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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 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 detailRecessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects
Marini, Carla; Hardies, Katia; Pisano, Tiziana et al

in American Journal of Medical Genetics. Part A (2017), 173(4), 1119-1123

We describe the clinical and whole genome sequencing (WGS) study of a non-consanguineous Italian family in which two siblings, a boy and a girl, manifesting a severe epileptic encephalopathy (EE) with ... [more ▼]

We describe the clinical and whole genome sequencing (WGS) study of a non-consanguineous Italian family in which two siblings, a boy and a girl, manifesting a severe epileptic encephalopathy (EE) with skeletal abnormalities, carried novel SLC35A3 compound heterozy- gous mutations. Both siblings exhibited infantile spasms, associated with focal, and tonic vibratory seizures from early infancy. EEG recordings showed a suppression-burst (SB) pattern and multifocal paroxysmal activity in both. In addition both had quadriplegia, acquired microcephaly, and severe intellectual disability. General examination showed distal arthrog- ryposis predominant in the hands in both siblings and severe left dorso-lumbar convex scoliosis in one. WGS of the siblings-parents quartet identified novel compound heterozygous mutations in SLC35A3 in both children. SLC35A3 encodes the major Golgi uridine diphosphate N-acetylglucosamine transporter. With this study, we add SLC35A3 to the gene list of epilepsies. Neurological symptoms and skeletal abnormalities might result from impaired glycosylation of proteins involved in normal development and function of the central nervous system and skeletal apparatus. [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 detailTargeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients
de Kovel, Carolien G.F.; Brilstra, Eva H.; van Kempen J.A. et al

in Molecular Genetics & Genomic Medicine (2016), 4(5), 568-80

Background Many genes are candidates for involvement in epileptic encephalopathy (EE) because one or a few possibly pathogenic variants have been found in patients, but insufficient genetic or functional ... [more ▼]

Background Many genes are candidates for involvement in epileptic encephalopathy (EE) because one or a few possibly pathogenic variants have been found in patients, but insufficient genetic or functional evidence exists for a definite annotation. Methods To increase the number of validated EE genes, we sequenced 26 known and 351 candidate genes for EE in 360 patients. Variants in 25 genes known to be involved in EE or related phenotypes were followed up in 41 patients. We prioritized the candidate genes, and followed up 31 variants in this prioritized subset of candidate genes. Results Twenty-nine genotypes in known genes for EE (19) or related diseases (10), dominant as well as recessive or X-linked, were classified as likely pathogenic variants. Among those, likely pathogenic de novo variants were found in EE genes that act dominantly, including the recently identified genes EEF1A2, KCNB1 and the X-linked gene IQSEC2. A de novo frameshift variant in candidate gene HNRNPU was the only de novo variant found among the followed-up candidate genes, and the patient's phenotype was similar to a few recent publications. Conclusion Mutations in genes described in OMIM as, for example, intellectual disability gene can lead to phenotypes that get classified as EE in the clinic. We confirmed existing literature reports that de novo loss-of-function HNRNPUmutations lead to severe developmental delay and febrile seizures in the first year of life. [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 detailThe phenotypic spectrum of SCN8A encephalopathy
Larsen, Jan; Carvill, Gemma L.; Gardella, Elena et al

in Neurology (2015), 84(5), 480-489

Objective: SCN8A encodes the sodium channel voltage-gated α8-subunit (Nav1.6). SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. We aimed to delineate the ... [more ▼]

Objective: SCN8A encodes the sodium channel voltage-gated α8-subunit (Nav1.6). SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. We aimed to delineate the phenotype associated with SCN8A mutations. Methods: We used high-throughput sequence analysis of the SCN8A gene in 683 patients with a range of epileptic encephalopathies. In addition, we ascertained cases with SCN8A mutations from other centers. A detailed clinical history was obtained together with a review of EEG and imaging data. Results: Seventeen patients with de novo heterozygous mutations of SCN8A were studied. Seizure onset occurred at a mean age of 5 months (range: 1 day to 18 months); in general, seizures were not triggered by fever. Fifteen of 17 patients had multiple seizure types including focal, tonic, clonic, myoclonic and absence seizures, and epileptic spasms; seizures were refractory to antiepileptic therapy. Development was normal in 12 patients and slowed after seizure onset, often with regression; 5 patients had delayed development from birth. All patients developed intellectual disability, ranging from mild to severe. Motor manifestations were prominent including hypotonia, dystonia, hyperreflexia, and ataxia. EEG findings comprised moderate to severe background slowing with focal or multifocal epileptiform discharges. Conclusion: SCN8A encephalopathy presents in infancy with multiple seizure types including focal seizures and spasms in some cases. Outcome is often poor and includes hypotonia and movement disorders. The majority of mutations arise de novo, although we observed a single case of somatic mosaicism in an unaffected parent. [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)