Figure. Communication profiles across genetic neurodevelopmental disorders. Left: Heatmap reproduced from the recent preprint by Hsu et al. (2026), based on data from the Simons Searchlight and SPARK cohorts, showing multiple measures of communicative ability across genetic neurodevelopmental disorders. Measures include Vineland-3 expressive and receptive subdomains, speech milestone items, and single-item questionnaire responses. Across conditions, different measures of communication tend to agree, suggesting that both standardized scales and simple parent-reported questions capture related aspects of communicative function, although the strength of impairment differs by genetic etiology. Right: Scatterplot derived from the Vineland-3 values shown in the table on the left, plotting mean expressive versus receptive v-scores for each genetic condition. While communication abilities differ substantially across disorders, expressive and receptive skills generally move in parallel, with clear gene-specific profiles. STXBP1-related disorders show particularly low scores in both domains, consistent with the severe early developmental impairment observed clinically, whereas other conditions cluster at higher levels of communicative ability. Together, these data illustrate how large cohort datasets make it possible to map communication phenotypes across many genetic disorders simultaneously, revealing both shared patterns and disorder-specific signatures.

New blog post: The Landscape of Communication in Genetic Neurodevelopmental Disorders

Hsu et al. compare communication abilities across many genetic neurodevelopmental disorders.

www.epilepsygenetics.net/the-landscap...

#RareDisease #Neurogenetics #Autism #Epilepsy #Genetics

Seizure frequency by individual and semiology. Seizure frequency is represented overall (A) and by semiology (B-D) over the first 18 years of life. Each segment of the y-axis represents one individual, with panel A being grouped by clinical diagnosis: Dravet syndrome (top), genetic epilepsy with febrile seizures plus (GEFS+; middle), and non-Dravet developmental and epileptic encephalopathy (nd-DEE; bottom). The x-axis represents age on a logarithmic scale from 0-18 years. Seizure frequency is indicated by color as outlined in the legend. White space indicates months where seizure frequency is unknown for a given individual.

Preprint alert 🧬

Characterizing SCN1A-Related Disorders Using Real-World Data Across 681 Patient-Years.

Real-world data adds texture and scale to natural history studies — and helps sharpen endpoints for upcoming SCN1A trials.

🔗 www.medrxiv.org/content/10.6...

#Epilepsy #SCN1A #RareDisease

Figure 1. There are different ways to gain understanding of rare disease phenotypes, ranging from approaches with large patient numbers and core phenotypes to smaller studies with highly granular phenotypes. In our blog post, we use the analogy of the different phases of water (ice, water, vapor) to represent the three main approaches to phenotype studies. Importantly, these approaches are not mutually exclusive but complement each other. For example, Natural History Studies and clinical trial readiness studies would be limited if longitudinal phenotype studies were not available to provide a broad overview of the disease trajectory. However, in turn, these longitudinal studies depend on large-scale phenotyping studies to provide an overview of broader disease patterns and subgroups.

Phenotypes are like Water | Beyond the Ion Channel

...for #RareDiseaseDay 2026, I revisited a 2023 post arguing that phenotypes exist in phases: ice, water, and vapour

🔗https://epilepsygenetics.blog/2026/02/28/phenotypes-are-like-water-rare-disease-day-2026/

Figure 1. Pediatric CSF immune profiling highlights a distinct intrathecal signature in MS. This figure shows that while B cells are increased across acquired demyelinating syndromes (ADS), pediatric multiple sclerosis (MS) is uniquely characterized by marked expansion of antibody-secreting cells (ASCs) and relative reduction of CD14+ myeloid cells in the cerebrospinal fluid (CSF). The upper panels display cell frequencies and the lower panels absolute counts (cells/mL) across diagnostic groups: non-inflammatory neurological disease (NIND), peripheral inflammatory neurological disease (PIND), autoimmune encephalitides (AIE), inherited disorders of white matter (IDWM), other ADS, myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD), and MS. Together, the enrichment of ASCs and relative depletion of CD14+ myeloid cells in MS support the concept that MS establishes compartmentalized humoral immune activity within the CNS early in disease, distinguishing it from MOGAD and other ADS. Adapted from Espinoza et al., 2025 (CC BY-NC-ND 4.0).

An Atlas into Pediatric Neuroimmunity | Beyond the Ion Channel

We profiled CSF immune landscapes in 85 children.

Rare disease discovery requires biobanking beyond genomics.

epilepsygenetics.blog/2026/02/23/a...

Figure. Functional landscape of CACNA1A variants across structure, biophysics, and phenotype. A. Schematic of the hCaV2.1 channel topology illustrating domains DI–DIV as transmembrane segments, with S4 voltage-sensing regions highlighted in light blue. De novo missense variants are shown in red and population variants from gnomAD in gray. B. Hierarchical clustering heatmap of CACNA1A variants based on z scores of electrophysiological parameters. Each row represents a single variant and each column corresponds to an individual functional parameter. z score magnitudes are color-coded as indicated in the inset. The dendrogram groups variants with similar functional profiles. C. Forest plots showing odds ratios from logistic regression analyses for peak current density, V1/2 activation, and V1/2 inactivation across 16 phenotypes. Solid circles denote statistically significant associations and horizontal bars represent 95% confidence intervals. Analyses include data from both the GeneDx cohort and the clinically reviewed cohort. Modified from Kurganov et al., 2025. Figures used with permission as co-author of the publication.

Decoding CACNA1A | Beyond the Ion Channel

We analyzed 42 CACNA1A missense variants and linked functional data to phenotype. Half showed loss of current.

Function simplifies. Phenotype remains complex.

🔗https://epilepsygenetics.blog/2026/02/18/decoding-cacna1a-how-function-shapes-phenotypes/

Figure 1. A modern map for an old pathway. Schematic of interstitial solute and fluid clearance in the brain as conceptualized in the glymphatic model. Cerebrospinal fluid (CSF) enters along para-arterial spaces, exchanges with interstitial fluid through astrocyte endfeet enriched in aquaporin-4 (AQP4), and exits along paravenous routes carrying metabolic waste toward the bloodstream and cervical lymphatics. While the anatomical components — perivascular spaces, astrocytes, CSF flow, and interstitial solute movement — have long been recognized, the “glymphatic system” framework, introduced in 2012, integrates these elements into a unified clearance pathway. This model has been influential in linking sleep, fluid dynamics, and neurodegeneration, even as the precise mechanisms and relative contributions of bulk flow versus diffusion remain under active investigation.

I wrote about how neuroscience advances not only through new data, but through new language.

“Glymphatic system” (introduced in 2012), E–I imbalance in epilepsy, mirror neurons, channelopathies — all useful frameworks.

But frameworks are not mechanisms.

epilepsygenetics.blog/2026/02/15/g...

Figure 1. Minimal fusion at scale. Our animation of synaptic vesicle fusion displayed at the Emirati Health Services booth at World Health Expo WHX 2026 in Dubai. The installation visualized SNARE complex assembly guided by MUNC-18 (STXBP1), attempting to illustrate disease mechanisms in synaptic disorders. It was projected prominently in the South Hall and formed part of the broader exhibition space.

Minimal Fusion at WHX 2026 | Beyond the Ion Channel

At WHX 2026 in Dubai, participants were greeted by a large scale animation of synaptic vesicle fusion that we developed to visualize mechanisms in genetic neurodevelopmental disorders.

epilepsygenetics.blog/2026/02/13/m...

Figure. Longitudinal trajectories in TBC1D24-related disorders. Left: Age-dependent frequency of neurological features. Seizure types including focal seizures, myoclonic seizures, and status epilepticus are most common in early infancy and early childhood. Movement disorders such as tremor and ataxia become more prominent later, illustrating how the clinical picture evolves over time. Right: Individual seizure frequencies across the lifespan. Each row represents one person, with color indicating seizure burden from seizure-free to many seizures per day. Most individuals experience the highest seizure burden in infancy, with fluctuating but often persistent drug-resistant epilepsy over time. Figure adapted from Mondragon et al., 2025.

The Long Arc of TBC1D24 | Beyond the Ion Channel

…we just published our blog post on our longitudinal reconstruction of TBC1D24-related disorders, tracking nearly 200 patient-years.

🔗 Read more: epilepsygenetics.blog/2026/02/07/t...

Protocol and Recruitment. Here we present a comprehensive and feasible protocol for evaluating the natural history of STXBP1 (STARR) and SYNGAP1 (ProMMiS) using existing outcome measures within the framework of a clinical visit. Recruitment is ongoing, with n=323 individuals evaluated to date. Study protocol includes standardized clinical assessments, parent-reported outcomes, quantitative EEG and movement sensors, and detailed seizure histories. Consortium structures have been established for both studies allowing data generation from multiple sites in an FDA-compliant format for collaboration with industry partners, advocacy organizations, and researchers.

Preprint alert 🚀

Our new paper outlines a prospective NHS protocol built to support clinical trial readiness in SYNGAP1 and STXBP1.

The protocol already powers STARR and ProMMiS.

🔗 www.medrxiv.org/content/10.6...

#SYNGAP1 #STXBP1 #DEE #ClinicalTrials

Figure 1. Each point represents a gene–disease assertion curated by the ClinGen Epilepsy Gene Curation Expert Panel, positioned by the date of its most recent evaluation and arranged vertically by strength of evidence. Darker blues indicate stronger support, with Definitive gene–disease relationships at the top and Refuted relationships at the bottom. The vertical spread reflects jitter added for visibility, emphasizing that evidence strength behaves more like a gradient than a set of rigid tiers. Gene labels are shown to highlight how individual genes move within this landscape of confidence. This is the broader context for USP25. Strength of gene-disease associations is not an isolated debate for any particular gene, but part of the ongoing process by which gene–disease claims are tested against accumulating data that either support or question validity. All gene–disease validity classifications shown here are publicly available through the ClinGen gene validity curation interface.

USP25 and the gravity well of evidence | Beyond the Ion Channel

…we just published a new post about how gene–disease claims change over time. Using USP25 as an example, we explore how accumulating data can deepen confidence or lead to reclassification.

🔗 epilepsygenetics.blog/2026/01/31/u...

Figure 1. Conceptual illustration of cure versus treat as a Babel-like translation problem in rare disease. Echoing the visual language of RF Kuang’s Babel cover, twin Oxford-like towers face each other across a fractured silver-working tablet, the Translation Gap. Floating pages and cryptic glyphs evoke untranslatable meaning, where promise, hope, and trust accumulate. In rare disease, these gaps shape expectations, advocacy narratives, and the clinician–family contract.

Cure vs. Treat | Beyond the Ion Channel

...we just published a new post exploring how “cure” and “treat” mean different things to scientists and families — and why the translation gap between those words matters so much in rare disease.
epilepsygenetics.blog/2026/01/29/c...

Figure 1. Artistic adaptation of a forecast map originally produced by the U.S. National Weather Service (NOAA). Colors indicate the maximum probability of exceeding warning criteria, meaning the likelihood that a given location will experience winter weather severe enough to trigger official warnings (such as heavy snowfall, ice accumulation, or dangerous travel conditions) at some point during the event. Warmer colors reflect a higher probability that warning thresholds will be met or exceeded. The map illustrates the expected large-scale impact pattern of Winter Storm Fern across the United States in January 2026, re-rendered here for conceptual and narrative purposes rather than operational forecasting.

Ten Years of Accumulation: Snow-Day Thoughts Between Jonas and Fern | Beyond the Ion Channel

...we just published a new post reflecting on how a decade of progress reshaped epilepsy genetics between two historic winter storms.

epilepsygenetics.blog/2026/01/27/t...

Figure 1. UNC13A (MUNC13-1) as a synaptic priming factor and the landscape of UNC13A missense variation in neurodevelopmental disorders. Top panels (a–d): Working model of the Munc18–Munc13 route to SNARE complex assembly during synaptic vesicle priming and fusion. (a) Membrane association and pre-alignment: interactions between synaptic vesicle synaptobrevin/VAMP2 (Syb2) and the MUN domain, together with C1–C2B binding to DAG/PIP2, position vesicles near the plasma membrane and facilitate engagement of the Munc18-1/Syntaxin-1 (Syx1) complex. (b) Priming: coordinated Munc18-1/Syx1/Munc13 interactions promote Syb2 binding and stabilize a primed intermediate. (c) Proofreading and nucleation: entry of SNAP-25 (SN25) supports N-terminal SNARE nucleation and formation of a half-zippered SNARE complex, releasing Syntaxin-1 from Munc18-1 clamping. (d) Completion: full SNARE zippering drives membrane merger and vesicle fusion. Adapted from Figure 8 in Nature Communications (2019), licensed under CC BY 4.0 (changes made: figure cropped and incorporated into composite). Bottom panel: Pathogenic missense variants identified in UNC13A overlaid on a domain schematic, highlighting a recurrent “UNC13A hinge” hotspot, together with a gene-wide tolerance landscape derived from population variation (MetaDome/gnomAD-based tolerance scores; red = intolerant, blue = tolerant). Reproduced/adapted from Asadollahi et al. (2025) licensed under CC BY 4.0 (changes made: figure cropped and incorporated into composite; author is a coauthor).\

𝗨𝗡𝗖𝟭𝟯𝗔 𝗮𝗻𝗱 𝘁𝗵𝗲 𝗴𝗮𝘁𝗲 𝗼𝗳 𝘀𝘆𝗻𝗮𝗽𝘁𝗶𝗰 𝗿𝗲𝗹𝗲𝗮𝘀𝗲 | 𝗕𝗲𝘆𝗼𝗻𝗱 𝘁𝗵𝗲 𝗜𝗼𝗻 𝗖𝗵𝗮𝗻𝗻𝗲𝗹

...we just published a new post on UNC13A, a synaptic priming gene that sits beside STXBP1 at the gate of neurotransmitter release.https://epilepsygenetics.blog/2026/01/24/unc13a-and-the-gate-of-synaptic-release/

...and here is the link

epilepsygenetics.blog/2026/01/21/t...

Figure 1. Spectraplakins, including MACF1, are large cytoskeletal scaffold proteins that crosslink actin filaments and microtubules to coordinate cellular architecture, polarity, and intracellular organization. This group of proteins has a modular architecture consisting of an N-terminal actin-binding domain, central spectrin-repeat rod regions, and C-terminal microtubule-binding motifs (left). These complex proteins have various functions in neurons, including regulation of neurite outgrowth, axon guidance, synapse organization, and intracellular trafficking (right). Figures from Cusseddu et al. (2021) under a Creative Commons CC BY license.

The MACF1 puzzle: when a cytoskeletal giant causes multiple brain disorders | Beyond the Ion Channel

...we just published our new post on why interpreting MACF1 variants is so difficult, highlighting how this massive spectraplakin gene can produce distinct neurodevelopmental phenotypes.

Figure 1. Quantitative EEG features in genetic epilepsies. Using machine learning, we were able to extract specific qEEG features that were more most important in separating controls from individuals with STXBP1-, SYNGAP1-, and SCN1A-related epilepsies (feature importance, left). The global alpha-delta ratio is a previously studied qEEG feature. When assessing this across age groups and various genetic epilepsies, we saw that this measure is most prominent in STXBP1-related disorders across all age groups, while it was only significantly lower than controls in other conditions (e.g. SCN1A) at specific ages.

Signals in the noise – qEEG patterns in genetic epilepsies | Beyond the Ion Channel

...we just published our new post on extracting hidden qEEG signals from routine clinical EEGs, showing patterns in STXBP1-, SCN1A-, and SYNGAP1-related epilepsies.

epilepsygenetics.blog/2026/01/17/s...

Figure 1. Visualizing the new ACMG/AMP points-based classification system. The diagram shows how different combinations of evidence criteria contribute to variant interpretation under the updated framework. Each bar represents a typical evidence scenario, broken down by individual ACMG/AMP rules such as PVS1 (very strong), PS2–PS4 (strong), PM1–PM6 (moderate), and PP1–PP5 (supporting). Conflicting evidence is indicated by hatched bars, highlighting situations where pathogenic and benign signals pull in opposite directions. Colored background zones indicate the thresholds that define final classifications: Pathogenic (≥10 points), Likely Pathogenic (6–9 points), VUS (0–5 points), Likely Benign (−1 to −6 points), and Benign (≤−7 points, or BA1 as a stand-alone benign criterion). This new quantitative framework turns what once felt like a “word salad” of rules into a transparent and teachable scoring system, marking a quiet revolution in how we approach clinical variant interpretation.

The quiet revolution – revising ACMG criteria for epilepsy genes | Beyond the Ion Channel

...we just published our blog post on the revision of ACMG criteria for epilepsy-related sodium channels

epilepsygenetics.blog/2025/09/04/t...

The quiet revolution – revising ACMG criteria for epilepsy genes

VUS. The story begins with a patient in clinic. A young child with severe epilepsy, carrying a variant in SCN1A, the classic gene for Dravet Syndrome. But the variant is labeled a variant of uncertain significance (VUS). Dravet…

Figure 1. The Ice Neurons of Delaware County. When I moved to the United States in 2014, I first encountered a phenomenon on frozen ponds that I had never seen in Europe: neuron-like dendritic patterns etched into lake ice after snowfall. These “ice neurons” arise when wet, heavy snow falls on thin ice, followed by rapid thaw and refreeze. Meltwater seeps through cracks and imperfections, radiating outward in branching channels reminiscent of axons and dendrites. In Delaware County, with its many shallow ponds and frequent freeze–thaw cycles, these conditions align perfectly—creating striking natural structures at the intersection of weather and biology.

The gentle singularity that cannot draw a synapse | Beyond the Ion Channel

..we just published our blog post on the struggle of generative AI to draw a synapse.

epilepsygenetics.blog/2025/08/30/t...

The gentle singularity that cannot draw a synapse

Singularity. A few months ago, Sam Altman, the CEO of OpenAI, published a short essay about the future of artificial intelligence. His central message was a gentle role for AI—a vision in which technology supports us quietly in the background…

Figure 1. Function of RANBP2 and neuroimaging in ANE. Figure. Structural model of RanBP2/Nup358 and neuroimaging in acute necrotizing encephalopathy. RanBP2/Nup358 is a major component of the cytoplasmic filaments of the nuclear pore complex, which has an eightfold symmetry with each symmetrical unit referred to as a ‘spoke’. Five copies of RanBP2/Nup358 are found at each spoke, for a total of 40 copies per pore. The N-terminal domain attaches to the pore and is the spot where ANE1 mutations cluster. On the right, magnetic resonance imaging from a 3-year-old child presenting with a viral prodrome and rapid neurological decline. T2-weighted axial images demonstrate the characteristic bilateral thalamic lesions typical of acute necrotizing encephalopathy (figure adapted from Palazzo et al., 2022 under CC BY 4.0, http://creativecommons.org/licenses/by/4.0/).

Influenza and acute necrotizing encephalopathy – the genetic dimension | Beyond the Ion Channel

...we just published our blog post on Acute necrotizing encephalopathy (ANE).

epilepsygenetics.blog/2025/08/28/i...

Influenza and acute necrotizing encephalopathy – the genetic dimension

ANE. A rare complication with hidden genetic clues. Imagine a healthy child who goes to bed with a fever and wakes up unable to recognize their parents, slipping rapidly into coma. This is the terrifying course of acute…

Figure 1. Gene ontology enrichment and overlapping genes in a cross-species analysis for immature granule cell (imGCs). On the left, the top biological pathways are shown for imGC-enriched genes across humans, macaques, pigs, and mice. These pathways, grouped and color-coded by Gene Ontology (GO) terms, highlighting the processes most important for immature neurons, such as neuronal development, synaptic plasticity, and ion transport. This view emphasizes that, while the precise genes differ from species to species, the biological themes remain consistent. On the right, a Venn diagram illustrates how few imGC-enriched genes are shared between species. Only a small set of genes is common to all four, with an additional subset found only in humans and macaques. The lists of shared genes in the boxes serve as concrete examples of this limited overlap, reinforcing the central message of the study: processes can be conserved even when the genes executing them diverge. [Figure modified from data provided by the authors].

Different genes, convergent processes – rare disease lessons from neurogenesis | Beyond the Ion Channel

...we just published our blog post on the recent publication by Zhou et al. in Nature Neuroscience

epilepsygenetics.blog/2025/08/26/d...

Different genes, convergent processes – rare disease lessons from neurogenesis

A paradox in the hippocampus. Immature dentate granule cells are often described as the “plasticity reserve” of the hippocampus. They provide a pool of neurons that integrate into existing circuits, supporting learning,…

Figure 1. Placental weight and fetal growth stratification with corresponding methylation pathways. The nine-block classification system (left) combines placental weight (x-axis, low to high) and fetal-to-placental weight ratio (y-axis, high to low) to categorize neonatal growth patterns. In our cohort, analyses focused on three groups: light placenta with heavy infant (Group A), light placenta with balanced infant growth (Group D), and balanced placenta and infant (Group E, highlighted in red). DNA methylation differences across these groups revealed pathway-specific alterations (right), with gene-set enrichment analyses pointing to biological processes relevant for neurodevelopmental vulnerability in congenital heart disease.

The placental mirror – methylation and neurodevelopment in congenital heart disease – Beyond the Ion Channel

...we just published our blog post on our recent publication on neuronal signatures in umbilical cord blood methylation patterns.

epilepsygenetics.blog/2025/08/24/t...

The placental mirror – methylation and neurodevelopment in congenital heart disease

Neurodevelopment. Congenital heart disease (CHD) refers to a broad group of structural abnormalities of the heart that are present at birth and affect approximately 1% of all live births. Over the past two decades,…

Figure 1. Dunes at Rehoboth Beach, Delaware. A stretch near the beach, looking at the beach from the boardwalk facing away from the crowds. Much like rare disease research, some of the most valuable insights happen off the expected path when looking in a different direction. This can often happens in spaces that are less visible.

Three things the beach told me about science in 2025 | Beyond the Ion Channel

...we just published our annual blog post about insights into rare disease research at the beach

epilepsygenetics.blog/2025/08/16/t...

Three things the beach told me about science in 2025

Rehoboth. It has been a while since I posted my annual post-beach-vacation thoughts about how my experiences at the shore made me think about science. I initially started these posts after a vacation in Marielyst, Denmark when I realized that my…

Figure 1. Miami plot of genome-wide association studies (GWAS) for stuttering in females (top) and males (bottom) of European ancestry. The female GWAS analyzed 570,071 individuals (40,137 cases), identifying nine genome-wide significant loci. The male GWAS included 374,279 individuals (38,257 cases), identifying ten such loci. The x-axis shows genomic coordinates (hg19), the y-axis the −log10(P) values from logistic regression. Dashed lines mark the significance threshold (P < 5 × 10⁻⁸). Genes shown are predicted functional candidates for each locus from the Open Targets Genetics V2G pipeline. This side-by-side view highlights both shared and sex-specific genetic architecture in stuttering (modified from Polikowsky et al, 2025 under a modified from Polikowsky et al., 2025 under a Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/)

Chasing the Demosthenes gene – the complex genetics of stuttering | Beyond the Ion Channel

...we just published our blog post on a recent large-scale genetic study on stuttering.

epilepsygenetics.blog/2025/08/13/c...

Chasing the Demosthenes gene – the complex genetics of stuttering

Fluency. When we think of stuttering, we might first think of speech therapy, of pauses and repetitions, and of the courage it takes to speak when words get stuck. But what if we could step back and see its genetic architecture laid…