Samuel F. Berkovic
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View article: Functional consequence of pathogenic GABRA3 variants determines whether X-linked inheritance is dominant or recessive
Functional consequence of pathogenic GABRA3 variants determines whether X-linked inheritance is dominant or recessive Open
Disorders of GABRA3, the only epilepsy-associated GABA-A receptor subunit gene on the X chromosome, have eluded clinical clarity due to ambiguous inheritance patterns and variable phenotypes. The long-standing assumption that all pathogeni…
View article: Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia
Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia Open
Focal cortical dysplasias (FCDs) are malformations of cortical development associated with drug-resistant focal epilepsy. We analysed surgical tissue from 28 consecutive cases recruited from adult and pediatric epilepsy surgery programs. W…
View article: SUDEP risk is influenced by longevity genomics: a polygenic risk score study
SUDEP risk is influenced by longevity genomics: a polygenic risk score study Open
The Amelia Roberts Fund; CURE Epilepsy; Epilepsy Society, UK; Finding A Cure for Epilepsy and Seizures (FACES).
View article: Phenotypic Spectrum in Individuals With Pathogenic <i>GABRG2</i> Loss- and Gain-of-Function Variants
Phenotypic Spectrum in Individuals With Pathogenic <i>GABRG2</i> Loss- and Gain-of-Function Variants Open
Our findings indicate that the severity of disease associated with pathogenic GABRG2 variants depends on the functional consequences of the variants. Null variants are associated with a mild phenotype and missense LoF variants with …
View article: Twins with temporal lobe epilepsy: genetic contributions to hippocampal sclerosis and other subtypes
Twins with temporal lobe epilepsy: genetic contributions to hippocampal sclerosis and other subtypes Open
Temporal lobe epilepsy is the most common focal epilepsy in adults. While temporal lobe epilepsy was historically perceived to have a largely acquired aetiology, growing evidence points to important genetic contributions. There are several…
View article: Precision therapies for genetic epilepsies in 2025: Promises and pitfalls
Precision therapies for genetic epilepsies in 2025: Promises and pitfalls Open
By targeting the underlying etiology, precision therapies offer an exciting paradigm shift to improve the stagnant outcomes of drug‐resistant epilepsies, including developmental and epileptic encephalopathies. Unlike conventional antiseizu…
View article: Improving genetic diagnostic yield in familial and sporadic cerebral cavernous malformations: detection of copy number and deep Intronic variants
Improving genetic diagnostic yield in familial and sporadic cerebral cavernous malformations: detection of copy number and deep Intronic variants Open
Cerebral cavernous malformations (CCMs) are intracranial vascular lesions associated with risk of haemorrhages and seizures. While the majority are sporadic and often associated with somatic variants in PIK3CA and MAP3K3, around 20% are fa…
View article: Toxoplasma gondii seropositivity as a risk factor for epilepsy: A discordant monozygotic twin study
Toxoplasma gondii seropositivity as a risk factor for epilepsy: A discordant monozygotic twin study Open
In our cohort of MZ twins discordant for epilepsy, we found no evidence for an association between T. gondii seropositivity and epilepsy. Larger carefully controlled studies are warranted.
View article: Genome-wide association meta-analyses of drug-resistant epilepsy
Genome-wide association meta-analyses of drug-resistant epilepsy Open
This work is part of the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 279062 (EpiPGX) and the Centers for Common Disease Genomics (CCDG) program, funded by the National Human Genome Research Institu…
View article: Progressive Myoclonus Epilepsy: Distinctive <scp>MRI</scp> Changes in Cerebellar and Motor Networks
Progressive Myoclonus Epilepsy: Distinctive <span>MRI</span> Changes in Cerebellar and Motor Networks Open
Objective Progressive myoclonus epilepsy (PME) is a rare generalized epilepsy syndrome with a well‐characterized genetic basis. The brain networks that are affected to give rise to the distinctive symptoms of PME are less well understood. …
View article: Pathogenic ultra-rare variants in<i>SLC6A1, SLC6A11, GAD1 and GAD2</i>are new & recurrent GABAergic loci for GGE syndromes
Pathogenic ultra-rare variants in<i>SLC6A1, SLC6A11, GAD1 and GAD2</i>are new & recurrent GABAergic loci for GGE syndromes Open
There is a wealth of biological evidence that supports the concept that GABAergic inhibition is causal to some genetic generalized epilepsy (GGE) syndromes. Much is known about postsynaptic GABAAR channelopathies, however, the presynaptic …
View article: Identifying individuals with rare disease variants by inferring shared ancestral haplotypes from SNP array data
Identifying individuals with rare disease variants by inferring shared ancestral haplotypes from SNP array data Open
We describe FoundHaplo, an identity-by-descent algorithm that can be used to screen untyped disease-causing variants using single nucleotide polymorphism (SNP) array data. FoundHaplo leverages knowledge of shared disease haplotypes for inh…
View article: Sleep‐related hypermotor epilepsy—No longer controversial
Sleep‐related hypermotor epilepsy—No longer controversial Open
The evolution from nocturnal paroxysmal dystonia (NPD)to sleep-related hypermotor epilepsy (SHE) is a complexand fascinating journey, marked by numerous twists anddiscoveries.1 This topic was recently reviewed by Fotedarand Luders,2 who er…
View article: Phenotypic heterogeneity in familial epilepsies is influenced by polygenic risk for generalized and focal epilepsies
Phenotypic heterogeneity in familial epilepsies is influenced by polygenic risk for generalized and focal epilepsies Open
Objective Although previous research shows that generalized and focal epilepsies have at least some distinct genetic influences, it remains uncertain why some families manifest both types of epilepsy. We tested two hypotheses: (1) families…
View article: <scp><i>PAK3</i></scp> pathogenic variant associated with sleep‐related hypermotor epilepsy in a family with parental mosaicism
<span><i>PAK3</i></span> pathogenic variant associated with sleep‐related hypermotor epilepsy in a family with parental mosaicism Open
Protein‐activated kinases mediate spine morphogenesis and synaptic plasticity. PAK3 is part of the p21‐activated kinases (PAKs) family of Ras‐signaling serine/threonine kinases. Pathogenic variants in the X‐linked gene PAK3 have been descr…
View article: Development and characterization of a pentylenetetrazol-induced convulsive seizure model in non-anaesthetized sheep
Development and characterization of a pentylenetetrazol-induced convulsive seizure model in non-anaesthetized sheep Open
The pathophysiology of seizures is complex and could contribute to a range of morbidities including sudden unexpected death of epilepsy (SUDEP). A better understanding of seizure-induced pathophysiology can lead to the development of targe…
View article: Pathogenic Ultra-Rare Variants in SLC6A1, SLC6A11, GAD1 and GAD2 are New &amp; Recurrent GABAergic Loci for Genetic Generalised Epilepsy
Pathogenic Ultra-Rare Variants in SLC6A1, SLC6A11, GAD1 and GAD2 are New & Recurrent GABAergic Loci for Genetic Generalised Epilepsy Open
View article: Novel, complex configurations of the <i>MARCHF6</i> repeat expansion associated with progressive myoclonic epilepsy and familial adult myoclonic epilepsy
Novel, complex configurations of the <i>MARCHF6</i> repeat expansion associated with progressive myoclonic epilepsy and familial adult myoclonic epilepsy Open
Repeat expansions are a known cause of progressive myoclonic epilepsy (PME) and familial adult myoclonic epilepsy (FAME). We hypothesized that PME and FAME may have an overlapping phenotypic spectrum and searched for pathogenic repeat expa…
View article: Investigating the effect of polygenic background on epilepsy phenotype in ‘monogenic’ families
Investigating the effect of polygenic background on epilepsy phenotype in ‘monogenic’ families Open
View article: Plasma and CSF neurofilament light chain distinguish neurodegenerative from primary psychiatric conditions in a clinical setting
Plasma and CSF neurofilament light chain distinguish neurodegenerative from primary psychiatric conditions in a clinical setting Open
INTRODUCTION People with neurodegenerative disorders (ND) frequently face diagnostic delay and misdiagnosis. We investigated blood and cerebrospinal fluid (CSF) neurofilament light chain (NfL) to distinguish ND from primary psychiatric dis…
View article: Inflation of polygenic risk scores caused by sample overlap and relatedness: Examples of a major risk of bias
Inflation of polygenic risk scores caused by sample overlap and relatedness: Examples of a major risk of bias Open
View article: Plasma and CSF neurofilament light chain distinguish neurodegenerative from primary psychiatric conditions in a clinical setting
Plasma and CSF neurofilament light chain distinguish neurodegenerative from primary psychiatric conditions in a clinical setting Open
INTRODUCTION Many patients with neurodegenerative disorders (ND) face diagnostic delay and misdiagnosis. We investigated blood and cerebrospinal fluid (CSF) neurofilament light chain (NfL) to distinguish ND from primary psychiatric disorde…
View article: Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement
Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement Open
Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but r…
View article: Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike–Wave Activation in Sleep <scp>(D/EE‐SWAS</scp>)
Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike–Wave Activation in Sleep <span>(D/EE‐SWAS</span>) Open
Objective To understand the etiological landscape and phenotypic differences between 2 developmental and epileptic encephalopathy (DEE) syndromes: DEE with spike–wave activation in sleep (DEE‐SWAS) and epileptic encephalopathy with spike–w…
View article: Experience of the first adult-focussed undiagnosed disease program in Australia (AHA-UDP): solving rare and puzzling genetic disorders is ageless
Experience of the first adult-focussed undiagnosed disease program in Australia (AHA-UDP): solving rare and puzzling genetic disorders is ageless Open
Background Significant recent efforts have facilitated increased access to clinical genetics assessment and genomic sequencing for children with rare diseases in many centres, but there remains a service gap for adults. The Austin Health A…
View article: Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy
Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy Open
Importance: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution…
View article: Familial aggregation of seizure outcomes in four familial epilepsy cohorts
Familial aggregation of seizure outcomes in four familial epilepsy cohorts Open
Objective To assess the possible effects of genetics on seizure outcome by estimating the familial aggregation of three outcome measures: seizure remission, history of ≥4 tonic–clonic seizures, and seizure control for individuals taking an…
View article: Diagnostic utility of plasma ptau217, ptau181, GFAP for Alzheimer disease in a heterogeneous younger onset dementia clinical cohort
Diagnostic utility of plasma ptau217, ptau181, GFAP for Alzheimer disease in a heterogeneous younger onset dementia clinical cohort Open
Objective We investigated diagnostic utility of phosphorylated tau 217 and 181 (ptau217, ptau181), glial fibrillary acidic protein (GFAP), amyloid beta 42 and 40 (Aβ42, Aβ40), neurofilament light (NfL) to distinguish AD from non-AD conditi…
View article: Applying the ILAE diagnostic criteria for Lennox‐Gastaut syndrome in the real‐world setting: A multicenter retrospective cohort study
Applying the ILAE diagnostic criteria for Lennox‐Gastaut syndrome in the real‐world setting: A multicenter retrospective cohort study Open
Objective Lennox‐Gastaut syndrome (LGS) is an archetypal developmental and epileptic encephalopathy, for which novel treatments are emerging. Diagnostic criteria for LGS have recently been defined by the International League Against Epilep…
View article: Exploring individual fixel-based white matter abnormalities in epilepsy
Exploring individual fixel-based white matter abnormalities in epilepsy Open
Diffusion MRI has provided insight into the widespread structural connectivity changes that characterize epilepsies. Although syndrome-specific white matter abnormalities have been demonstrated, studies to date have predominantly relied on…