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See detailClinical spectrum of STX1B-related epileptic disorders
Wolking, Stefan; May, Patrick UL; Mei, Davide et al

in Neurology (2019), 92

Objective: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and to establish genotype-phenotype correlations by ... [more ▼]

Objective: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and to establish genotype-phenotype correlations by identifying further disease-related variants. Methods: We used next generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. Results: We describe fifteen new variants in STX1B which are distributed across the whole gene. We discerned four different phenotypic groups across the newly identified and previously published patients (49 in 23 families): 1) Six sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development and without permanent neurological deficits; 2) two patients of genetic generalized epilepsy without febrile seizures and cognitive deficits; 3) thirteen patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; 4) two patients with focal epilepsy. Nonsense mutations were found more often in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. Conclusion: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the ILAE classification. Variants in STX1B are protean, and able to contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies. [less ▲]

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See detailRare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study
May, Patrick UL; Girard, Simon; Harrer, Merle et al

in Lancet Neurology (2018), 17(8), 699-708

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We ... [more ▼]

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. Methods For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes. Findings Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41–4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05–2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02–2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors. Interpretation Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy. [less ▲]

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See detailDe novo Variants in Neurodevelopmental Disorders with Epilepsy
Heyne, Henrike O.; Singh, Tarijinder; Stamberger, Hannah et al

in Nature Genetics (2018)

Epilepsy is a frequent feature of neurodevelopmental disorders (NDD) but little is known about genetic differences between NDD with and without epilepsy. We analyzed de novo variants (DNV) in 6753 parent ... [more ▼]

Epilepsy is a frequent feature of neurodevelopmental disorders (NDD) but little is known about genetic differences between NDD with and without epilepsy. We analyzed de novo variants (DNV) in 6753 parent-offspring trios ascertained for different NDD. In the subset of 1942 individuals with NDD with epilepsy, we identified 33 genes with a significant excess of DNV, of which SNAP25 and GABRB2 had previously only limited evidence for disease association. Joint analysis of all individuals with NDD also implicated CACNA1E as a novel disease gene. Comparing NDD with and without epilepsy, we found missense DNV, DNV in specific genes, age of recruitment and severity of intellectual disability to be associated with epilepsy. We further demonstrate to what extent our results impact current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDD with epilepsy. [less ▲]

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See detailApplication of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data
Allen, Andrew S.; Berkovic, Samuel F.; Bridgers, Joshua et al

in European Journal of Human Genetics (2017)

The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox–Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly ... [more ▼]

The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox–Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients with IS or LGS. The contribution of autosomal recessive genetic variation, however, is less well understood. We implemented a rare variant transmission disequilibrium test (TDT) to search for autosomal recessive epileptic encephalopathy genes in a cohort of 320 outbred patient–parent trios that were generally prescreened for rare metabolic disorders. In the current sample, our rare variant transmission disequilibrium test did not identify individual genes with significantly distorted transmission over expectation after correcting for the multiple tests. While the rare variant transmission disequilibrium test did not find evidence of a role for individual autosomal recessive genes, our current sample is insufficiently powered to assess the overall role of autosomal recessive genotypes in an outbred epileptic encephalopathy population. [less ▲]

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See detailDe Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies.
Appenzeller, Silke; Balling, Rudi UL; Barisic, Nina et al

in American Journal of Human Genetics (2017), 100(1), 179-

In the list of consortium members for the Epilepsy Phenome/Genome Project, member Dina Amrom’s name was misspelled as Amron. The authors regret the error.

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See detailThe Spectrum Of De Novo Variants In Neurodevelopmental Disorders With Epilepsy
Heyne, Henrike O.; EuroEPINOMICS RES Consortium; Abou Jamra, Rami et al

E-print/Working paper (2017)

Neurodevelopmental disorders (NDD) with epilepsy constitute a complex and heterogeneous phenotypic spectrum of largely unclear genetic architecture. We conducted exome-wide enrichment analyses for protein ... [more ▼]

Neurodevelopmental disorders (NDD) with epilepsy constitute a complex and heterogeneous phenotypic spectrum of largely unclear genetic architecture. We conducted exome-wide enrichment analyses for protein-altering de novo variants (DNV) in 7088 parent-offspring trios with NDD of which 2151 were comorbid with epilepsy. In this cohort, the genetic spectrum of epileptic encephalopathy (EE) and nonspecific NDD with epilepsy were markedly similar. We identified 33 genes significantly enriched for DNV in NDD with epilepsy, of which 27.3 were associated with therapeutic consequences. These 33 DNV-enriched genes were more often associated with synaptic transmission but less with chromatin modification when compared to NDD without epilepsy. On average, only 53 of the DNV-enriched genes were represented on available diagnostic sequencing panels, so our findings should drive significant improvements of genetic testing approaches. [less ▲]

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See detailCHD2 myoclonic encephalopathy is frequently associated with self-induced seizures
Thomas, Rhys H.; Zhang, Lin Mei; Carvill, Gemma L. et al

in Neurology (2015), 84(9), 951-958

Objective: To delineate the phenotype of early childhood epileptic encephalopathy due to de novo mutations of CHD2, which encodes the chromodomain helicase DNA binding protein 2. Methods: We analyzed the ... [more ▼]

Objective: To delineate the phenotype of early childhood epileptic encephalopathy due to de novo mutations of CHD2, which encodes the chromodomain helicase DNA binding protein 2. Methods: We analyzed the medical history, MRI, and video-EEG recordings of 9 individuals with de novo CHD2 mutations and one with a de novo 15q26 deletion encompassing CHD2. Results: Seizures began at a mean of 26 months (12–42) with myoclonic seizures in all 10 cases. Seven exhibited exquisite clinical photosensitivity; 6 self-induced with the television. Absence seizures occurred in 9 patients including typical (4), atypical (2), and absence seizures with eyelid myoclonias (4). Generalized tonic-clonic seizures occurred in 9 of 10 cases with a mean onset of 5.8 years. Convulsive and nonconvulsive status epilepticus were later features (6/10, mean onset 9 years). Tonic (40%) and atonic (30%) seizures also occurred. In 3 cases, an unusual seizure type, the atonic-myoclonic-absence was captured on video. A phenotypic spectrum was identified with 7 cases having moderate to severe intellectual disability and refractory seizures including tonic attacks. Their mean age at onset was 23 months. Three cases had a later age at onset (34 months) with relative preservation of intellect and an initial response to antiepileptic medication. Conclusion: The phenotypic spectrum of CHD2 encephalopathy has distinctive features of myoclonic epilepsy, marked clinical photosensitivity, atonic-myoclonic-absence, and intellectual disability ranging from mild to severe. Recognition of this genetic entity will permit earlier diagnosis and enable the development of targeted therapies. [less ▲]

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See detailCHD2 variants are a risk factor for photosensitivity in epilepsy
Galizia, Elizabeth C.; Myers, Candace T.; Leu, Costin et al

in Brain (2015)

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See detailInvestigation of GRIN2A in common epilepsy phenotypes.
Lal, Dennis; Steinbrucker, Sandra; Schubert, Julian et al

in Epilepsy research (2015), 115

Recently, mutations and deletions in the GRIN2A gene have been identified to predispose to benign and severe idiopathic focal epilepsies (IFE), revealing a higher incidence of GRIN2A alterations among the ... [more ▼]

Recently, mutations and deletions in the GRIN2A gene have been identified to predispose to benign and severe idiopathic focal epilepsies (IFE), revealing a higher incidence of GRIN2A alterations among the more severe phenotypes. This study aimed to explore the phenotypic boundaries of GRIN2A mutations by investigating patients with the two most common epilepsy syndromes: (i) idiopathic generalized epilepsy (IGE) and (ii) temporal lobe epilepsy (TLE). Whole exome sequencing data of 238 patients with IGE as well as Sanger sequencing of 84 patients with TLE were evaluated for GRIN2A sequence alterations. Two additional independent cohorts comprising 1469 IGE and 330 TLE patients were screened for structural deletions (>40kb) involving GRIN2A. Apart from a presumably benign, non-segregating variant in a patient with juvenile absence epilepsy, neither mutations nor deletions were detected in either cohort. These findings suggest that mutations in GRIN2A preferentially are involved in genetic variance of pediatric IFE and do not contribute significantly to either adult focal epilepsies as TLE or generalized epilepsies. [less ▲]

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See detailMutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes
Schubert, Julian; Siekierska, Aleksandra; Langlois, Melanie UL et al

in Nature Genetics (2014), 46(12), 1327-32

Febrile seizures affect 2–4% of all children1 and have a strong genetic component2. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2)3, 4, 5 have been identified that cause febrile ... [more ▼]

Febrile seizures affect 2–4% of all children1 and have a strong genetic component2. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2)3, 4, 5 have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B6, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees7, 8 identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes. [less ▲]

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See detailDe Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies
Appenzeller, Silke; Balling, Rudi UL; Barisic, Nina et al

in American Journal of Human Genetics (2014), 4

Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic ... [more ▼]

Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the “classical” epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10−4), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction. [less ▲]

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See detailDe novo mutations in HCN1 cause early infantile epileptic encephalopathy
Nava, Caroline; Dalle, Carine; Rastetter, Agnès et al

in Nature Genetics (2014)

Detailed reference viewed: 145 (16 UL)