The power of paralogs in epilepsy genetics | Beyond the Ion Channel

...we just published our post on our recent publication on the importance of identical variants at conserved sites in epilepsy genes.

epilepsygenetics.blog/2025/07/29/t...

The power of paralogs in epilepsy genetics

Paralogs. Every week in our variant review meetings, we encounter a familiar issue: understanding a missense variant of uncertain significance. Unless it matches a known disease-associated variant or is found to be de novo, our confidence often stalls.…

Figure 1. Impressions from the 2025 STXBP1 Summit+, including Sarah’s award as the 2025 Clinical Champion, our “Bee Brave” painted stone at our conference table, the interactive word cloud at the start of the meeting, the epic Colorado sunrise, and a view of the Westin in Westminster, Colorado that hosted the STXBP1 family meeting for the second time in 2025. More impressions of the 2025 STXBP1 Summit+ can be found at https://www.stxbp1disorders.org/2025-summit.

The rare disease with fastest growing knowledge – the 2025 STXBP1 Summit+ | Beyond the Ion Channel

...we just published our blog post on the 2025 STXBP1 Family Summit+ in Westminster, Colorado

epilepsygenetics.blog/2025/07/26/t...

Figure 1. Schematic representation of overlapping 3q26.3-3q27.2 deletions, and genes involved. The smallest region of overlap (light blue) is 0.43 Mb, encompassing 20 protein-coding genes including AP2M1. The AP2M1 gene encodes a presynaptic adapter protein involved in initiating the first step of synaptic vesicle recycling. The recurrent AP2M1 p.Arg170Trp variant had previously been identified to impair synaptic vesicle recycling and cause genetic epilepsies with clinical features of myoclonic astatic epilepsies (MAE). However, prior to the publication by Gear et al., 2025, haploinsufficiency in AP2M1 had not been known as a disease mechanism (adapted from Gear et al., 2025 under a under the terms of the Creative Commons Attribution and Supplemental data by Helbig et al., 2019).

AP2M1 and the mystery of missing haploinsufficient genes | Beyond the Ion Channel

...we just published our blog post on AP2M1 as the candidate gene in the 3q27 microdeletion

...and the broader issue of missing haploinsufficient genes

epilepsygenetics.blog/2025/07/21/a...

RT @NeuroWoodworks: An astrocyte sculpture made out of cherry wood. Neurons are not the only important cells of the brain!!!

Figure 1. Burden analysis of rare variants in 34,000 individuals of the 100,000 Genomes Project before applying additional prioritization filters. Well-established epilepsy genes including SCN1A, KCNQ2, and DEPDC5 show strong associations, including associations through different analysis methods (duplicate dots for SCN1A). This QQ plot was generated from the Open Access Supplemental Data by Cipriani and collaborators. The insert compares data from the 100K Genomes Project to raw Epi25 data from the Epi25 browser.

Beyond the Ion Channel | RBFOX3 and the Hunt for Epilepsy Genes in 100,000 Genomes

...we just published our post of the discovery of RBFOX3 as a candidate gene from the 100,000 Genomes Project

Epilepsy Genetics Graduation 2025. Our ENGIN fellowship team 2025 including (left to right from myself) our incoming fellow Riley Kessler, graduating fellow Laura McGarry, and current fellowship director Jill McKee. The CHOP Neurology graduation typically takes place in the Philadelphia College of Physicians aka the “hall of old white men with beards”. This is us under the portrait of Alfred Stillé (1813–1900) who advanced American medicine through education reforms and who help shape modern medical professionalism by being a critical part in founding the American Medical Association.

Five principles for teaching epilepsy genetics | Beyond the Ion Channel

...our blog post celebrating the 5th anniversary of our ENGIN epilepsy genetics fellowship

epilepsygenetics.blog/2025/07/08/f...

RT @NTFabiano: This is the Atlas of Cognitive Disorders

RT @DiseaseGenes: The Spectrum of Neurologic Phenotypes Associated With NUS1 Pathogenic Variants: A Comprehensive Case Series

Predicting genetic epilepsies through EMR fingerprints EMR. Clinical data on rare disease is not necessarily rare; it is our ability to unlock already existing data that is rare. Over the last decade, we have tried to understand the fingerprints that r…

Predicting genetic epilepsies through EMR fingerprints | Beyond the Ion Channel

...we just published our post on EMR-based prediction of genetic etiologies in childhood epilepsies.

epilepsygenetics.blog/2025/07/01/p...

RT @tangming2005: Writing online has taught me more than I ever expected. Here’s why I do it and what I’ve learned along the way.

GABRA2-related encephalopathy: Identification of two phenotypes with distinctive electroclinical features - PubMed Pathogenic variants in γ-aminobutyric acid type A (GABA_A) receptor subunit genes are increasingly associated with epilepsy and neurodevelopmental disorders. Pathogenic variants in GABRA2,…

...GABRA2-related disorders follow the pattern of other GABA-A phenotypes

...early-onset DEE with presumed GoF

...milder presentation with LoF

GABRA2-related encephalopathy: Identification of two phenotypes with distinctive electroclinical features pubmed.ncbi.nlm.nih.gov/40528577/

Revisiting SYNGAP1 through a disease-concept model DCM. This is my second blog post on SYNGAP1-related disorders within a month, which highlights how fast the area of clinical trial readiness is moving for one of the most common synapse disorders. …

Revisiting SYNGAP1 through a disease-concept model epilepsygenetics.blog/2025/06/20/r...

Figure 1. Some impressions from the Million Dollar Bike Ride 2025. The fridge magnets of the various MDBRs that have raised more than $1M for STXBP1 research over the last few years. Lucy and Erin at the Bike Ride on June 14th. Me, just having finished the 70 miles. Group photo of Lulu’s Crew at this year’s Million Dollar Bike Ride in Philadelphia.

The 70-mile synapse – riding for Lulu’s Crew | Beyond the Ion Channel

...here is my blog post on this year's Million Dollar Bike Ride.

epilepsygenetics.blog/2025/06/17/t...

HCN2 has an unusual range of associated phenotypes

...NDD with LoF variants

...GEFS+ with GoF variants

HCN2-Associated Neurodevelopmental Disorders: Data from Patients and Xenopus Cell Models - PubMed pubmed.ncbi.nlm.nih.gov/40468825/

Figure 1. Longitudinal trajectories and severities of hemiplegic migraines and seizures in individuals with pediatric CACNA1A-related disorders. All events are plotted left to right, with graphs starting at age 0. (Note: Multiple events within a year were collapsed into 1 event.) Intensity is ranked from 1 (mildest—smallest dot and lightest color) to 5 (most severe—largest dot and darkest color). Above the x-axis: hemiplegic migraine (HM) events (shades of blue). Below the x-axis: seizures (shades of yellow to red). Each individual demonstrated a unique pattern. A noteworthy finding was that no HM events occurred before the age of 1 [modified author manuscript from Schaare et al., 2025 under a Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND)]

CACNA1A-related hemiplegic migraine—the big unknown | Beyond the Ion Channel

...we just published out blog post on the longitudinal trajectory of hemiplegic migraines in CACNA1A-related disorders.

epilepsygenetics.net/2025/06/13/c...

Statistical Rethinking 2023 See full course materials and topical outline here: https://github.com/rmcelreath/stat_rethinking_2024

...visualizing statistics

...a good reminder that "visual intuition" is key to understanding abstract concepts.

RT @rlmcelreath: For the new kids in back: If you hate statistics, you'll love my free lectures. t.co/GnOYGex9Yg t.co/GnOYGex9Yg

...a nice overview of probability distributions for data science

RT @mdancho84: Understanding probability is essential in data science.

In 4 minutes, I'll demolish your confusion.

Let's go!

RT @Brain1878: Computational neuropsychiatry seeks to explain neurological and psychiatric disorders in terms of neuronal message passing. Bottemanne et al. argue that these models may not apply to vascular pathologies and severe tauopathy & synucleinopathy. t.co/sVBsum6fc5 t.co/sVBsum6fc5

The history of epilepsy genetics. Over the last three decades, epilepsy genetics has moved from initial gene discovery, a period of stagnation, gene discoveries through next generation sequencing technologies, to the current post-genomic era where detailed description of phenotypic features and translation into therapeutic modalities current represent the main challenges (modified from Ruggiero et al., 2023). These various transitions would not have occurred without the ongoing involvement and guidance of the ILAE Genetics Commission.

A bittersweet goodbye – my decade on the ILAE Genetics Commission

...here is my blog post on the work of the ILAE Epilepsy Genetics Commission over the last decade

epilepsygenetics.blog/2025/06/06/a...

Missense ABI2 variants linked to a neurodevelopmental disorder with intellectual disability, epilepsy, hypoplasia of the corpus callosum, and white matter abnormalities The Abelson-interactor 2 gene ( ABI2) encodes a protein that functions as a regulator of Rac-dependent actin cytoskeleton dynamics, a highly coordinated structural framework essential for maintaining…

RT @DiseaseGenes:
RT @DiseaseGenes: RT @FranMartinezGr: Missense ABI2 variants linked to a neurodevelopmental disorder with intellectual disability, epilepsy, hypoplasia of the corpus callosum, and white matter abnormalities #RareDisease #Genetics #morbidgene t.co/uk7zjKjzsS

Understanding the SCN8A fingerprint through real-world data | Beyond the Ion Channel Nav1.6. It has been several years since I last wrote a blog post about SCN8A. A wide range of clinical presentations have been described since, and significant progress has been made towards…

Understanding the SCN8A fingerprint through real-world data | Beyond The Ion Channel

epilepsygenetics.net/2025/06/04/u...

RT @Nature: Most proteins are left-handed, but scientists have found an ancient molecule that works in both mirror-image forms

RT @tangming2005: 6 web tools to explore genomics data

Curiosity underlies a breakthrough in rare disease We must recognise and protect the pipelines that lead from research to real-world benefit

Both translational and fundamental curiosity-driven research are needed to fuel the incredible progress we're seeing in genomic medicine; an important message in this article and and some lovely quotes from @sarahlwynn.bsky.social
www.ft.com/content/25dd...

Figure 1. Introducing Citizen Helbig. I was naturalized as a United States citizen in Philadelphia today, alongside fellow new citizens from 25 countries, ranging from Afghanistan to Uganda. Also, I was wearing my STXBP1 sock for my naturalization ceremony.

I became a US citizen today.

...here is my blog post on Life, Liberty, and the Pursuit of Precision Medicine.

epilepsygenetics.net/2025/05/29/l...

The edge of SYNGAP1 – familial variants in a complex neurodevelopmental disorder | Beyond the Ion Channel Bridge the gap. There are very few conditions that I have learned as much about in the last three years as SYNGAP1-related disorders. We just passed the critical milestone of 100 SYNGAPians followed…

The edge of SYNGAP1 – familial variants in a complex neurodevelopmental disorder | Beyond the Ion Channel epilepsygenetics.net/2025/05/27/t...

RT @mdancho84: The 10 types of clustering that all data scientists need to know.

Let's dive in:

A
RT @tangming2005: Thread: Multi-omics sounds cool—until you actually try it. Here's are the nuances.
1/
You’ve got RNA-seq.
Methylation.
Proteomics.
Time to “integrate” the data.
But how? And why?
Let’s break it down.

Distribution of familial variants in SYNGAP1 highlighting the five familial variants identified in this study against the backdrop of other SYNGAP1 variants identified in individuals in the SYNGAP1 Prospective Multidisciplinary Multi-­ Site (ProMMiS) natural history study.

Families 1–3 harbor pathogenic, protein-­ truncating variants, which have a clear loss-­ of-­ function effect in SYNGAP1 (A). Families 4–5 harbor missense variants of unclear clinical significance in SYNGAP1. These variants are not conclusively explanatory for the neurodevelopmental symptoms reported in these individuals (B).

Publication alert - our paper on familial SYNGAP1 just came online

Familial SYNGAP1 variants define the boundaries of a complex neurodevelopmental disorder with epilepsy - PubMed pubmed.ncbi.nlm.nih.gov/40407699/