Global modified-Delphi consensus on comorbidities and prognosis of SCN8A-related epilepsy and/or neurodevelopmental disorders.

OBJECTIVES: We aimed to develop consensus on comorbidities (frequency, severity, and prognosis) and overall outcomes in epilepsy, development, and cognition for the five phenotypes of SCN8A-related disorders. METHODS: A core panel consisting of 13 clinicians, 1 researcher, and 6 caregivers was formed and split into three workgroups. One group focused on comorbidities and prognosis. All groups performed a literature review and developed questions for use in a modified-Delphi process. Twenty-eight clinicians, one researcher, and 13 caregivers from 16 countries participated in three rounds of the modified-Delphi process. Consensus was defined as follows: strong consensus ≥80% fully agree; moderate consensus ≥80% fully or partially agree, <10% disagree; and modest consensus 67%-79% fully or partially agree, <10% disagree. RESULTS: Consensus was reached on the presence of 14 comorbidities in patients with Severe Developmental and Epileptic Encephalopathy (Severe DEE) spanning non-seizure neurological disorders and other organ systems; impacts were mostly severe and unlikely to improve or resolve. Across Mild/Moderate Developmental and Epileptic Encephalopathy (Mild/Moderate DEE), Neurodevelopmental Delay with Generalized Epilepsy (NDDwGE), and NDD without Epilepsy (NDDwoE) phenotypes, cognitive and sleep-related comorbidities as well as fine and gross motor delays may be present but are less severe and more likely to improve compared to Severe DEE. There was no consensus on comorbidities in the SeL(F)IE phenotype but strong conesensus that seizures would largely resolve. Seizure freedom is rare in patients with Severe DEE but may occur in some with Mild/Moderate DEE and NDDwGE. SIGNIFICANCE: Significant comorbidities are present in most phenotypes of SCN8A-related disorders but are most severe and pervasive in the Severe DEE phenotype. We hope that this work will improve recognition, early intervention, and long-term management for patients with these comorbidities and provide the basis for future evidence-based studies on optimal treatments of SCN8A-related disorders. Identifying the prognosis of patients with SCN8A-related disorders will also improve care and quality-of-life for patients and their caregivers.

Global modified Delphi consensus on diagnosis, phenotypes, and treatment of SCN8A-related epilepsy and/or neurodevelopmental disorders.

OBJECTIVE: We aimed to develop consensus for diagnosis/management of SCN8A-related disorders. Utilizing a modified Delphi process, a global cohort of experienced clinicians and caregivers provided input on diagnosis, phenotypes, treatment, and management of SCN8A-related disorders. METHODS: A Core Panel (13 clinicians, one researcher, six caregivers), divided into three subgroups (diagnosis/phenotypes, treatment, comorbidities/prognosis), performed a literature review and developed questions for the modified Delphi process. Twenty-eight expert clinicians, one researcher, and 13 caregivers from 16 countries participated in the subsequent three survey rounds. We defined consensus as follows: strong consensus, ≥80% fully agree; moderate consensus, ≥80% fully/partially agree, <10% disagree; and modest consensus, 67%-79% fully/partially agree, <10% disagree. RESULTS: Early diagnosis is important for long-term clinical outcomes in SCN8A-related disorders. There are five phenotypes: three with early seizure onset (severe developmental and epileptic encephalopathy [DEE], mild/moderate DEE, self-limited (familial) infantile epilepsy [SeL(F)IE]) and two with later/no seizure onset (neurodevelopmental delay with generalized epilepsy [NDDwGE], NDD without epilepsy [NDDwoE]). Caregivers represented six patients with severe DEE, five mild/moderate DEE, one NDDwGE, and one NDDwoE. Phenotypes vary by age at seizures/developmental delay onset, seizure type, electroencephalographic/magnetic resonance imaging findings, and first-line treatment. Gain of function (GOF) versus loss of function (LOF) is valuable for informing treatment. Sodium channel blockers are optimal first-line treatment for GOF, severe DEE, mild/moderate DEE, and SeL(F)IE; levetiracetam is relatively contraindicated in GOF patients. First-line treatment for NDDwGE is valproate, ethosuximide, or lamotrigine; sodium channel blockers are relatively contraindicated in LOF patients. SIGNIFICANCE: This is the first-ever global consensus for the diagnosis and treatment of SCN8A-related disorders. This consensus will reduce knowledge gaps in disease recognition and inform preferred treatment across this heterogeneous disorder. Consensus of this type allows more clinicians to provide evidence-based care and empowers SCN8A families to advocate for their children.

Phylogenomics, Lineage Diversification Rates, and the Evolution of Diadromy in Clupeiformes (Anchovies, Herrings, Sardines, and Relatives).

Migration independently evolved numerous times in animals, with a myriad of ecological and evolutionary implications. In fishes, perhaps the most extreme form of migration is diadromy, the migration between marine and freshwater environments. Key and longstanding questions are: how many times has diadromy evolved in fishes, how frequently do diadromous clades give rise to non-diadromous species, and does diadromy influence lineage diversification rates? Many diadromous fishes have large geographic ranges with constituent populations that use isolated freshwater habitats. This may limit gene flow among some populations, increasing the likelihood of speciation in diadromous lineages relative to non-diadromous lineages. Alternatively, diadromy may reduce lineage diversification rates if migration is associated with enhanced dispersal capacity that facilitates gene flow within and between populations. Clupeiformes (herrings, sardines, shads and anchovies) is a model clade for testing hypotheses about the evolution of diadromy because it includes an exceptionally high proportion of diadromous species and several independent evolutionary origins of diadromy. However, relationships among major clupeiform lineages remain unresolved and existing phylogenies sparsely sampled diadromous species, limiting the resolution of phylogenetically-informed statistical analyses. We assembled a phylogenomic dataset and used multi-species coalescent and concatenation-based approaches to generate the most comprehensive, highly-resolved clupeiform phylogeny to date, clarifying associations among several major clades and identifying recalcitrant relationships needing further examination. We determined that variation in rates of sequence evolution (heterotachy) and base-composition (non-stationarity) had little impact on our results. Using this phylogeny, we characterized evolutionary patterns of diadromy and tested for differences in lineage diversification rates between diadromous, marine, and freshwater lineages. We identified thirteen transitions to diadromy, all during the Cenozoic Era (ten origins of anadromy, two origins of catadromy, and one origin of amphidromy), and seven losses of diadromy. Two diadromous lineages rapidly generated non-diadromous species, demonstrating that diadromy is not an evolutionary dead-end. We discovered considerably faster transition rates out of diadromy than to diadromy. The largest lineage diversification rate increase in Clupeiformes was associated with a transition to diadromy, but we uncovered little statistical support for categorically faster lineage diversification rates in diadromous versus non-diadromous fishes. We propose that diadromy may increase the potential for accelerated lineage diversification, particularly in species that migrate long distances. However, this potential may only be realized in certain biogeographic contexts, such as when diadromy allows access to ecosystems in which there is limited competition from incumbent species.

Gene Expression Patterns Associated with Survival in Glioblastoma.

The aim of this study was to investigate gene expression alterations associated with overall survival (OS) in glioblastoma (GBM). Using the Nanostring nCounter platform, we identified four genes (COL1A2, IGFBP3, NGFR, and WIF1) that achieved statistical significance when comparing GBM with non-neoplastic brain tissue. The four genes were included in a multivariate Cox Proportional Hazard model, along with age, extent of resection, and O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation, to create a unique glioblastoma prognostic index (GPI). The GPI score inversely correlated with survival: patient with a high GPI had a median OS of 7.5 months (18-month OS = 9.7%) whereas patients with a low GPI had a median OS of 20.1 months (18-month OS = 54.5%; log rank p-value = 0.004). The GPI score was then validated in 188 GBM patients from The Cancer Genome Atlas (TCGA) from a national data base; similarly, patients with a high GPI had a median OS of 10.5 months (18-month OS = 12.4%) versus 16.9 months (18-month OS = 41.5%) for low GPI (log rank p-value = 0.0003). We conclude that this novel mRNA-based prognostic index could be useful in classifying GBM patients into risk groups and refine prognosis estimates to better inform treatment decisions or stratification into clinical trials.

Museum genomics reveals the hybrid origin of an extinct crater lake endemic.

Crater lake fishes are common evolutionary model systems, with recent studies suggesting a key role for gene flow in promoting rapid adaptation and speciation. However, the study of these young lakes can be complicated by human-mediated extinctions. Museum genomics approaches integrating genetic data from recently extinct species are therefore critical to understanding the complex evolutionary histories of these fragile systems. Here, we examine the evolutionary history of an extinct Southern Hemisphere crater lake endemic, the rainbowfish Melanotaenia eachamensis. We undertook comprehensive sampling of extant rainbowfish populations of the Atherton Tablelands of Australia alongside historical museum material to understand the evolutionary origins of the extinct crater lake population and the dynamics of gene flow across the ecoregion. The extinct crater lake species is genetically distinct from all other nearby populations due to historic introgression between two proximate riverine lineages, similar to other prominent crater lake speciation systems, but this historic gene flow has not been sufficient to induce a species flock. Our results suggest that museum genomics approaches can be successfully combined with extant sampling to unravel complex speciation dynamics involving recently extinct species.

Machine learning models reveal distinct disease subgroups and improve diagnostic and prognostic accuracy for individuals with pathogenic SCN8A gain-of-function variants.

Distinguishing clinical subgroups for patients suffering with diseases characterized by a wide phenotypic spectrum is essential for developing precision therapies. Patients with gain-of-function (GOF) variants in the SCN8A gene exhibit substantial clinical heterogeneity, viewed historically as a linear spectrum ranging from mild to severe. To test for hidden clinical subgroups, we applied two machine-learning algorithms to analyze a dataset of patient features collected by the International SCN8A Patient Registry. We used two research methodologies: a supervised approach that incorporated feature severity cutoffs based on clinical conventions, and an unsupervised approach employing an entirely data-driven strategy. Both approaches found statistical support for three distinct subgroups and were validated by correlation analyses using external variables. However, distinguishing features of the three subgroups within each approach were not concordant, suggesting a more complex phenotypic landscape. The unsupervised approach yielded strong support for a model involving three partially ordered subgroups rather than a linear spectrum. Application of these machine-learning approaches may lead to improved prognosis and clinical management of individuals with SCN8A GOF variants and provide insights into the underlying mechanisms of the disease.

Deep learning-based differentiation of peripheral high-flow and low-flow vascular malformations in T2-weighted short tau inversion recovery MRI.

BACKGROUND: Differentiation of high-flow from low-flow vascular malformations (VMs) is crucial for therapeutic management of this orphan disease. OBJECTIVE: A convolutional neural network (CNN) was evaluated for differentiation of peripheral vascular malformations (VMs) on T2-weighted short tau inversion recovery (STIR) MRI. METHODS: 527 MRIs (386 low-flow and 141 high-flow VMs) were randomly divided into training, validation and test set for this single-center study. 1) Results of the CNN's diagnostic performance were compared with that of two expert and four junior radiologists. 2) The influence of CNN's prediction on the radiologists' performance and diagnostic certainty was evaluated. 3) Junior radiologists' performance after self-training was compared with that of the CNN. RESULTS: Compared with the expert radiologists the CNN achieved similar accuracy (92% vs. 97%, p = 0.11), sensitivity (80% vs. 93%, p = 0.16) and specificity (97% vs. 100%, p = 0.50). In comparison to the junior radiologists, the CNN had a higher specificity and accuracy (97% vs. 80%, p <  0.001; 92% vs. 77%, p <  0.001). CNN assistance had no significant influence on their diagnostic performance and certainty. After self-training, the junior radiologists' specificity and accuracy improved and were comparable to that of the CNN. CONCLUSIONS: Diagnostic performance of the CNN for differentiating high-flow from low-flow VM was comparable to that of expert radiologists. CNN did not significantly improve the simulated daily practice of junior radiologists, self-training was more effective.

Sex differences in physiological response to increased neuronal excitability in a knockin mouse model of pediatric epilepsy.

BACKGROUND: Epilepsy is a common neurological disease; however, few if any of the currently marketed antiseizure medications prevent or cure epilepsy. Discovery of pathological processes in the early stages of epileptogenesis has been challenging given the common use of preclinical models that induce seizures in physiologically normal animals. Moreover, despite known sex dimorphism in neurological diseases, females are rarely included in preclinical epilepsy models. METHODS: We characterized sex differences in mice carrying a pathogenic knockin variant (p.N1768D) in the Scn8a gene that causes spontaneous tonic-clonic seizures (TCs) at ∼3 months of age and found that heterozygous females are more resilient than males in mortality and morbidity. To investigate the cellular mechanisms that underlie female resilience, we utilized blood-brain barrier (BBB) and hippocampal transcriptomic analyses in heterozygous mice before seizure onset (pre-TC) and in mice that experienced ∼20 TCs (post-TC). RESULTS: In the pre-TC latent phase, both sexes exhibited leaky BBB; however, patterns of gene expression were sexually dimorphic. Females exhibited enhanced oxidative phosphorylation and protein biogenesis, while males activated gliosis and CREB signaling. After seizure onset (chronic phase), females exhibited a metabolic switch to lipid metabolism, while males exhibited increased gliosis and BBB dysfunction and a strong activation of neuroinflammatory pathways. CONCLUSION: The results underscore the central role of oxidative stress and BBB permeability in the early stages of epileptogenesis, as well as sex dimorphism in response to increasing neuronal hyperexcitability. Our results also highlight the need to include both sexes in preclinical studies to effectively translate results of drug efficacy studies.

Leukocyte differential gene expression prognostic value for high versus low seizure frequency in temporal lobe epilepsy.

BACKGROUND: This study was performed to test the hypothesis that systemic leukocyte gene expression has prognostic value differentiating low from high seizure frequency refractory temporal lobe epilepsy (TLE). METHODS: A consecutive series of patients with refractory temporal lobe epilepsy was studied. Based on a median baseline seizure frequency of 2.0 seizures per month, low versus high seizure frequency was defined as ≤ 2 seizures/month and > 2 seizures/month, respectively. Systemic leukocyte gene expression was analyzed for prognostic value for TLE seizure frequency. All differentially expressed genes were analyzed, with Ingenuity® Pathway Analysis (IPA®) and Reactome, to identify leukocyte gene expression and biological pathways with prognostic value for seizure frequency. RESULTS: There were ten males and six females with a mean age of 39.4 years (range: 16 to 62 years, standard error of mean: 3.6 years). There were five patients in the high and eleven patients in the low seizure frequency cohorts, respectively. Based on a threshold of twofold change (p < 0.001, FC > 2.0, FDR < 0.05) and expression within at least two pathways from both Reactome and Ingenuity® Pathway Analysis (IPA®), 13 differentially expressed leukocyte genes were identified which were all over-expressed in the low when compared to the high seizure frequency groups, including NCF2, HMOX1, RHOB, FCGR2A, PRKCD, RAC2, TLR1, CHP1, TNFRSF1A, IFNGR1, LYN, MYD88, and CASP1. Similar analysis identified four differentially expressed genes which were all over-expressed in the high when compared to the low seizure frequency groups, including AK1, F2R, GNB5, and TYMS. CONCLUSIONS: Low and high seizure frequency TLE are predicted by the respective upregulation and downregulation of specific leukocyte genes involved in canonical pathways of neuroinflammation, oxidative stress and lipid peroxidation, GABA (γ-aminobutyric acid) inhibition, and AMPA and NMDA receptor signaling. Furthermore, high seizure frequency-TLE is distinguished prognostically from low seizure frequency-TLE by differentially increased specific leukocyte gene expression involved in GABA inhibition and NMDA receptor signaling. High and low seizure frequency patients appear to represent two mechanistically different forms of temporal lobe epilepsy based on leukocyte gene expression.

Greater female than male resilience to mortality and morbidity in the Scn8a mouse model of pediatric epilepsy.

AIMS: Females and males of all ages are affected by epilepsy; however, unlike many clinical studies, most preclinical research has focused on males. Genetic variants in the voltage-gated sodium channel gene, SCN8A, are associated with a broad spectrum of neurological and epileptic syndromes. Here we investigate sex differences in the natural history of the Scn8a-N1768D knockin mouse model of pediatric epilepsy. METHODS: We utilize 24/7 video to monitor juveniles and adults of both sexes to investigate variability in seizure activity (e.g. onset and frequency), mortality and morbidity, response to cannabinoids, and mode of death. We also monitor sleep architecture using a noninvasive piezoelectric method in order to identify factors that influence seizure severity and outcome. RESULTS: Both sexes had nearly 100% penetrance in seizure onset and early mortality. However, adult heterozygous (D/+) females were more resilient as exhibited by the ability to tolerate more seizures over a longer lifespan. Homozygous (D/D) juveniles did not exhibit a sex difference in overall survival. Female estrus cycle was disrupted before seizure onset, while sleep was disrupted in both sexes in association with seizure onset. Females typically died while in convulsive status epilepticus; however, a high proportion of males died while not experiencing behavioral seizures. Only juvenile and adult males benefited from cannabinoid administration. CONCLUSIONS: These results support the hypothesis that factors associated with sexual differentiation play a role in the neurobiology of epilepsy and point to the importance of including both sexes in the design of studies to identify new epilepsy therapies.

Phylogeography of a widespread Australian freshwater fish, western carp gudgeon (Eleotridae: Hypseleotris klunzingeri): Cryptic species, hybrid zones, and strong intra-specific divergences.

Despite belonging to the most abundant and widespread genus of freshwater fishes in the region, the carp gudgeons of eastern Australia (genus Hypseleotris) have proved taxonomically and ecologically problematic to science since the 19th century. Several molecular studies and a recent taxonomic revision have now shed light on the complex biology and evolutionary history that underlies this group. These studies have demonstrated that carp gudgeons include a sexual/unisexual complex (five sexual species plus an assortment of hemiclonal lineages), many members of which also co-occur with an independent sexual relative, the western carp gudgeon (H. klunzingeri). Here, we fill yet another knowledge gap for this important group by presenting a detailed molecular phylogeographic assessment of the western carp gudgeon across its entire and extensive geographic range. We use a suite of nuclear genetic markers (SNPs and allozymes) plus a matrilineal genealogy (cytb) to demonstrate that H. klunzingeri s.l. also displays considerable taxonomic and phylogeographic complexity. All molecular datasets concur in recognizing the presence of multiple candidate species, two instances of historic between-species admixture, and the existence of a natural hybrid zone between two of the three candidate species found in the Murray-Darling Basin. We also discuss the major phylogeographic patterns evident within each taxon. Together, these analyses provide a robust molecular, taxonomic, and distributional framework to underpin future morphological and ecological investigations on this prominent member of regional freshwater ecosystems in eastern Australia.

Clinical severity is correlated with age at seizure onset and biophysical properties of recurrent gain of function variants associated with SCN8A-related epilepsy.

OBJECTIVE: Genetic variants in the SCN8A gene underlie a wide spectrum of neurodevelopmental phenotypes including several distinct seizure types and a host of comorbidities. One of the major challenges facing clinicians and researchers alike is to identify genotype-phenotype (G-P) correlations that may improve prognosis, guide treatment decisions, and lead to precision medicine approaches. METHODS: We investigated G-P correlations among 270 participants harboring gain-of-function (GOF) variants enrolled in the International SCN8A Registry, a patient-driven online database. We performed correlation analyses stratifying the cohort by clinical phenotypes to identify diagnostic features that differ among patients with varying levels of clinical severity, and that differ among patients with distinct GOF variants. RESULTS: Our analyses confirm positive correlations between age at seizure onset and developmental skills acquisition (developmental quotient), rate of seizure freedom, and percentage of cohort with developmental delays, and identify negative correlations with number of current and weaned antiseizure medications. This set of features is more detrimentally affected in individuals with a priori expectations of more severe clinical phenotypes. Our analyses also reveal a significant correlation between a severity index combining clinical features of individuals with a particular highly recurrent variant and an independent electrophysiological score assigned to each variant based on in vitro testing. SIGNIFICANCE: This is one of the first studies to identify statistically significant G-P correlations for individual SCN8A variants with GOF properties. The results suggest that individual GOF variants (1) are predictive of clinical severity for individuals carrying those variants and (2) may underlie distinct clinical phenotypes of SCN8A disease, thus helping to explain the wide SCN8A-related epilepsy disease spectrum. These results also suggest that certain features present at initial diagnosis are predictive of clinical severity, and with more informed treatment plans, may serve to improve prognosis for patients with SCN8A GOF variants.

The International SCN8A Patient Registry: A Scientific Resource to Advance the Understanding and Treatment of a Rare Pediatric Neurodevelopmental Syndrome.

Genetic variants in the SCN8A gene underlie a wide spectrum of neurodevelopmental phenotypes that range from severe epileptic encephalopathy to benign familial infantile epilepsy to neurodevelopmental delays with or without seizures. A host of additional comorbidities also contribute to the phenotypic spectrum. As a result of the recent identification of the genetic etiology and the length of time it often takes to diagnose patients, little data are available on the natural history of these conditions. The International SCN8A Patient Registry was developed in 2015 to fill gaps in understanding the spectrum of the disease and its natural history, as well as the lived experiences of individuals with SCN8A syndrome. Another goal of the registry is to collect longitudinal data from participants on a regular basis. In this article, we describe the construction and structure of the International SCN8A Patient Registry, present the type of information available, and highlight particular analyses that demonstrate how registry data can provide insights into the clinical management of SCN8A syndrome.

Diversification of the sleepers (Gobiiformes: Gobioidei: Eleotridae) and evolution of the root gobioid families.

Eleotridae (sleepers) and five smaller families are the earliest diverging lineages within Gobioidei. Most inhabit freshwaters in and around the Indo-Pacific, but Eleotridae also includes species that have invaded the Neotropics as well as several inland radiations in the freshwaters of Australia, New Zealand, and New Guinea. Previous efforts to infer phylogeny of these families have been based on sets of mitochondrial or nuclear loci and have yielded uncertain resolution of clades within Eleotridae. We expand the taxon sampling of previous studies and use genomic data from nuclear ultraconserved elements (UCEs) to infer phylogeny, then calibrate the hypothesis with recently discovered fossils. Our hypothesis clarifies ambiguously resolved relationships, provides a timescale for divergences, and indicates the core crown Eleotridae diverged over a short period 24.3-26.3 Ma in the late Oligocene. Within Eleotridae, we evaluate diversification dynamics with BAMM and find evidence for an overall slowdown in diversification over the past 35 Ma, but with a sharp increase 3.5 Ma in the genus Mogurnda, a clade of brightly colored species found in the freshwaters of Australia and New Guinea.

Distinguishing Loss-of-Function and Gain-of-Function SCN8A Variants Using a Random Forest Classification Model Trained on Clinical Features.

Background and Objectives: Pathogenic variants at the voltage-gated sodium channel gene, SCN8A, are associated with a wide spectrum of clinical disease outcomes. A critical challenge for neurologists is to determine whether patients carry gain-of-function (GOF) or loss-of-function (LOF) variants to guide treatment decisions, yet in vitro studies to infer channel function are often not feasible in the clinic. In this study, we develop a predictive modeling approach to classify variants based on clinical features present at initial diagnosis. Methods: We performed an exhaustive search for individuals deemed to carry SCN8A GOF and LOF variants by means of in vitro studies in heterologous cell systems, or because the variant was classified as truncating, and recorded clinical features. This resulted in a total of 69 LOF variants: 34 missense and 35 truncating variants, including 9 nonsense, 13 frameshift, 6 splice site, 6 indels, and 1 large deletion. We then assembled a truth set of variants with known functional effects, excluding individuals carrying variants at other loci associated with epilepsy. We then trained a predictive model based on random forest using this truth set of 45 LOF variants and 45 GOF variants randomly selected from a set of variants tested by in vitro methods. Results: Phenotypic categories assigned to individuals correlated strongly with GOF or LOF variants. All patients with GOF variants experienced early-onset seizures (mean age at onset = 4.5 ± 3.1 months) while only 64.4% patients with LOF variants had seizures, most of which were late-onset absence seizures (mean age at onset = 40.0 ± 38.1 months). With high accuracy (95.4%), our model including 5 key clinical features classified individuals with GOF and LOF variants into 2 distinct cohorts differing in age at seizure onset, development of seizures, seizure type, intellectual disability, and developmental and epileptic encephalopathy. Discussion: The results support the hypothesis that patients with SCN8A GOF and LOF variants represent distinct clinical phenotypes. The clinical model developed in this study has great utility because it provides a rapid and highly accurate platform for predicting the functional class of patient variants during SCN8A diagnosis, which can aid in initial treatment decisions and improve prognosis.

Eye movement defects in KO zebrafish reveals SRPK3 as a causative gene for an X-linked intellectual disability.

Intellectual disability (ID) is a common neurodevelopmental disorder characterized by significantly impaired intellectual and adaptive functioning. X-linked ID (XLID) disorders, caused by defects in genes on the X chromosome, affect 1.7 out of 1,000 males. Employing exome sequencing, we identified three missense mutations (c.475C>G; p.H159D, c.1373C>A; p.T458N, and c.1585G>A; p.E529K) in the SRPK3 gene in seven XLID patients from three independent families. Clinical features common to the patients are intellectual disability, agenesis of the corpus callosum, abnormal smooth pursuit eye movement, and ataxia. SRPK proteins are known to be involved in mRNA processing and, recently, synaptic vesicle and neurotransmitter release. In order to validate SRPK3 as a novel XLID gene, we established a knockout (KO) model of the SRPK3 orthologue in zebrafish. In day 5 of larval stage, KO zebrafish showed significant defects in spontaneous eye movement and swim bladder inflation. In adult KO zebrafish, we found agenesis of cerebellar structures and impairments in social interaction. These results suggest an important role of SRPK3 in eye movements, which might reflect learning problems, intellectual disability, and other psychiatric disorders.

Phylogenomics and biogeography of arid-adapted Chlamydogobius goby fishes.

The progressive aridification of the Australian continent from âˆ¼ 20 million years ago posed severe challenges for the persistence of its resident biota. A key question involves the role of refugial habitats - specifically, their ability to mediate the effects of habitat loss and fragmentation, and their potential to shape opportunities for allopatric speciation. With freshwater species, for example, the patchiness, or absence, of water will constrain distributions. However, aridity may not necessarily isolate populations if disjunct refugia experience frequent hydrological connections. To investigate this potential dichotomy, we explored the evolutionary history of the Chlamydogobius gobies (Gobiiformes: Gobiidae), an arid-adapted genus of six small, benthic fish species that exploit all types of waterbodies (i.e. desert springs, waterholes and bore-fed wetlands, coastal estuarine creeks and mangroves) across parts of central and northern Australia. We used Anchored Phylogenomics to generate a highly resolved phylogeny of the group from sequence data for 260 nuclear loci. Buttressed by companion allozyme and mtDNA datasets, our molecular findings infer the diversification of Chlamydogobius in arid Australia, and provide a phylogenetic structure that cannot be simply explained by invoking allopatric speciation events reflecting current geographic proximity. Our findings are generally consistent with the existing morphological delimitation of species, with one exception: at the shallowest nodes of phylogenetic reconstruction, the molecular data do not fully support the current dichotomous delineation of C. japalpa from C. eremius in Kati Thanda-Lake Eyre-associated waterbodies. Together these findings illustrate the ability of structural (hydrological) connections to generate patterns of connectivity and isolation for an ecologically moderate disperser in response to ongoing habitat aridification. Finally, we explore the implications of these results for the immediate management of threatened (C. gloveri) and critically endangered (C. micropterus, C. squamigenus) congeners.

Deficiency in Re-Orienting of Attention in Adults with Attention-Deficit Hyperactivity Disorder.

Objective: To characterize potential brain indexes of attention deficit hyperactivity disorder (ADHD) in adults. Methods: In an effort to develop objective, laboratory-based tests that can help to establish ADHD diagnosis, the brain indexes of distractibility was investigated in a group of adults. We used event-related brain potentials (ERPs) and performance measures in a forced-choice visual task. Results: Behaviorally aberrant distractibility in the ADHD group was significantly higher. Across three ERP components of distraction: N1 enhancement, P300 (P3a), and Reorienting Negativity (RON) the significant difference between ADHD and matched controls was found in the amplitude of the RON. We used non-parametric randomization tests, enabling us to statistically validated this difference between-group. Conclusions: Our main results of this feasibility study suggest that among other ERP components associated with auditory distraction, the RON response is promising index for a potential biomarker of deficient re-orienting of attention in adults s with ADHD.

Utilization and impact of cardiovascular magnetic resonance on patient management in heart failure: insights from the SCMR Registry.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is an important diagnostic test used in the evaluation of patients with heart failure (HF). However, the demographics and clinical characteristics of those undergoing CMR for evaluation of HF are unknown. Further, the impact of CMR on subsequent HF patient care is unclear. The goal of this study was to describe the characteristics of patients undergoing CMR for HF and to determine the extent to which CMR leads to changes in downstream patient management by comparing pre-CMR indications and post-CMR diagnoses. METHODS: We utilized the Society for Cardiovascular Magnetic Resonance (SCMR) Registry as our data source and abstracted data for patients undergoing CMR scanning for HF indications from 2013 to 2019. Descriptive statistics (percentages, proportions) were performed on key CMR and clinical variables of the patient population. The Fisher's exact test was used when comparing categorical variables. The Wilcoxon rank sum test was used to compare continuous variables. RESULTS: 3,837 patients were included in our study. 94% of the CMRs were performed in the United States with China, South Korea and India also contributing cases. Median age of HF patients was 59.3 years (IQR, 47.1, 68.3 years) with 67% of the scans occurring on women. Almost 2/3 of the patients were scanned on 3T CMR scanners. Overall, 49% of patients who underwent CMR scanning for HF had a change between the pre-test indication and post CMR diagnosis. 53% of patients undergoing scanning on 3T had a change between the pre-test indication and post CMR diagnosis when compared to 44% of patients who were scanned on 1.5T (p < 0.01). CONCLUSION: Our results suggest a potential impact of CMR scanning on downstream diagnosis of patients referred for CMR for HF, with a larger potential impact on those scanned on 3T CMR scanners.

Whole exome sequencing and co-expression analysis identify an SCN1A variant that modifies pathogenicity in a family with genetic epilepsy and febrile seizures plus.

OBJECTIVE: Family members carrying the same SCN1A variant often exhibit differences in the clinical severity of epilepsy. This variable expressivity suggests that other factors aside from the primary sodium channel variant influence the clinical manifestation. However, identifying such factors has proven challenging in humans. METHODS: We perform whole exome sequencing (WES) in a large family in which an SCN1A variant (p.K1372E) is segregating that is associated with a broad spectrum of phenotypes ranging from lack of epilepsy, to febrile seizures and absence seizures, to Dravet syndrome. We assessed the hypothesis that the severity of the SCN1A-related phenotype was affected by alternate alleles at a modifier locus (or loci). RESULTS: One of our top candidates identified by WES was a second variant in the SCN1A gene (p.L375S) that was shared exclusively by unaffected carriers of the K1372E allele. To test the hypothesized that L375S variant nullifies the loss-of-function effect of K1372E, we transiently expressed Nav1.1 carrying the two variants in HEK293T cells and compared their biophysical properties with the wild-type (WT) variant, and then co-expressed WT with K1372E or L375S with K1372E in equal quantity and tested the functional consequence. The data demonstrated that co-expression of the L375S and K1372E alleles reversed the loss-of-function property brought by the K1372E variant, whereas WT-K1372E co-expression remained partial loss-of-function. SIGNIFICANCE: These results support the hypothesis that L375S counteracts the loss-of-function effect of K1372E such that individuals carrying both alleles in trans do not present epilepsy-related symptoms. We demonstrate that monogenic epilepsies with wide expressivity can be modified by additional variants in the disease gene, providing a novel framework for the gene-phenotype relationship in genetic epilepsies.