the stability or predictability of the environment will interact with expression of the underlying phenotypic variation. To address biological complexity below the species level, we investigated variability across years in morphology and annual growth increments between and within two sympatric lake charr Salvelinus namaycush ecotypes in Rush Lake, USA. A rapid phenotypic shift in body and head shape was found within a decade. The magnitude and direction of the observed phenotypic change were consistent in both ecotypes, which suggests similar pathways caused the variation over time. Over the same time period, annual growth increments declined for both lake charr ecotypes and corresponded with a consistent phenotypic shift of each ecotype. Despite ecotype-specific annual growth changes in response to winter conditions, the observed annual growth shift for both ecotypes was linked, to some degree, with variation in the environment. Particularly, a declining trend in regional cloud cover was associated with an increase of early-stage (ages 1-3) annual growth for lake charr of Rush Lake. Underlying mechanisms causing changes in growth rates and constrained morphological modulation are not fully understood. An improved knowledge of the biology hidden within the expression of phenotypic variation promises to clarify our understanding of temporal morphological diversity and instability., Competing Interests: The authors declare that they have no competing interests., (© 2021 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Purpose: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy., Methods: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy., Results: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism., Conclusion: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

In a polyphenic species, differences in resource use are expected among ecotypes, and homogeneity in resource use is expected within an ecotype. Yet, using a broad resource spectrum has been identified as a strategy for fishes living in unproductive northern environments, where food is patchily distributed and ephemeral. We investigated whether specialization of trophic resources by individuals occurred within the generalist piscivore ecotype of lake trout from Great Bear Lake, Canada, reflective of a form of diversity. Four distinct dietary patterns of resource use within this lake trout ecotype were detected from fatty acid composition, with some variation linked to spatial patterns within Great Bear Lake. Feeding habits of different groups within the ecotype were not associated with detectable morphological or genetic differentiation, suggesting that behavioral plasticity caused the trophic differences. A low level of genetic differentiation was detected between exceptionally large-sized individuals and other piscivore individuals. We demonstrated that individual trophic specialization can occur within an ecotype inhabiting a geologically young system (8,000-10,000 yr BP), a lake that sustains high levels of phenotypic diversity of lake trout overall. The characterization of niche use among individuals, as done in this study, is necessary to understand the role that individual variation can play at the beginning of differentiation processes., Competing Interests: The authors declare that they have no competing interests., (© 2021 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Chromosome 1q41-q42 deletion syndrome is a rare cause of intellectual disability, seizures, dysmorphology, and multiple anomalies. Two genes in the 1q41-q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic disease. Patients with WDR26 encephalopathy overlap clinically with those with 1q41-q42 deletion syndrome, whereas only one patient with FBXO28 encephalopathy has been described. Seizures are a prominent feature of 1q41-q42 deletion syndrome; therefore, we hypothesized that pathogenic FBXO28 variants cause developmental and epileptic encephalopathies (DEEs). We describe nine new patients with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features, albeit different to those typically seen in 1q41-q42 deletion syndrome and WDR26 encephalopathy. We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual impairment, drug-resistant epilepsy, and hyperkinetic movement disorders., (© 2020 International League Against Epilepsy.)

A cognitive intervention that may reduce weight and caloric intake is inhibitory control training (ICT; having individuals repeatedly withhold dominant responses to unhealthy food images). We conducted a randomized controlled trial where 100 individuals with overweight or obesity were assigned to complete a generic (n = 48) or food-specific ICT (n = 52) training four times per week for four weeks. Weight and caloric intake were obtained at baseline, four-weeks, and 12-weeks. Participants also completed high-calorie and neutral go/no-go tasks while N2 event-related potential (ERP) data, a neural indicator of inhibitory control, was measured at all visits. Results from mixed model analyses indicate that neither weight, caloric intake, nor N2 ERP component amplitude towards high-calorie foods changed at post-testing or at the 12-week follow up. Regression analyses suggest that individuals with smaller N2 difference amplitudes to food may show greater weight loss and reductions in caloric intake after a generic ICT, while individuals with larger N2 difference amplitudes to food may show greater weight loss and reductions in caloric intake after a food-specific ICT. Overall, multiple food-specific or generic ICT sessions over the course of a four-week period do not affect overall weight loss, caloric intake, or N2 ERP amplitude., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Peripherally inserted central catheters are a popular means of obtaining central venous access in critically ill patients. However, there is limited data regarding the rapidity of the peripherally inserted central catheter procedure in the presence of acute illness or obesity, both of which may impede central venous catheter placement. We aimed to determine the feasibility, safety, and duration of peripherally inserted central catheter placement in critically ill patients, including obese patients and patients in shock., Methods: This retrospective cohort study was performed using data on 55 peripherally inserted central catheters placed in a 30-bed multidisciplinary intensive care unit in Mayo Clinic Hospital, Phoenix, Arizona. Information on the time required to complete each step of the peripherally inserted central catheter procedure, associated complications, and patient characteristics was obtained from a prospectively assembled internal quality assurance database created through random convenience sampling., Results: The Median Procedure Time, beginning with the first needle puncture and ending when the procedure is complete, was 14 (interquartile range: 9-20) min. Neither critical illness nor obesity resulted in a statistically significant increase in the time required to complete the peripherally inserted central catheter procedure. Three (5.5%) minor complications were observed., Conclusion: Critical illness and obesity do not delay the acquisition of vascular access when placing a peripherally inserted central catheter. Concerns of delayed vascular access in critically ill patients should not deter a physician from selecting a peripherally inserted central catheter to provide vascular access when it would otherwise be appropriate.

Barrier removal is a recognized solution for reversing river fragmentation, but restoring connectivity can have consequences for both desirable and undesirable species, resulting in a connectivity conundrum. Selectively passing desirable taxa while restricting the dispersal of undesirable taxa (selective connectivity) would solve many aspects of the connectivity conundrum. Selective connectivity is a technical challenge of sorting an assortment of things. Multiattribute sorting systems exist in other fields, although none have yet been devised for freely moving organisms within a river. We describe an approach to selective fish passage that integrates ecology and biology with engineering designs modeled after material recycling processes that mirror the stages of fish passage: approach, entry, passage, and fate. A key feature of this concept is the integration of multiple sorting processes each targeting a specific attribute. Leveraging concepts from other sectors to improve river ecosystem function may yield fast, reliable solutions to the connectivity conundrum., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Institute of Biological Sciences.)

Error-monitoring processes may be affected by transdiagnostic dimensions of psychopathology symptoms including trait anxiety, worry, and severity of depressive symptoms. We tested the relationship between continuous measures of anxiety and depressive symptomology and neural correlates of error-monitoring as measured by time-frequency domain delta and theta oscillatory power and time-domain error-related negativity (ERN) amplitude extracted from the electroencephalogram (EEG). Secondary analyses tested for diagnostic group differences in error-related neural responses in individuals with generalized anxiety disorder (GAD), major depressive disorder (MDD), and comorbid psychiatric disorders. About 178 participants (104 female, M[SD] age  = 21.7[4.6]) with a wide range of psychopathology symptoms completed a modified version of the Eriksen flanker task and symptom questionnaires. Residualized difference values between correct and error trials for delta/theta power and error/correct ERN amplitude were used as dependent variables. Linear regression analyses adjusted for age, sex, and task accuracy showed nonsignificant associations of symptom dimension measures with error-related residualized delta/theta power or residualized ERN amplitude. Subset analyses on those with confirmed psychopathology diagnoses also did not predict residualized error-related delta/theta power nor residualized ERN amplitude (n GAD  = 14, n MDD  = 28, n Comorbid  = 19, n Control  = 85). Taken in the context of the previous literature, results suggest a heterogeneous relationship between depressive and anxiety symptom dimensions and neurophysiological indices of error-monitoring., (© 2020 Society for Psychophysiological Research.)

Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules. Pathogenic variants in NUP genes have been linked to several inherited human diseases, including a number with progressive neurological degeneration. We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development. Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals. Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1 (also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS., Competing Interests: Declaration of Interests N.D. has served on scientific advisory boards for Sarepta, Biomarin, and Avexis. I.E.S. has served on scientific advisory boards for UCB, Eisai, GlaxoSmithKline, BioMarin, Nutricia, Rogcon, and Xenon Pharmaceuticals; editorial boards of the Annals of Neurology, Neurology, and Epileptic Disorders; may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has received speaker honoraria from GlaxoSmithKline, Athena Diagnostics, UCB, BioMarin, and Eisai; and has received funding for travel from Athena Diagnostics, UCB, Biocodex, GlaxoSmithKline, Biomarin, and Eisai. H.C.M. is a member of scientific advisory boards for Lennox Gastaut Syndrome Foundation, Dravet Syndrome Foundation, and SPARK. K.R. has served on advisory boards for UCB, Eisai, Liva Nova, and Novartis; has received research funding from UCB, Jansen-Cilag, Novartis, Zogenix, Liva Nova, Eisai, and AFT Pharmaceuticals; and received speaker honoraria from UCB and Biomarin. All other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Control programs are implemented to mitigate the damage caused by invasive species worldwide. In the highly invaded Great Lakes, the climate is expected to become warmer with more extreme weather and variable precipitation, resulting in shorter iced-over periods and variable tributary flows as well as changes to pH and river hydrology and hydrogeomorphology. We review how climate change influences physiology, behavior, and demography of a damaging invasive species, sea lamprey (Petromyzon marinus), in the Great Lakes, and the consequences for sea lamprey control efforts. Sea lamprey control relies on surveys to monitor abundance of larval sea lamprey in Great Lakes tributaries. The abundance of parasitic, juvenile sea lampreys in the lakes is calculated by surveying wounding rates on lake trout (Salvelinus namaycush), and trap surveys are used to enumerate adult spawning runs. Chemical control using lampricides (i.e., lamprey pesticides) to target larval sea lamprey and barriers to prevent adult lamprey from reaching spawning grounds are the most important tools used for sea lamprey population control. We describe how climate change could affect larval survival in rivers, growth and maturation in lakes, phenology and the spawning migration as adults return to rivers, and the overall abundance and distribution of sea lamprey in the Great Lakes. Our review suggests that Great Lakes sea lamprey may benefit from climate change with longer growing seasons, more rapid growth, and greater access to spawning habitat, but uncertainties remain about the future availability and suitability of larval habitats. Consideration of the biology of invasive species and adaptation of the timing, intensity, and frequency of control efforts is critical to the management of biological invasions in a changing world, such as sea lamprey in the Great Lakes., (© 2019 John Wiley & Sons Ltd.)

Background: It is critical to evaluate the combined impact of age and body mass index on the cumulative likelihood of live birth following in vitro fertilization, as achieving a lower body mass index before infertility treatment often is recommended for women with overweight and obesity. It is important to consider whether achieving a particular body mass index, thus resulting in an older age at in vitro fertilization cycle start, is beneficial or harmful to the likelihood of live birth., Objectives: To evaluate the combined impact of age and body mass index on the cumulative live birth rate following in vitro fertilization to inform when delaying in vitro fertilization treatment to achieve a lower body mass index may be beneficial or detrimental to the likelihood of live birth., Study Design: This is a retrospective study using linked fresh and cryopreserved/frozen cycles from January 2014 to December 2015 from the Society for Reproductive Technology Clinic Outcome Reporting System, representing >90% of in vitro fertilization cycles performed in the United States. The primary outcome was live birth as measured by cumulative live birth rate. Secondary outcomes included implantation rate, clinical pregnancy rate, and miscarriage rate. Poisson and logistic regression were used to calculate risk and odds ratios with 95% confidence intervals to determine differences in implantation, clinical pregnancy, and miscarriage, as appropriate, among first fresh in vitro fertilization cycles compared across age (years) and body mass index (kg/m 2 ) categories. Cox regression was used to calculate hazard ratios with 95% confidence intervals to determine differences in the cumulative live birth rate using fresh plus linked frozen embryo transfer cycles., Results: There were 51,959 first fresh cycles using autologous eggs and 16,067 subsequent frozen embryo transfer cycles. There were 21,395 live births, for an overall cumulative live birth rate of 41.2% per cycle start. The implantation rate, clinical pregnancy rate, and cumulative live birth rate decreased with increasing body mass index and age, and the miscarriage rate increased with increasing body mass index and age (linear trend P<.001 for all). Body mass index had a greater influence on live birth at younger ages as compared with older ages., Conclusions: Age-related decline in fertility has a greater impact than body mass index on the cumulative live birth rate at older ages, suggesting that taking time to achieve lower body mass index before in vitro fertilization may be detrimental for older women with overweight or obesity. Delaying conception to lose weight before in vitro fertilization should be informed by the combination of age and body mass index., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The impact of individual differences on performance monitoring and psychopathology is a question of active debate. Personality traits associated with psychopathology may be related to poor internal performance monitoring (as measured by the error-related negativity [ERN]) but intact external performance monitoring (as measured by the reward positivity [RewP]), suggesting that there are underlying neural differences between internal and external performance monitoring processes. We tested the relationships between individual difference measures of perfectionism, locus of control, and ERN, error-positivity (Pe), and RewP component difference amplitude in a healthy undergraduate sample. A total of 128 participants (69 female, M(SD)age = 20.6(2.0) years) completed two tasks: a modified version of the Eriksen Flanker and a doors gambling task along with the Frost Multidimensional Perfectionism scale, the Rotter Locus of Control scale, and the Levenson Multidimensional Locus of Control scale to quantify perfectionism and locus of control traits, respectively. Linear regressions adjusting for age and gender showed that neither ΔERN nor ΔRewP amplitude were significantly moderated by perfectionism or locus of control scores. Findings suggest that, in psychiatrically-healthy individuals, there is not a strong link between perfectionism, locus of control, and ERN or RewP amplitude. Future research on individual difference measures in people with psychopathology may provide further insight into how these personality traits affect performance monitoring., Competing Interests: The authors have declared that no competing interests exist.

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.

Infantile spasms (IS) is a developmental and epileptic encephalopathy with heterogeneous etiologies including many genetic causes. Genetic studies have identified pathogenic variants in over 30 genes as causes of IS. Many of these genetic causes are extremely rare, with only one reported incidence in an individual with IS. To better understand the genetic landscape of IS, we used targeted sequencing to screen 42 candidate IS genes and 53 established developmental and epileptic encephalopathy genes in 92 individual with IS. We identified a genetic diagnosis for 7.6% of our cohort, including pathogenic variants in KCNB1 (n = 2), GNAO1 (n = 1), STXBP1 (n = 1), SLC35A2 (n = 1), TBL1XR1 (n = 1), and KIF1A (n = 1). Our data emphasize the genetic heterogeneity of IS and will inform the diagnosis and management of individuals with this devastating disorder., (Copyright © 2019. Published by Elsevier B.V.)