Holger Lerche

Long-read genome sequencing resolves complex structural variants in exome-negative developmental and epileptic encephalopathy

This study evaluates the diagnostic value of long-read genome sequencing in DEE patients, finding it particularly effective for resolving complex structural variants not detected by short-read sequencing.

SynTEF1 restores the functional disease phenotype of SCA27B in an hiPSC-derived neuronal model

This study shows that SynTEF1 restores FGF14 expression and neuronal function in SCA27B patient-derived neurons.

Gene Portals: A Framework for Integrating Clinical, Functional, and Structural Evidence into Rare Disease Variant Classification

The paper introduces Gene Portals, a framework that integrates clinical, functional, and structural data for rare disease variant classification, demonstrating its utility across five gene-specific portals.

Transcription factor binding and individual genetic risk for valproate teratogenicity

The paper investigates how genetic variants affecting transcription factor binding contribute to valproate-induced birth defects and identifies EP300 as a key regulator involved in this process.

Electrophysiological signatures of a developmental delay in a stem cell model of KCNQ2 developmental and epileptic encephalopathy

This study investigates the developmental impact of KCNQ2 loss-of-function variants in patient iPSC-derived neurons, showing reduced M-currents and disrupted oscillatory activity linked to developmental delay and seizures.

Predicting Drug Response with Multi-Task Gradient-Boosted Trees in Epilepsy

This paper predicts drug response in epilepsy using multi-task gradient-boosted trees, identifying key genomic and clinical features that influence treatment outcomes.

Early postnatal CA3 hyperexcitability drives hippocampal development and epileptogenesis in SCN2A developmental and epileptic encephalopathy

This study shows that early postnatal CA3 hyperexcitability drives hippocampal development and epileptogenesis in SCN2A-DEE, suggesting it as a therapeutic target.

Comprehensive reanalysis for CNVs in exome sequencing data from unsolved rare disease cases results in new diagnoses

The paper reanalyzes exome sequencing data from rare disease cases to identify previously undetected copy number variants, resulting in diagnoses for 51 families and partial explanations for 34 individuals.

Effective excitability captures network dynamics across development and phenotypes

The paper develops a dynamical system model to characterize in vitro neuronal network bursting dynamics across development and cell types, finding that effective excitability reliably captures these differences.

Optimizing clinical interpretability of functional evidence in epilepsy-related ion channel variants

The paper develops a Bayesian framework to integrate functional evidence into clinical variant interpretation for epilepsy-related ion channel genes, identifying key parameters that influence pathogenicity classification.

Axonopathy and altered synaptic development in early hippocampal epileptogenesis of Dravet syndrome

This study uses single-cell RNA sequencing in a Dravet syndrome mouse model to identify early transcriptomic changes and axonopathy in interneurons during epileptogenesis.

Direct fluorescent labeling of NF186 and NaV1.6 in living primary neurons using bioorthogonal click chemistry

This paper develops a method to label and image AIS proteins in living neurons using unnatural amino acids and bioorthogonal click chemistry, demonstrating its application to study NaV1.6 variants.

Retigabine and gabapentin restore channel function and neuronal firing of an epilepsy-associated dominant-negative KCNQ5 variant

This study shows that retigabine and gabapentin restore K+ currents and reduce neuronal firing in a dominant-negative KCNQ5 variant associated with epilepsy.

Learning with phenotypic similarity improves the prediction of functional effects of missense variants in voltage-gated sodium channels

The paper develops a machine learning framework that uses phenotypic similarity to predict the functional effects of missense variants in voltage-gated sodium channels, achieving high accuracy and robustness.

Linking neuronal and hemodynamic network signatures in the resting human brain

This study examines the relationship between BOLD-fMRI and EEG signals in the resting human brain, finding frequency- and network-specific time-lags and correlations.

Predicting the functional effects of voltage-gated potassium channel missense variants with multi-task learning

This paper develops a multi-task learning model to predict the functional effects of voltage-gated potassium channel variants, achieving improved accuracy over standard methods.

Dravet variant SCN1AA1783V impairs interneuron firing predominantly by altered channel activation

This paper characterizes the functional impact of the SCN1AA1783V variant in Dravet syndrome by combining electrophysiology, computational modeling, and in vitro validation, showing impaired interneuron firing due to altered channel activation.

Ultra-rare constrained missense variants in the epilepsies: Shared and specific enrichment patterns in neuronal gene-sets

The paper analyzes ultra-rare variants in epilepsy patients to identify gene-set enrichment patterns and differential impacts in neuronal gene categories.

Predicting Functional Effects of Missense Variants in Voltage-Gated Sodium and Calcium Channels

The paper predicts functional effects of missense variants in voltage-gated sodium and calcium channels using machine learning, achieving high accuracy in distinguishing gain and loss of function variants.

Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy

The paper analyzes genetic variants in 6,994 individuals with neurodevelopmental disorder with epilepsy to assess diagnostic yield and identify ultra-rare variants in associated genes.

Mutant Plasticity Related Gene 1 (PRG1) acts as a potential modifier in SCN1A related epilepsy

The paper identifies a PRG1 mutation that modifies SCN1A-related epilepsy in humans by exacerbating seizure susceptibility in a mouse model.

Heterogeneous Contribution of Microdeletions in the Development of Common Generalized and Focal epilepsies

This study examines the role of microdeletions in different epilepsy subtypes, finding enriched contributions in Genetic Generalized Epilepsy but not in Rolandic or Adult Focal Epilepsy.