Author: "Nava, C." / Topic: epilepsy - Searchworks@Jio Institute Digital Library Search Results

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1. Patients with KCNH1 -related intellectual disability without distinctive features of Zimmermann-Laband/Temple-Baraitser syndrome.

Author: Aubert Mucca M, Patat O, Whalen S, Arnaud L, Barcia G, Buratti J, Cogné B, Doummar D, Karsenty C, Kenis S, Leguern E, Lesca G, Nava C, Nizon M, Piton A, Valence S, Villard L, Weckhuysen S, Keren B, and Mignot C
Subjects: Abnormalities, Multiple, Craniofacial Abnormalities, Ether-A-Go-Go Potassium Channels chemistry, Ether-A-Go-Go Potassium Channels genetics, Fibromatosis, Gingival, Hallux abnormalities, Hand Deformities, Congenital, Humans, Nails, Malformed, Phenotype, Thumb abnormalities, Epilepsy diagnosis, Epilepsy genetics, Intellectual Disability diagnosis, Intellectual Disability genetics, Intellectual Disability pathology
Abstract: De novo missense variants in KCNH1 encoding Kv10.1 are responsible for two clinically recognisable phenotypes: Temple-Baraitser syndrome (TBS) and Zimmermann-Laband syndrome (ZLS). The clinical overlap between these two syndromes suggests that they belong to a spectrum of KCNH1 -related encephalopathies. Affected patients have severe intellectual disability (ID) with or without epilepsy, hypertrichosis and distinctive features such as gingival hyperplasia and nail hypoplasia/aplasia (present in 20/23 reported cases).We report a series of seven patients with ID and de novo pathogenic KCNH1 variants identified by whole-exome sequencing or an epilepsy gene panel in whom the diagnosis of TBS/ZLS had not been first considered. Four of these variants, p.(Thr294Met), p.(Ala492Asp), p.(Thr493Asn) and p.(Gly496Arg), were located in the transmembrane domains S3 and S6 of Kv10.1 and one, p.(Arg693Gln), in its C-terminal cyclic nucleotide-binding homology domain (CNBHD). Clinical reappraisal by the referring clinical geneticists confirmed the absence of the distinctive gingival and nail features of TBS/ZLS.Our study expands the phenotypical spectrum of KCNH1 -related encephalopathies to individuals with an attenuated extraneurological phenotype preventing a clinical diagnosis of TBS or ZLS. This subtype may be related to recurrent substitutions of the Gly496, suggesting a genotype-phenotype correlation and, possibly, to variants in the CNBHD domain., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2022
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2. The EPIGENE network: A French initiative to harmonize and improve the nationwide diagnosis of monogenic epilepsies.

Author: Arnaud L, Abi Warde MT, Barcia G, de Bellescize J, Chatron N, Faoucher M, de Saint Martin A, Héron D, Jedraszak G, Lacoste C, Lèbre AS, Jenneson-Lyver M, Labalme A, Leguern E, Mignot C, Milh M, Nabbout R, Nava C, Panagiotakaki E, Piton A, Schaefer E, Thevenon J, Villard L, Ville D, and Lesca G
Subjects: Cadherins genetics, Child, France, Genetic Testing methods, High-Throughput Nucleotide Sequencing, Humans, Mutation, Nerve Tissue Proteins genetics, Potassium Channels, Sodium-Activated, Protocadherins, Epilepsy diagnosis, Epilepsy genetics, Genetic Predisposition to Disease
Abstract: Background: The EPIGENE network was created in 2014 by four multidisciplinary teams composed of geneticists, pediatric neurologists and neurologists specialized in epileptology and neurophysiology. The ambition of the network was to harmonize and improve the diagnostic strategy of Mendelian epileptic disorders using next-generation sequencing, in France. Over the years, five additional centers have joined EPIGENE and the network has been working in close collaboration, since 2018, with the French reference center for rare epilepsies (CRéER)., Results: Since 2014, biannual meetings have led to the design of four successive versions of a monogenic epilepsy gene panel (PAGEM), increasing from 68 to 144 genes. A total of 4035 index cases with epileptic disorders have been analyzed with a diagnostic yield of 31% (n = 1265/4035). The top 10 genes, SCN1A, KCNQ2, STXBP1, SCN2A, SCN8A, PRRT2, PCDH19, KCNT1, SYNGAP1, and GRIN2A, account for one-sixth of patients and half of the diagnoses provided by the PAGEM., Conclusion: These results suggest that a gene-panel approach is an efficient first-tier test for the genetic diagnosis of Mendelian epileptic disorders. In a near future, French patients with "drug-resistant epilepsies with seizure-onset in the first two-years of life" can benefit from whole-genome sequencing (WGS), as a second line genetic screening with the implementation of the 2025 French Genomic Medicine Plan. The EPIGENE network has also promoted scientific collaborations on genetic epilepsies within CRéER., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
Published: 2022
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3. GM3 synthase deficiency in non-Amish patients.

Author: Heide S, Jacquemont ML, Cheillan D, Renouil M, Tallot M, Schwartz CE, Miquel J, Bintner M, Rodriguez D, Darcel F, Buratti J, Haye D, Passemard S, Gras D, Perrin L, Capri Y, Gérard B, Piton A, Keren B, Thauvin-Robinet C, Duffourd Y, Faivre L, Poe C, Pervillé A, Héron D, Thévenon J, Arnaud L, LeGuern E, La Selva L, Vetro A, Guerrini R, Nava C, and Mignot C
Subjects: Homozygote, Humans, Sialyltransferases deficiency, Sialyltransferases genetics, Epilepsy complications, Epilepsy genetics
Abstract: Purpose: Biallelic loss-of-function variants in ST3GAL5 cause GM3 synthase deficiency (GM3SD) responsible for Amish infantile epilepsy syndrome. All Amish patients carry the homozygous p.(Arg288Ter) variant arising from a founder effect. To date only 10 patients from 4 non-Amish families have been reported. Thus, the phenotypical spectrum of GM3SD due to other variants and other genetic backgrounds is still poorly known., Methods: We collected clinical and molecular data from 16 non-Amish patients with pathogenic ST3GAL5 variants resulting in GM3SD., Results: We identified 12 families originating from Reunion Island, Ivory Coast, Italy, and Algeria and carrying 6 ST3GAL5 variants, 5 of which were novel. Genealogical investigations and/or haplotype analyses showed that 3 of these variants were founder alleles. Glycosphingolipids quantification in patients' plasma confirmed the pathogenicity of 4 novel variants. All patients (N = 16), aged 2 to 12 years, had severe to profound intellectual disability, 14 of 16 had a hyperkinetic movement disorder, 11 of 16 had epilepsy and 9 of 16 had microcephaly. Other main features were progressive skin pigmentation anomalies, optic atrophy or pale papillae, and hearing loss., Conclusion: The phenotype of non-Amish patients with GM3SD is similar to the Amish infantile epilepsy syndrome, which suggests that GM3SD is associated with a narrow and severe clinical spectrum., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Published: 2022
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4. KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum.

Author: Bonardi CM, Heyne HO, Fiannacca M, Fitzgerald MP, Gardella E, Gunning B, Olofsson K, Lesca G, Verbeek N, Stamberger H, Striano P, Zara F, Mancardi MM, Nava C, Syrbe S, Buono S, Baulac S, Coppola A, Weckhuysen S, Schoonjans AS, Ceulemans B, Sarret C, Baumgartner T, Muhle H, Portes VD, Toulouse J, Nougues MC, Rossi M, Demarquay G, Ville D, Hirsch E, Maurey H, Willems M, de Bellescize J, Altuzarra CD, Villeneuve N, Bartolomei F, Picard F, Hornemann F, Koolen DA, Kroes HY, Reale C, Fenger CD, Tan WH, Dibbens L, Bearden DR, Møller RS, and Rubboli G
Subjects: Adolescent, Child, Child, Preschool, Cohort Studies, Female, Genotype, Humans, Infant, Male, Mutation, Phenotype, Young Adult, Epilepsy genetics, Nerve Tissue Proteins genetics, Potassium Channels, Sodium-Activated genetics
Abstract: Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in ∼50% of the patients, sudden unexplained death in epilepsy in one individual; and (iv) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the autosomal dominant or sporadic sleep-related hypermotor epilepsy-associated mutations to be clustered around the RCK2 domain in the C terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS developmental and epileptic encephalopathies did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset developmental and epileptic encephalopathies as well as of focal epilepsies, namely autosomal dominant or sporadic sleep-related hypermotor epilepsy., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Published: 2021
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5. Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy.

Author: Voisin N, Schnur RE, Douzgou S, Hiatt SM, Rustad CF, Brown NJ, Earl DL, Keren B, Levchenko O, Geuer S, Verheyen S, Johnson D, Zarate YA, Hančárová M, Amor DJ, Bebin EM, Blatterer J, Brusco A, Cappuccio G, Charrow J, Chatron N, Cooper GM, Courtin T, Dadali E, Delafontaine J, Del Giudice E, Doco M, Douglas G, Eisenkölbl A, Funari T, Giannuzzi G, Gruber-Sedlmayr U, Guex N, Heron D, Holla ØL, Hurst ACE, Juusola J, Kronn D, Lavrov A, Lee C, Lorrain S, Merckoll E, Mikhaleva A, Norman J, Pradervand S, Prchalová D, Rhodes L, Sanders VR, Sedláček Z, Seebacher HA, Sellars EA, Sirchia F, Takenouchi T, Tanaka AJ, Taska-Tench H, Tønne E, Tveten K, Vitiello G, Vlčková M, Uehara T, Nava C, Yalcin B, Kosaki K, Donnai D, Mundlos S, Brunetti-Pierri N, Chung WK, and Reymond A
Subjects: Adolescent, Amino Acid Sequence, Animals, Brain Diseases etiology, Child, Child, Preschool, Epilepsy complications, Evolution, Molecular, Female, Gene Frequency, Humans, Infant, Male, Mice, Models, Molecular, Nuclear Proteins chemistry, Nuclear Proteins deficiency, Phenotype, Protein Stability, Syndrome, Transcriptional Elongation Factors chemistry, Transcriptional Elongation Factors genetics, Young Adult, Zebrafish genetics, Brain Diseases genetics, Epilepsy genetics, Fused Kidney genetics, Intellectual Disability genetics, Mutation, Missense, Nuclear Proteins genetics, Osteochondrodysplasias genetics
Abstract: The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Published: 2021
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6. De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy.

Author: Klöckner C, Sticht H, Zacher P, Popp B, Babcock HE, Bakker DP, Barwick K, Bonfert MV, Bönnemann CG, Brilstra EH, Chung WK, Clarke AJ, Devine P, Donkervoort S, Fraser JL, Friedman J, Gates A, Ghoumid J, Hobson E, Horvath G, Keller-Ramey J, Keren B, Kurian MA, Lee V, Leppig KA, Lundgren J, McDonald MT, McLaughlin HM, McTague A, Mefford HC, Mignot C, Mikati MA, Nava C, Raymond FL, Sampson JR, Sanchis-Juan A, Shashi V, Shieh JTC, Shinawi M, Slavotinek A, Stödberg T, Stong N, Sullivan JA, Taylor AC, Toler TL, van den Boogaard MJ, van der Crabben SN, van Gassen KLI, van Jaarsveld RH, Van Ziffle J, Wadley AF, Wagner M, Wigby K, Wortmann SB, Zarate YA, Møller RS, Lemke JR, and Platzer K
Subjects: Child, Preschool, Humans, Phenotype, Brain Diseases, Epilepsy genetics, Intellectual Disability, Neurodevelopmental Disorders genetics, Synaptosomal-Associated Protein 25 genetics
Abstract: Purpose: This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals., Methods: Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed., Results: The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex., Conclusion: We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed "SNAREopathies."
Published: 2021
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7. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

Author: O'Donnell-Luria AH, Pais LS, Faundes V, Wood JC, Sveden A, Luria V, Abou Jamra R, Accogli A, Amburgey K, Anderlid BM, Azzarello-Burri S, Basinger AA, Bianchini C, Bird LM, Buchert R, Carre W, Ceulemans S, Charles P, Cox H, Culliton L, Currò A, Demurger F, Dowling JJ, Duban-Bedu B, Dubourg C, Eiset SE, Escobar LF, Ferrarini A, Haack TB, Hashim M, Heide S, Helbig KL, Helbig I, Heredia R, Héron D, Isidor B, Jonasson AR, Joset P, Keren B, Kok F, Kroes HY, Lavillaureix A, Lu X, Maas SM, Maegawa GHB, Marcelis CLM, Mark PR, Masruha MR, McLaughlin HM, McWalter K, Melchinger EU, Mercimek-Andrews S, Nava C, Pendziwiat M, Person R, Ramelli GP, Ramos LLP, Rauch A, Reavey C, Renieri A, Rieß A, Sanchez-Valle A, Sattar S, Saunders C, Schwarz N, Smol T, Srour M, Steindl K, Syrbe S, Taylor JC, Telegrafi A, Thiffault I, Trauner DA, van der Linden H Jr, van Koningsbruggen S, Villard L, Vogel I, Vogt J, Weber YG, Wentzensen IM, Widjaja E, Zak J, Baxter S, Banka S, and Rodan LH
Subjects: Adolescent, Adult, Child, Child, Preschool, Epilepsy pathology, Female, Haploinsufficiency, Humans, Infant, Male, Neurodevelopmental Disorders pathology, Pedigree, Phenotype, Young Adult, DNA-Binding Proteins genetics, Epilepsy etiology, Genetic Variation, Heterozygote, Neurodevelopmental Disorders etiology
Abstract: We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Published: 2019
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8. Novel GABRA2 variants in epileptic encephalopathy and intellectual disability with seizures.

Author: Maljevic S, Keren B, Aung YH, Forster IC, Mignot C, Buratti J, Lafitte A, Freihuber C, Rodan LH, Bergin A, Hubert L, Poirier K, Munnich A, Besmond C, Hauser N, Miller R, McWalter K, Nabbout R, Héron D, Leguern E, Depienne C, Petrou S, and Nava C
Subjects: Humans, Receptors, GABA-A, Seizures, Epilepsy, Epilepsy, Generalized, Intellectual Disability
Published: 2019
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9. De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy.

Author: Tran Mau-Them F, Guibaud L, Duplomb L, Keren B, Lindstrom K, Marey I, Mochel F, van den Boogaard MJ, Oegema R, Nava C, Masurel A, Jouan T, Jansen FE, Au M, Chen AH, Cho M, Duffourd Y, Lozier E, Konovalov F, Sharkov A, Korostelev S, Urteaga B, Dickson P, Vera M, Martínez-Agosto JA, Begemann A, Zweier M, Schmitt-Mechelke T, Rauch A, Philippe C, van Gassen K, Nelson S, Graham JM Jr, Friedman J, Faivre L, Lin HJ, Thauvin-Robinet C, and Vitobello A
Subjects: Adolescent, Adult, Central Nervous System diagnostic imaging, Central Nervous System pathology, Child, Electroencephalography, Epilepsy diagnostic imaging, Epilepsy physiopathology, Female, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Mutation, Neurodevelopmental Disorders diagnostic imaging, Neurodevelopmental Disorders physiopathology, Phenotype, Seizures diagnostic imaging, Seizures physiopathology, Exome Sequencing, Young Adult, Carrier Proteins genetics, Epilepsy genetics, Neurodevelopmental Disorders genetics, Nuclear Proteins genetics, Seizures genetics
Abstract: Purpose: Developmental and epileptic encephalopathies (DEEs) are severe clinical conditions characterized by stagnation or decline of cognitive and behavioral abilities preceded, accompanied or followed by seizures. Because DEEs are clinically and genetically heterogeneous, next-generation sequencing, especially exome sequencing (ES), is becoming a first-tier strategy to identify the molecular etiologies of these disorders., Methods: We combined ES analysis and international data sharing., Results: We identified 11 unrelated individuals with DEE and de novo heterozygous truncating variants in the interferon regulatory factor 2-binding protein-like gene (IRF2BPL). The 11 individuals allowed for delineation of a consistent neurodevelopmental disorder characterized by mostly normal initial psychomotor development followed by severe global neurological regression and epilepsy with nonspecific electroencephalogram (EEG) abnormalities and variable central nervous system (CNS) anomalies. IRF2BPL, also known as enhanced at puberty protein 1 (EAP1), encodes a transcriptional regulator containing a C-terminal RING-finger domain common to E3 ubiquitin ligases. This domain is required for its repressive and transactivating transcriptional properties. The variants identified are expected to encode a protein lacking the C-terminal RING-finger domain., Conclusions: These data support the causative role of truncating IRF2BPL variants in pediatric neurodegeneration and expand the spectrum of transcriptional regulators identified as molecular factors implicated in genetic developmental and epileptic encephalopathies.
Published: 2019
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10. The landscape of epilepsy-related GATOR1 variants.

Author: Baldassari S, Picard F, Verbeek NE, van Kempen M, Brilstra EH, Lesca G, Conti V, Guerrini R, Bisulli F, Licchetta L, Pippucci T, Tinuper P, Hirsch E, de Saint Martin A, Chelly J, Rudolf G, Chipaux M, Ferrand-Sorbets S, Dorfmüller G, Sisodiya S, Balestrini S, Schoeler N, Hernandez-Hernandez L, Krithika S, Oegema R, Hagebeuk E, Gunning B, Deckers C, Berghuis B, Wegner I, Niks E, Jansen FE, Braun K, de Jong D, Rubboli G, Talvik I, Sander V, Uldall P, Jacquemont ML, Nava C, Leguern E, Julia S, Gambardella A, d'Orsi G, Crichiutti G, Faivre L, Darmency V, Benova B, Krsek P, Biraben A, Lebre AS, Jennesson M, Sattar S, Marchal C, Nordli DR Jr, Lindstrom K, Striano P, Lomax LB, Kiss C, Bartolomei F, Lepine AF, Schoonjans AS, Stouffs K, Jansen A, Panagiotakaki E, Ricard-Mousnier B, Thevenon J, de Bellescize J, Catenoix H, Dorn T, Zenker M, Müller-Schlüter K, Brandt C, Krey I, Polster T, Wolff M, Balci M, Rostasy K, Achaz G, Zacher P, Becher T, Cloppenborg T, Yuskaitis CJ, Weckhuysen S, Poduri A, Lemke JR, Møller RS, and Baulac S
Subjects: Adolescent, Brugada Syndrome genetics, Brugada Syndrome mortality, Brugada Syndrome physiopathology, Child, Child, Preschool, DNA Copy Number Variations genetics, Epilepsy complications, Epilepsy epidemiology, Epilepsy physiopathology, Female, Genetic Predisposition to Disease, Humans, INDEL Mutation genetics, Infant, Infant, Newborn, Loss of Function Mutation genetics, Male, Mechanistic Target of Rapamycin Complex 1 genetics, Multiprotein Complexes genetics, Pedigree, Seizures complications, Seizures epidemiology, Seizures genetics, Seizures physiopathology, Signal Transduction genetics, Epilepsy genetics, GTPase-Activating Proteins genetics, Repressor Proteins genetics, Tumor Suppressor Proteins genetics
Abstract: Purpose: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants., Results: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign., Conclusion: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.
Published: 2019
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11. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.

Author: Helbig KL, Lauerer RJ, Bahr JC, Souza IA, Myers CT, Uysal B, Schwarz N, Gandini MA, Huang S, Keren B, Mignot C, Afenjar A, Billette de Villemeur T, Héron D, Nava C, Valence S, Buratti J, Fagerberg CR, Soerensen KP, Kibaek M, Kamsteeg EJ, Koolen DA, Gunning B, Schelhaas HJ, Kruer MC, Fox J, Bakhtiari S, Jarrar R, Padilla-Lopez S, Lindstrom K, Jin SC, Zeng X, Bilguvar K, Papavasileiou A, Xing Q, Zhu C, Boysen K, Vairo F, Lanpher BC, Klee EW, Tillema JM, Payne ET, Cousin MA, Kruisselbrink TM, Wick MJ, Baker J, Haan E, Smith N, Sadeghpour A, Davis EE, Katsanis N, Corbett MA, MacLennan AH, Gecz J, Biskup S, Goldmann E, Rodan LH, Kichula E, Segal E, Jackson KE, Asamoah A, Dimmock D, McCarrier J, Botto LD, Filloux F, Tvrdik T, Cascino GD, Klingerman S, Neumann C, Wang R, Jacobsen JC, Nolan MA, Snell RG, Lehnert K, Sadleir LG, Anderlid BM, Kvarnung M, Guerrini R, Friez MJ, Lyons MJ, Leonhard J, Kringlen G, Casas K, El Achkar CM, Smith LA, Rotenberg A, Poduri A, Sanchis-Juan A, Carss KJ, Rankin J, Zeman A, Raymond FL, Blyth M, Kerr B, Ruiz K, Urquhart J, Hughes I, Banka S, Hedrich UBS, Scheffer IE, Helbig I, Zamponi GW, Lerche H, and Mefford HC
Subjects: Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Male, Neurodevelopmental Disorders genetics, Calcium Channels, R-Type genetics, Cation Transport Proteins genetics, Contracture genetics, Dyskinesias genetics, Epilepsy genetics, Genetic Variation genetics, Megalencephaly genetics, Spasms, Infantile genetics
Abstract: Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α 1 -subunit of the voltage-gated Ca V 2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed Ca V 2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Published: 2018
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12. Early-onset encephalopathy with paroxysmal movement disorders and epileptic seizures without hemiplegic attacks: About three children with novel ATP1A3 mutations.

Author: Marzin P, Mignot C, Dorison N, Dufour L, Ville D, Kaminska A, Panagiotakaki E, Dienpendaele AS, Penniello MJ, Nougues MC, Keren B, Depienne C, Nava C, Milh M, Villard L, Richelme C, Rivier C, Whalen S, Heron D, Lesca G, and Doummar D
Subjects: Adolescent, Brain physiopathology, Child, Child, Preschool, Epilepsy diagnosis, Epilepsy physiopathology, Female, Hemiplegia genetics, Hemiplegia physiopathology, Humans, Male, Movement Disorders diagnosis, Movement Disorders physiopathology, Seizures diagnosis, Seizures physiopathology, Epilepsy genetics, Movement Disorders genetics, Mutation, Seizures genetics, Sodium-Potassium-Exchanging ATPase genetics
Abstract: Objective: Heterozygous mutations in the ATP1A3 gene are responsible for various neurological disorders, ranging from early-onset alternating hemiplegia of childhood to adult-onset dystonia-parkinsonism. Next generation sequencing allowed the description of other phenotypes, including early-onset epileptic encephalopathy in two patients. We report on three more patients carrying ATP1A3 mutations with a close phenotype and discuss the relationship of this phenotype to alternating hemiplegia of childhood., Methods: The patients' DNA underwent next generation sequencing. A retrospective analysis of clinical case records is reported., Results: Each of the three patients had an unreported heterozygous de novo sequence variant in ATP1A3. These patients shared a similar phenotype characterized by early-onset attacks of movement disorders, some of which proved to be epileptic, and severe developmental delay. (Hemi)plegic attacks had not been considered before genetic testing., Significance: Together with the two previously reported cases, our patients confirm that ATP1A3 mutations are associated with a phenotype combining features of early-onset encephalopathy, epilepsy and dystonic fits, as in the most severe forms of alternating hemiplegia of childhood, but in which (hemi)plegic attacks are absent or only suspected retrospectively., (Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)
Published: 2018
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13. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.

Author: Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, Laporte AD, Nassif C, Diallo O, Monlong J, Cadieux-Dion M, Dobrzeniecka S, Meloche C, Retterer K, Cho MT, Rosenfeld JA, Bi W, Massicotte C, Miguet M, Brunga L, Regan BM, Mo K, Tam C, Schneider A, Hollingsworth G, FitzPatrick DR, Donaldson A, Canham N, Blair E, Kerr B, Fry AE, Thomas RH, Shelagh J, Hurst JA, Brittain H, Blyth M, Lebel RR, Gerkes EH, Davis-Keppen L, Stein Q, Chung WK, Dorison SJ, Benke PJ, Fassi E, Corsten-Janssen N, Kamsteeg EJ, Mau-Them FT, Bruel AL, Verloes A, Õunap K, Wojcik MH, Albert DVF, Venkateswaran S, Ware T, Jones D, Liu YC, Mohammad SS, Bizargity P, Bacino CA, Leuzzi V, Martinelli S, Dallapiccola B, Tartaglia M, Blumkin L, Wierenga KJ, Purcarin G, O'Byrne JJ, Stockler S, Lehman A, Keren B, Nougues MC, Mignot C, Auvin S, Nava C, Hiatt SM, Bebin M, Shao Y, Scaglia F, Lalani SR, Frye RE, Jarjour IT, Jacques S, Boucher RM, Riou E, Srour M, Carmant L, Lortie A, Major P, Diadori P, Dubeau F, D'Anjou G, Bourque G, Berkovic SF, Sadleir LG, Campeau PM, Kibar Z, Lafrenière RG, Girard SL, Mercimek-Mahmutoglu S, Boelman C, Rouleau GA, Scheffer IE, Mefford HC, Andrade DM, Rossignol E, Minassian BA, and Michaud JL
Subjects: Child, Child, Preschool, Female, Genome, Human genetics, Genome-Wide Association Study methods, Humans, Intellectual Disability genetics, Male, Recurrence, Seizures genetics, Brain Diseases genetics, Epilepsy genetics, Mutation genetics
Abstract: Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Published: 2017
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14. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.

Author: Wolff M, Johannesen KM, Hedrich UBS, Masnada S, Rubboli G, Gardella E, Lesca G, Ville D, Milh M, Villard L, Afenjar A, Chantot-Bastaraud S, Mignot C, Lardennois C, Nava C, Schwarz N, Gérard M, Perrin L, Doummar D, Auvin S, Miranda MJ, Hempel M, Brilstra E, Knoers N, Verbeek N, van Kempen M, Braun KP, Mancini G, Biskup S, Hörtnagel K, Döcker M, Bast T, Loddenkemper T, Wong-Kisiel L, Baumeister FM, Fazeli W, Striano P, Dilena R, Fontana E, Zara F, Kurlemann G, Klepper J, Thoene JG, Arndt DH, Deconinck N, Schmitt-Mechelke T, Maier O, Muhle H, Wical B, Finetti C, Brückner R, Pietz J, Golla G, Jillella D, Linnet KM, Charles P, Moog U, Õiglane-Shlik E, Mantovani JF, Park K, Deprez M, Lederer D, Mary S, Scalais E, Selim L, Van Coster R, Lagae L, Nikanorova M, Hjalgrim H, Korenke GC, Trivisano M, Specchio N, Ceulemans B, Dorn T, Helbig KL, Hardies K, Stamberger H, de Jonghe P, Weckhuysen S, Lemke JR, Krägeloh-Mann I, Helbig I, Kluger G, Lerche H, and Møller RS
Subjects: Adolescent, Adult, Age of Onset, Child, Child, Preschool, Denmark epidemiology, Epilepsy epidemiology, Female, Humans, Infant, Male, Mutation, Phenotype, Young Adult, Epilepsy drug therapy, Epilepsy genetics, Epilepsy physiopathology, NAV1.2 Voltage-Gated Sodium Channel genetics, NAV1.2 Voltage-Gated Sodium Channel physiology, Neurodevelopmental Disorders genetics, Sodium Channel Blockers therapeutic use
Abstract: Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Published: 2017
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15. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Author: Florian R. T., Kraft F., Leitao E., Kaya S., Klebe S., Magnin E., van Rootselaar A. -F., Buratti J., Kuhnel T., Schroder C., Giesselmann S., Tschernoster N., Altmueller J., Lamiral A., Keren B., Nava C., Bouteiller D., Forlani S., Jornea L., Kubica R., Ye T., Plassard D., Jost B., Meyer V., Deleuze J. -F., Delpu Y., Avarello M. D. M., Vijfhuizen L. S., Rudolf G., Hirsch E., Kroes T., Reif P. S., Rosenow F., Ganos C., Vidailhet M., Thivard L., Mathieu A., Bourgeron T., Kurth I., Rafehi H., Steenpass L., Horsthemke B., Berkovic S. F., Bisulli F., Brancati F., Canafoglia L., Casari G., Guerrini R., Ishiura H., Licchetta L., Mei D., Pippucci T., Sadleir L., Scheffer I. E., Striano P., Tinuper P., Tsuji S., Zara F., LeGuern E., Klein K. M., Labauge P., Bennett M. F., Bahlo M., Gecz J., Corbett M. A., Tijssen M. A. J., van den Maagdenberg A. M. J. M., Depienne C., Florian, R. T., Kraft, F., Leitao, E., Kaya, S., Klebe, S., Magnin, E., van Rootselaar, A. -F., Buratti, J., Kuhnel, T., Schroder, C., Giesselmann, S., Tschernoster, N., Altmueller, J., Lamiral, A., Keren, B., Nava, C., Bouteiller, D., Forlani, S., Jornea, L., Kubica, R., Ye, T., Plassard, D., Jost, B., Meyer, V., Deleuze, J. -F., Delpu, Y., Avarello, M. D. M., Vijfhuizen, L. S., Rudolf, G., Hirsch, E., Kroes, T., Reif, P. S., Rosenow, F., Ganos, C., Vidailhet, M., Thivard, L., Mathieu, A., Bourgeron, T., Kurth, I., Rafehi, H., Steenpass, L., Horsthemke, B., Berkovic, S. F., Bisulli, F., Brancati, F., Canafoglia, L., Casari, G., Guerrini, R., Ishiura, H., Licchetta, L., Mei, D., Pippucci, T., Sadleir, L., Scheffer, I. E., Striano, P., Tinuper, P., Tsuji, S., Zara, F., Leguern, E., Klein, K. M., Labauge, P., Bennett, M. F., Bahlo, M., Gecz, J., Corbett, M. A., Tijssen, M. A. J., van den Maagdenberg, A. M. J. M., Depienne, C., Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Amsterdam Neuroscience [Pays-Bas], Vrije Universiteit Amsterdam [Amsterdam] (VU)-University of Amsterdam [Amsterdam] (UvA)-VU University Medical Center [Amsterdam], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre for Molecular Medicine Cologne [Cologne] (CMMC), University Hospital of Cologne [Cologne], Cologne Center for Genomics [Cologne] (CCG), University of Cologne, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), genomic vision, Leiden University Medical Center (LUMC), Universiteit Leiden, Centre de référence des épilepsies rares [CHRU Strasbourg] (CRéER), Centre Hospitalier Régional Universitaire de Strasbourg (CHRU de Strasbourg), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, School of Biological Sciences [Adelaïde], University of Adelaide, Goethe-University Frankfurt am Main, Philipps Universität Marburg = Philipps University of Marburg, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne, Epilepsy Research Centre, University of Calgary, Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), South Australian Health and Medical Research Institute [ Adelaide] (SAHMRI), University Medical Center Groningen [Groningen] (UMCG), This study has been financially supported by three different grants from the Fondation Maladies rares to C.D. (2009, 2010, 2016), Assistance Publique des Hôpitaux de Paris (APHP), INSERM, the 'Investissements d’Avenir' programme ANR-10-IAIHU-06 (IHU-A-ICM), University Duisburg-Essen and University Hospital Essen. M.B. was supported by an Australian National Health and Medical Research Council (NHMRC) Program Grant (GNT1054618) and an NHMRC Senior Research Fellowship (GNT1102971). This work was also supported by the Victorian Government’s Operational Infrastructure Support Program and the NHMRC Independent Research Institute Infrastructure Support Scheme (IRIISS). Laura Canafoglia: Member of the European Reference Network on Rare and Complex epilepsies, ERN EpiCARE., We thank the families for their participation in this study, Agnès Rastetter (ICM, Paris, France) for RNA extraction, and Emmanuelle Apartis (Hôpital Saint-Antoine, Paris, France) for electrophysiological assessment of Family 1. DNA extraction and cell culture of lymphoblasts have been performed at the DNA and cell bank of ICM (Paris, France). RNA-seq has been performed on the GenomEast platform of IGBMC, Illkirch, France. WGS has been performed by the Centre National de Recherche en Génomique Humaine (CNRGH) Institut de Biologie François Jacob, Evry, France. We thank Jean-Louis Mandel and Nicolas Charlet-Berguerand (IGBMC, Strasbourg, France), Cécile Cazeneuve (Hôpital Pitié-Salpêtrière, Paris, France), Charles Marcaillou (Integragen, Evry, France) and Isabel Silveira (Porto, Portugal) for valuable discussions., FAME consortium : Berkovic SF, Bisulli F, Brancati F, Canafoglia L, Casari G, Guerrini R, Ishiura H, Licchetta L, Mei D, Pippucci T, Sadleir L, Scheffer IE, Striano P, Tinuper P, Tsuji S, Zara F., Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de Recherche en Génomique Humaine (CNRGH), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), RWTH Aachen University, Universität Duisburg-Essen [Essen], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Philipps University of Marburg, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Rahel T. Florian, Florian Kraft, Elsa Leitão, Sabine Kaya, Stephan Klebe, Eloi Magnin, Anne-Fleur van Rootselaar, Julien Buratti, Theresa Kühnel, Christopher Schröder, Sebastian Giesselmann, Nikolai Tschernoster, Janine Altmueller, Anaide Lamiral, Boris Keren, Caroline Nava, Delphine Bouteiller, Sylvie Forlani, Ludmila Jornea, Regina Kubica, Tao Ye, Damien Plassard, Bernard Jost, Vincent Meyer, Jean-François Deleuze, Yannick Delpu, Mario D.M. Avarello, Lisanne S. Vijfhuizen, Gabrielle Rudolf, Edouard Hirsch, Thessa Kroes, Philipp S. Reif, Felix Rosenow, Christos Ganos, Marie Vidailhet, Lionel Thivard, Alexandre Mathieu, Thomas Bourgeron, Ingo Kurth, Haloom Rafehi, Laura Steenpass, Bernhard Horsthemke, FAME consortium, Eric LeGuern, Karl Martin Klein, Pierre Labauge, Mark F. Bennett, Melanie Bahlo, Jozef Gecz, Mark A. Corbett, Marina A.J. Tijssen, Arn M.J.M. van den Maagdenberg, Christel Depienne, Francesca Bisulli, Laura Licchetta, Paolo Tinuper, MATHIEU, Alexandre, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: Male, MESH: Introns, [SDV]Life Sciences [q-bio], Medizin, MESH: DNA Repeat Expansion, Epilepsies, Myoclonic, [SDV.GEN] Life Sciences [q-bio]/Genetics, MARCH6, expansion, MESH: Ubiquitin-Protein Ligases/genetics, MESH: Aged, MESH: Middle Aged, DNA Repeat Expansion, Neurodegenerative diseases, MESH: Epilepsies, Myoclonic, Chromosome Mapping, Middle Aged, MESH: Epilepsies, Myoclonic/genetics, Pedigree, MESH: Young Adult, Female, ddc:500, MESH: Membrane Proteins, Technology Platforms, Genomic instability, Adult, Adolescent, MESH: Pedigree, Ubiquitin-Protein Ligases, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Familial Adult Myoclonic Epilepsy type 3, Article, Young Adult, Humans, Aged, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Epilepsy, Membrane Proteins, MESH: Adult, MESH: Membrane Proteins/genetics, MESH: Ubiquitin-Protein Ligases, MESH: Male, Introns, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Chromosome Mapping, MESH: Female, Neurological disorders
Abstract: Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements., Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.
Published: 2019

16. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy

Author: Mignot, C., von Stulpnage, C., Nava, C., Ville, D., Sanlaville, D., Lesca, G., Rastetter, A., Gachet, B., Marie, Y., Korenke, G. C., Borggraefe, I., Hoffmann-Zacharska, D., Szczepanik, E., Rudzka-Dybala, M., Uluc, Yis, Caglayan, H., Isapof, A., Marey, I., Panagiotakaki, E., Korff, C., Rossier, E., Riess, A., Beck-Woedl, S., Rauch, A., Zweier, C., Hoyer, J., Reis, A., Mironov, M., Bobylova, M., Mukhin, K., Hernandez-Hernandez, L., Maher, B., Sisodiya, S., Kuhn, M., Glaeser, D., Wechuysen, S., Myers, C. T., Mefford, H. C., Hortnagel, K., Biskup, S., Lemke, J. R., Heron, D., Kluger, G., Depienne, C., Craiu, D., De Jonghe, P., Helbig, I., Guerrini, R., Lehesjoki, A. -E., Marini, C., Muhle, H., Moller, R. S., Neubauer, B., Pal, D., Selmer, K., Stephani, U., Sterbova, K., Striano, P., Talvik, T., von Spiczak, S., Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie Pédiatrique [CHU Lyon], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique [HCL Groupement Hospitalier Est], Groupement hospitalier Lyon-Est, Université de Lyon, Klinikum Oldenburg [Oldenburg], Zentrum für Kinder- und Jugendmedizin, Dpt of Pediatric Neurology and Developmental Medicine and Epilepsy Center [Munich], University of Munich, Department of Medical Genetics, Institute of Mother and Child, Division of Child Neurology, Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), Dpt of Molecular Biology and Genetics Istanbul, Boǧaziçi üniversitesi = Boğaziçi University [Istanbul], Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques, Hospices Civils de Lyon (HCL)-Hôpital Femme Mère Enfant, Dpt de l'Enfant et de l'Adolescent, Neuropédiatrie [Genève], Hôpitaux Universitaires de Genève (HUG), Institute of Human Genetics [Tuebingen], University of Tuebingen, Institute of Medical Genetics and Applied Genomics [Tübingen], University of Tübingen, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Svt. Luka's Institute of Child Neurology and Epilepsy, Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Genetikum, Neurogenetics Group, Division of Genetic Medicine [Seattle], University of Washington [Seattle], CeGaT GmbH, Institut für Humangenetik, Universität Heidelberg [Heidelberg], Mignot, Cyril, von Stülpnagel, Celina, Korff, Christian, EuroEPINOMICS-RES MAE Working Grp, HAL-UPMC, Gestionnaire, Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Lyon-Est (GHE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Boğaziçi University [Istanbul], CHU Trousseau [APHP], and Universität Heidelberg [Heidelberg] = Heidelberg University
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, Encephalopathy, Myoclonic Jerk, SYNGAP1, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, fluids and secretions, Medizinische Fakultät, Intellectual disability, mental disorders, Genetics, medicine, ddc:610, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Exome, Genetics (clinical), reproductive and urinary physiology, ddc:618, business.industry, medicine.disease, Hypotonia, 3. Good health, 030104 developmental biology, Autism, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Mae Euroepinomics-Res Mae; International audience; Objective We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype–phenotype correlations.Methods We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed.Results We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3′ and 5′ exons. Seizures in patients with mutations in exons 4–5 were more pharmacoresponsive than in patients with mutations in exons 8–15.Conclusions SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.
Published: 2016

17. Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2

Author: Marina A. J. Tijssen, Mark A. Corbett, Zaid Afawi, Paolo Tinuper, Shoji Tsuji, Rachel Straussberg, Ilan Blatt, Samuel F. Berkovic, Francesco Brancati, Amy L Schneider, Lynette G. Sadleir, Sanjay M. Sisodiya, Renzo Guerrini, Shreyasee Chakraborty, Alfredo Berardelli, Silvana Franceschetti, Jozef Gecz, Luciano Xumerle, Pierre Labauge, Liana Veneziano, Simona Balestrini, Ingo Helbig, Martin A. Smith, Laura Canafoglia, Carlo Di Bonaventura, Hiroyuki Ishiura, Boris Keren, Manuela Pendziwiat, Rahel T. Florian, Sylvie Forlani, Anne Fleur van Rootselaar, Giorgio Casari, Christel Depienne, Tommaso Pippucci, Douglas E. Crompton, Edouard Hirsch, Davide Mei, Laura Licchetta, Renee Carroll, Riaan van Coller, Ingrid E. Scheffer, Thessa Kroes, Pasquale Striano, Brigid M. Regan, Francesca Bisulli, Shaun Carswell, Antonio Suppa, Julien Buratti, Karl Martin Klein, Alison Gardner, Caroline Nava, Federico Zara, Melanie Bahlo, Sabine Kaya, Kathryn Friend, Antonietta Coppola, Massimo Delledonne, Aaron M. Wenger, Anthony Correll, Sara Baldassari, Arn M. J. M. van den Maagdenberg, Eric LeGuern, Rachael Catford, Gabrielle Rudolf, Salvatore Striano, Mark F. Bennett, Josemir W. Sander, Kirston Barton, Michele Iacomino, Corbett M.A., Kroes T., Veneziano L., Bennett M.F., Florian R., Schneider A.L., Coppola A., Licchetta L., Franceschetti S., Suppa A., Wenger A., Mei D., Pendziwiat M., Kaya S., Delledonne M., Straussberg R., Xumerle L., Regan B., Crompton D., van Rootselaar A.-F., Correll A., Catford R., Bisulli F., Chakraborty S., Baldassari S., Tinuper P., Barton K., Carswell S., Smith M., Berardelli A., Carroll R., Gardner A., Friend K.L., Blatt I., Iacomino M., Di Bonaventura C., Striano S., Buratti J., Keren B., Nava C., Forlani S., Rudolf G., Hirsch E., Leguern E., Labauge P., Balestrini S., Sander J.W., Afawi Z., Helbig I., Ishiura H., Tsuji S., Sisodiya S.M., Casari G., Sadleir L.G., van Coller R., Tijssen M.A.J., Klein K.M., van den Maagdenberg A.M.J.M., Zara F., Guerrini R., Berkovic S.F., Pippucci T., Canafoglia L., Bahlo M., Striano P., Scheffer I.E., Brancati F., Depienne C., Gecz J., Neurology, ANS - Brain Imaging, Movement Disorder (MD), Corbett, M. A., Kroes, T., Veneziano, L., Bennett, M. F., Florian, R., Schneider, A. L., Coppola, A., Licchetta, L., Franceschetti, S., Suppa, A., Wenger, A., Mei, D., Pendziwiat, M., Kaya, S., Delledonne, M., Straussberg, R., Xumerle, L., Regan, B., Crompton, D., van Rootselaar, A. -F., Correll, A., Catford, R., Bisulli, F., Chakraborty, S., Baldassari, S., Tinuper, P., Barton, K., Carswell, S., Smith, M., Berardelli, A., Carroll, R., Gardner, A., Friend, K. L., Blatt, I., Iacomino, M., Di Bonaventura, C., Striano, S., Buratti, J., Keren, B., Nava, C., Forlani, S., Rudolf, G., Hirsch, E., Leguern, E., Labauge, P., Balestrini, S., Sander, J. W., Afawi, Z., Helbig, I., Ishiura, H., Tsuji, S., Sisodiya, S. M., Casari, G., Sadleir, L. G., van Coller, R., Tijssen, M. A. J., Klein, K. M., van den Maagdenberg, A. M. J. M., Zara, F., Guerrini, R., Berkovic, S. F., Pippucci, T., Canafoglia, L., Bahlo, M., Striano, P., Scheffer, I. E., Brancati, F., Depienne, C., and Gecz, J.
Subjects: 0301 basic medicine, Male, Myoclonus, Medizin, General Physics and Astronomy, Epilepsies, Myoclonic, Epilepsies, Intronic variant, repeat expansions,STARD7, familial adult myoclonic epilepsy, chromosome 2, Epilepsy, 0302 clinical medicine, DOMINANT CORTICAL TREMOR, EXPRESSION ANALYSIS, PEDIGREE, LOCUS, LINKAGE, GENE, 2P11.1-Q12.2, REFINEMENT, MUTATION, BAFME, lcsh:Science, Child, Genetics, Multidisciplinary, DNA Repeat Expansion, Disease genetics, Chromosome Mapping, Middle Aged, Pedigree, Myoclonic Epilepsy, Child, Preschool, Chromosomes, Human, Pair 2, Pair 2, STARD7, Female, Adolescent, Adult, Carrier Proteins, Humans, Young Adult, Introns, Human, Science, Locus (genetics), Biology, Chromosomes, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, medicine, Preschool, Gene, Whole genome sequencing, Intron, Chromosome, General Chemistry, medicine.disease, 030104 developmental biology, Microsatellite instability, Myoclonic epilepsy, lcsh:Q, Familial Adult Myoclonic Epilepsy, Myoclonic, Carrier Protein, 030217 neurology & neurosurgery, Neurological disorders
Abstract: Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved., Familial cortical myoclonic tremor (FAME) has so far been mapped to regions on chromosome 2, 3, 5 and 8 and pentameric repeat expansions in SAMD12 were identified as cause of FAME1. Here, Corbett et al. identify ATTTT/ATTTC repeat expansions in intron 1 of STARD7 in individuals with FAME2.”
Published: 2019

18. Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy

Author: Rhonda E. Schnur, Fabio Sirchia, Olga Levchenko, Caroline Nava, Jane Juusola, Sarah Verheyen, Marketa Vlckova, Lindsay Rhodes, Gregory M. Cooper, Darina Prchalova, Thomas Courtin, Øystein L. Holla, David Kronn, Akemi J. Tanaka, E. Martina Bebin, Tara Funari, Miroslava Hancarova, Ennio Del Giudice, Nicolas Guex, Astrid Eisenkölbl, Dawn L. Earl, Toshiki Takenouchi, Ursula Gruber-Sedlmayr, Sedlácek Z, Sofia Douzgou, Heidelis A. Seebacher, Gerarda Cappuccio, Jasmin Blatterer, Anna Mikhaleva, Dian Donnai, Wendy K. Chung, Else Merckoll, Natasha J Brown, Elizabeth A. Sellars, Stefan Mundlos, Susan M. Hiatt, Giuliana Giannuzzi, Sinje Geuer, Giuseppina Vitiello, Séverine Lorrain, Alexandre Reymond, David J. Amor, Nicolas Chatron, Julien Delafontaine, Martine Doco, Kristian Tveten, Cecilie F. Rustad, Sylvain Pradervand, Delphine Héron, Alfredo Brusco, Elena L. Dadali, Nicola Brunetti-Pierri, Boris Keren, Yuri A. Zarate, Crystle Lee, Joel Charrow, Binnaz Yalcin, Heidi Taska-Tench, Elin Tønne, Tomoko Uehara, Alexander Lavrov, Jennifer Norman, Norine Voisin, Anna C.E. Hurst, Victoria R. Sanders, Ganka Douglas, Diana Johnson, Kenjiro Kosaki, Université de Lausanne = University of Lausanne (UNIL), Cooper Medical School of Rowan University [Camden] (CMSRU), Manchester University NHS Foundation Trust (MFT), University of Manchester [Manchester], HudsonAlpha Institute for Biotechnology [Huntsville, AL], Oslo University Hospital [Oslo], Victorian Clinical Genetics Services [Melbourne, VIC, Australia] (VCGS), Murdoch Children's Research Institute (MCRI), University of Melbourne, Seattle Children’s Hospital, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme [ CHU Pitié-Salpêtrière AP-HP] (GRC : DIA), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Research Centre for Medical Genetics [Moscow, Russia] (RCMG), Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, Medical University of Graz, Sheffield Children's NHS Foundation Trust, University of Arkansas at Little Rock, Charles University [Prague] (CU), University Hospital Motol [Prague], University of Alabama at Birmingham [ Birmingham] (UAB), Università degli studi di Torino = University of Turin (UNITO), Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino, University of Naples Federico II = Università degli studi di Napoli Federico II, Ann & Robert H. Lurie Children's Hospital of Chicago, Swiss Institute of Bioinformatics [Lausanne] (SIB), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), GeneDx [Gaithersburg, MD, USA], Johannes Kepler University Linz [Linz] (JKU), Telemark Hospital Trust [Skien, Norway], New York Medical College (NYMC), Integris Pediatric Neurology [Oklahoma City, OK, USA] (IPN), Institute for Maternal and Child Health - IRCCS 'Burlo Garofolo' [Trieste], Keio University School of Medicine [Tokyo, Japan], Columbia University [New York], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Dupuis, Christine, Voisin, N., Schnur, R. E., Douzgou, S., Hiatt, S. M., Rustad, C. F., Brown, N. J., Earl, D. L., Keren, B., Levchenko, O., Geuer, S., Verheyen, S., Johnson, D., Zarate, Y. A., Hancarova, M., Amor, D. J., Bebin, E. M., Blatterer, J., Brusco, A., Cappuccio, G., Charrow, J., Chatron, N., Cooper, G. M., Courtin, T., Dadali, E., Delafontaine, J., Del Giudice, E., Doco, M., Douglas, G., Eisenkolbl, A., Funari, T., Giannuzzi, G., Gruber-Sedlmayr, U., Guex, N., Heron, D., Holla, O. L., Hurst, A. C. E., Juusola, J., Kronn, D., Lavrov, A., Lee, C., Lorrain, S., Merckoll, E., Mikhaleva, A., Norman, J., Pradervand, S., Prchalova, D., Rhodes, L., Sanders, V. R., Sedlacek, Z., Seebacher, H. A., Sellars, E. A., Sirchia, F., Takenouchi, T., Tanaka, A. J., Taska-Tench, H., Tonne, E., Tveten, K., Vitiello, G., Vlckova, M., Uehara, T., Nava, C., Yalcin, B., Kosaki, K., Donnai, D., Mundlos, S., Brunetti Pierri, N., Chung, W. K., and Reymond, A.
Subjects: Male, Models, Molecular, Hypertrichosis, [SDV]Life Sciences [q-bio], Mesomelic Dysplasia, Transcriptome, Mice, Gene Frequency, Missense mutation, Child, Zebrafish, Genetics (clinical), Genetics, Brain Diseases, 0303 health sciences, biology, Protein Stability, 030305 genetics & heredity, AFF3, AFF4, horseshoe kidney, intellectual disability, mesomelic dysplasia, Nuclear Proteins, Syndrome, Phenotype, Ubiquitin ligase, [SDV] Life Sciences [q-bio], Child, Preschool, Female, Transcriptional Elongation Factors, Adolescent, Mutation, Missense, Osteochondrodysplasias, Article, Evolution, Molecular, Young Adult, 03 medical and health sciences, medicine, Animals, Humans, Amino Acid Sequence, Fused Kidney, 030304 developmental biology, Epilepsy, Infant, Horseshoe kidney, biology.organism_classification, medicine.disease, biology.protein
Abstract: International audience; The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3-and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.
Published: 2021

19. KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum

Author: An-Sofie Schoonjans, Christina Fenger, Joseph Toulouse, Nathalie Villeneuve, Marie-Christine Nougues, Martina Fiannacca, Wen-Hann Tan, Rikke S. Møller, Boudewijn Gunning, Julitta de Bellescize, David Bearden, Federico Zara, Hiltrud Muhle, Gaetan Lesca, Sarah Weckhuysen, Guido Rubboli, Berten Ceulemans, Tobias Baumgartner, Frauke Hornemann, Steffen Syrbe, Leanne M. Dibbens, Hannah Stamberger, Catherine Sarret, Maria Margherita Mancardi, Edouard Hirsch, Salvatore Buono, Chiara Reale, Kern Olofsson, Elena Gardella, Claudia M Bonardi, Hélène Maurey, Henrike O. Heyne, Fabienne Picard, Stéphanie Baulac, Pasquale Striano, Geneviève Demarquay, Fabrice Bartolomei, Antonietta Coppola, Massimiliano Rossi, Vincent des Portes, Hester Y. Kroes, Mark Fitzgerald, Nienke E. Verbeek, David A. Koolen, Caroline Nava, Dorothée Ville, Marjolaine Willems, Cecilia Altuzarra, Bonardi, Claudia M, Heyne, Henrike O, Fiannacca, Martina, Fitzgerald, Mark P, Dibbens, Leanne, Rubboli, Guido, Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Bonardi, Cm, Heyne, Ho, Fiannacca, M, Fitzgerald, Mp, Gardella, E, Gunning, B, Olofsson, K, Lesca, G, Verbeek, N, Stamberger, H, Striano, P, Zara, F, Mancardi, Mm, Nava, C, Syrbe, S, Buono, S, Baulac, S, Coppola, A, Weckhuysen, S, Schoonjans, A, Ceulemans, B, Sarret, C, Baumgartner, T, Muhle, H, des Portes, V, Toulouse, J, Nougues, Mc, Rossi, M, Demarquay, G, Ville, D, Hirsch, E, Maurey, H, Willems, M, de Bellescize, J, Altuzarra, Cd, Villeneuve, N, Bartolomei, F, Picard, F, Hornemann, F, Koolen, Da, Kroes, Hy, Reale, C, Fenger, Cd, Tan, Wh, Dibbens, L, Bearden, Dr, Møller, R, and Rubboli, G.
Subjects: Male, Potassium Channels, Adolescent, Genotype, KCNT1, Nerve Tissue Proteins, Potassium Channels, Sodium-Activated, Bioinformatics, Temporal lobe, Cohort Studies, 03 medical and health sciences, Epilepsy, Young Adult, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, medicine, epileptic encephalopathies, Missense mutation, Humans, Preschool, Child, 030304 developmental biology, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Seizure types, business.industry, developmental and epileptic encephalopathies, epilepsy of infancy with migrating focal seizures, sleep-related hypermotor epilepsy, Child, Preschool, Female, Infant, Mutation, Phenotype, West Syndrome, medicine.disease, 3. Good health, ddc:616.8, Epileptic spasms, Cohort, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Sodium-Activated, Neurology (clinical), Human medicine, business, 030217 neurology & neurosurgery
Abstract: Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in ∼50% of the patients, sudden unexplained death in epilepsy in one individual; and (iv) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype–phenotype considerations showed many of the autosomal dominant or sporadic sleep-related hypermotor epilepsy-associated mutations to be clustered around the RCK2 domain in the C terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS developmental and epileptic encephalopathies did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset developmental and epileptic encephalopathies as well as of focal epilepsies, namely autosomal dominant or sporadic sleep-related hypermotor epilepsy.
Published: 2020

20. Damaging de novo missense variants in EEF1A2lead to a developmental and degenerative epileptic-dyskinetic encephalopathy

Author: Laurine Perrin, Sha Tang, Brandon S. Guida, Tjitske Kleefstra, Marjolein H. Willemsen, Heather Stickney, Michael C. Kruer, Keri Ramsey, Heather C Mefford, Lynette G. Sadleir, Bobby P. C. Koeleman, Evelyn Sattlegger, Angela E. Lin, Sara A. Lewis, Marcello Scala, Sergio Padilla-Lopez, Luis O. Rohena, Joaquim Sa, Marie Laure Mathieu, Floor E. Jansen, Joy Y. Sebe, David W. Raible, Giorgio Casari, Gemma L. Carvill, Ingrid E. Scheffer, Paul A. Caruso, Robert Huether, Mariasavina Severino, Candace T. Myers, Eva H. Brilstra, Ashwin A. Bhandiwad, Katherine L. Helbig, Somayeh Bakhtiari, Sehribani Ulusoy Oktay, Gaetan Lesca, Vinodh Narayanan, Georgina Hollingsworth, Tyler N. Kruer, Christel Depienne, Valeria Capra, Pasquale Striano, Timothy Feyma, Deepak Gill, Andrea Accogli, Caroline Nava, Carvill, G. L., Helbig, K. L., Myers, C. T., Scala, M., Huether, R., Lewis, S., Kruer, T. N., Guida, B. S., Bakhtiari, S., Sebe, J., Tang, S., Stickney, H., Oktay, S. U., Bhandiwad, A. A., Ramsey, K., Narayanan, V., Feyma, T., Rohena, L. O., Accogli, A., Severino, M., Hollingsworth, G., Gill, D., Depienne, C., Nava, C., Sadleir, L. G., Caruso, P. A., Lin, A. E., Jansen, F. E., Koeleman, B., Brilstra, E., Willemsen, M. H., Kleefstra, T., Sa, J., Mathieu, M. -L., Perrin, L., Lesca, G., Striano, P., Casari, G., Scheffer, I. E., Raible, D., Sattlegger, E., Capra, V., Padilla-Lopez, S., Mefford, H. C., and Kruer, M. C.
Subjects: Adult, Male, de novo, Heterozygote, Adolescent, Encephalopathy, Choreoathetosis, Mutation, Missense, EEF1A2, Haploinsufficiency, Biology, Article, 03 medical and health sciences, Epilepsy, All institutes and research themes of the Radboud University Medical Center, Peptide Elongation Factor 1, Genetics, medicine, Missense mutation, Humans, Child, Genetics (clinical), 030304 developmental biology, Dystonia, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], 030305 genetics & heredity, Genetic Complementation Test, medicine.disease, yeast complementation assay, Protein Structure, Tertiary, dyskinesia, Child, Preschool, epilepsy, Cerebellar atrophy, Epilepsy, Generalized, Female, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract: Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein-damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic-dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors.
Published: 2020

21. HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond

Author: Shoji Ichikawa, Ilaria Rivolta, Anna Binda, Laurie S. Sadler, Sonia Figueiroa, Renzo Guerrini, Annick Laridon, Pasquale Striano, Katalin Sterbova, Bina Santoro, Petra Laššuthová, Maria Margherita Mancardi, Francesca Ragona, Anna Rosati, Fernando Kok, Laura Canafoglia, Daniele Frattini, Elena Freri, Christine Coubes, Davide Mei, Bobby P. C. Koeleman, Daniel Bauer, Carla Marini, Christel Depienne, Carlotta Spagnoli, Sophie Scheidecker, Carlo Fusco, Tiziana Granata, Barbara Castellotti, Eva H. Brilstra, Federico Melani, Cristina Garrido, Cinzia Gellera, A. Micheil Innes, Wilfrid Carré, Christèle Dubourg, Elena Parrini, Alessandro Porro, Caroline Nava, Maria Giardino, Sophie Julia, Manuela Santos, Yves Alembik, Eric LeGuern, Andrea Barbuti, Silvana Franceschetti, Federico Zara, Paul Kuentz, Raffaella Milanesi, Catherine Mercer, Carine Dalle, Julien Thevenon, Nicolas Deconinck, Agnès Rastetter, Laurent Pasquier, Kay Hamacher, Renske Oegema, Gerhard Thiel, Dario DiFrancesco, Tiziana Pisano, Chelsea Chambers, Jacopo C. DiFrancesco, Guillaume Smits, Katherine L. Helbig, Julie Soblet, Jana Neupauerová, Damien R Clark, Johannes R. Lemke, Radhika Dhamija, Anna Moroni, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University Medical Center [Utrecht], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], CHU Pontchaillou [Rennes], Les Hôpitaux Universitaires de Strasbourg (HUS), Children’s Hospital of Philadelphia (CHOP ), University Hospital Motol [Prague], University of Genoa (UNIGE), Université libre de Bruxelles (ULB), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Marini, C, Porro, A, Rastetter, A, Dalle, C, Rivolta, I, Bauer, D, Oegema, R, Nava, C, Parrini, E, Mei, D, Mercer, C, Dhamija, R, Chambers, C, Coubes, C, Thévenon, J, Kuentz, P, Julia, S, Pasquier, L, Dubourg, C, Carré, W, Rosati, A, Melani, F, Pisano, T, Giardino, M, Innes, A, Alembik, Y, Scheidecker, S, Santos, M, Figueiroa, S, Garrido, C, Fusco, C, Frattini, D, Spagnoli, C, Binda, A, Granata, T, Ragona, F, Freri, E, Franceschetti, S, Canafoglia, L, Castellotti, B, Gellera, C, Milanesi, R, Mancardi, M, Clark, D, Kok, F, Helbig, K, Ichikawa, S, Sadler, L, Neupauerová, J, Laššuthova, P, Šterbová, K, Laridon, A, Brilstra, E, Koeleman, B, Lemke, J, Zara, F, Striano, P, Soblet, J, Smits, G, Deconinck, N, Barbuti, A, Difrancesco, D, Leguern, E, Guerrini, R, Santoro, B, Hamacher, K, Thiel, G, Moroni, A, Di Francesco, J, and Depienne, C
Subjects: 0301 basic medicine, Proband, Male, Models, Molecular, Potassium Channels, [SDV]Life Sciences [q-bio], Medizin, medicine.disease_cause, Epileptogenesis, Membrane Potentials, Epilepsy, 0302 clinical medicine, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Missense mutation, Child, Genetics, Mutation, Middle Aged, Phenotype, 3. Good health, Transmembrane domain, clinical spectrum, epilepsy, HCN1, intellectual disability, ion channel, Child, Preschool, Epilepsy, Generalized, Female, Spasms, Infantile, Adult, Adolescent, CHO Cells, Biology, 03 medical and health sciences, Young Adult, Cricetulus, medicine, Animals, Humans, Generalized epilepsy, Genetic Association Studies, Aged, Infant, medicine.disease, Electric Stimulation, 030104 developmental biology, Mutagenesis, Site-Directed, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: International audience; Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.
Published: 2018

22. The landscape of epilepsy-related GATOR1 variants

Author: Johannes R. Lemke, Pia Zacher, Thomas Dorn, Laura Hernandez-Hernandez, Natasha E. Schoeler, Stéphanie Baulac, Sara Baldassari, Anne de Saint Martin, Eleni Panagiotakaki, Anne Fabienne Lepine, Markus Wolff, Arnaud Biraben, Renske Oegema, Edouard Hirsch, Anna Jansen, Charles Deckers, Nienke E. Verbeek, Fabienne Picard, Georg Dorfmüller, Sarah Ferrand-Sorbets, Barbora Benova, Francesca Bisulli, Inga Talvik, Kristin Lindstrom, Tilman Polster, Douglas R. Nordli, Tommaso Pippucci, Eva H. Brilstra, Shifteh Sattar, Erik H. Niks, Marie Line Jacquemont, Kees P.J. Braun, Karen Müller-Schlüter, Sanjay M. Sisodiya, Sarah Weckhuysen, Lysa Boissé Lomax, Sophie Julia, Brigitte Ricard-Mousnier, Mathilde Chipaux, Laura Licchetta, Gaetan Lesca, Bianca Berghuis, S. Krithika, Jamel Chelly, Renzo Guerrini, Hélène Catenoix, Annapurna Poduri, Melanie Jennesson, Pasquale Striano, Rikke S. Møller, Antonio Gambardella, Guillaume Achaz, Peter Uldall, Fabrice Bartolomei, Giuseppe d'Orsi, Laurence Faivre, Floor E. Jansen, An Sofie Schoonjans, Kevin Rostasy, Thomas Becher, Pavel Krsek, Julien Thevenon, Marjan J. A. van Kempen, Guido Rubboli, Cécile Marchal, Meral Balci, Boudewijn Gunning, Ilona Krey, Julitta de Bellescize, Veronique Darmency, Christopher J. Yuskaitis, Daniëlle de Jong, Giovanni Crichiutti, Paolo Tinuper, Katrien Stouffs, Valentin Sander, Anne-Sophie Lebre, Thomas Cloppenborg, Valerio Conti, Gabrielle Rudolf, Courtney Kiss, Eveline Hagebeuk, Caroline Nava, Eric LeGuern, Ilse Wegner, Christian Brandt, Martin Zenker, Simona Balestrini, Picard, Fabienne, Baldassari S., Picard F., Verbeek N.E., van Kempen M., Brilstra E.H., Lesca G., Conti V., Guerrini R., Bisulli F., Licchetta L., Pippucci T., Tinuper P., Hirsch E., de Saint Martin A., Chelly J., Rudolf G., Chipaux M., Ferrand-Sorbets S., Dorfmuller G., Sisodiya S., Balestrini S., Schoeler N., Hernandez-Hernandez L., Krithika S., Oegema R., Hagebeuk E., Gunning B., Deckers C., Berghuis B., Wegner I., Niks E., Jansen F.E., Braun K., de Jong D., Rubboli G., Talvik I., Sander V., Uldall P., Jacquemont M.-L., Nava C., Leguern E., Julia S., Gambardella A., d'Orsi G., Crichiutti G., Faivre L., Darmency V., Benova B., Krsek P., Biraben A., Lebre A.-S., Jennesson M., Sattar S., Marchal C., Nordli D.R., Lindstrom K., Striano P., Lomax L.B., Kiss C., Bartolomei F., Lepine A.F., Schoonjans A.-S., Stouffs K., Jansen A., Panagiotakaki E., Ricard-Mousnier B., Thevenon J., de Bellescize J., Catenoix H., Dorn T., Zenker M., Muller-Schluter K., Brandt C., Krey I., Polster T., Wolff M., Balci M., Rostasy K., Achaz G., Zacher P., Becher T., Cloppenborg T., Yuskaitis C.J., Weckhuysen S., Poduri A., Lemke J.R., Moller R.S., Baulac S., Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Genetics [Utrecht, the Netherlands], University Medical Center [Utrecht], Service de Génétique [HCL Groupement Hospitalier Est], Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Children's Hospital A. Meyer, Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Academic Center for Epileptology Kempenhaeghe & Maastricht UMC+ [Heeze], Danish Epilepsy Centre, Denmark and Aarhus University, Aarhus, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Université de Bourgogne (UB), Service de Neurophysiologie Clinique (CHU Dijon), CHU Pontchaillou [Rennes], Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques, Hospices Civils de Lyon (HCL)-Hôpital Femme Mère Enfant, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Bourgogne Franche-Comté [COMUE] (UBFC), Département d'Epilepsie, Sommeil et Neurophysiologie Pédiatrique [HCL, Lyon], Hospices Civils de Lyon (HCL), Institute of Human Genetics, University Hospital Magdeburg, Institut de Systématique, Evolution, Biodiversité (ISYEB ), Muséum national d'Histoire naturelle (MNHN)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupement hospitalier Lyon-Est, Centre de recherche en neurosciences de Lyon (CRNL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]
Subjects: Male, 0301 basic medicine, Proband, DEPDC5, SUDEP, 030105 genetics & heredity, Bioinformatics, Loss of Function Mutation/genetics, Epilepsy, INDEL Mutation, Loss of Function Mutation, mTORC1 pathway, Genetics(clinical), Child, Genetics (clinical), Multiprotein Complexes/genetics, Brugada Syndrome, DNA Copy Number Variation, Brugada syndrome, INDEL Mutation/genetics, GTPase-Activating Proteins, NPRL3, Seizure, Phenotype, Pedigree, 3. Good health, Brugada Syndrome/genetics, Child, Preschool, Female, Human, Signal Transduction, DNA Copy Number Variations, Adolescent, Seizures/complications, Mechanistic Target of Rapamycin Complex 1/genetics, DNA Copy Number Variations/genetics, Mechanistic Target of Rapamycin Complex 1, Tumor Suppressor Proteins/genetics, Article, Focal cortical dysplasia, 03 medical and health sciences, Seizures, GTPase-Activating Proteins/genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic focal epilepsy, Epilepsy/complications, Repressor Proteins/genetics, business.industry, GTPase-Activating Protein, Tumor Suppressor Proteins, Infant, Newborn, Correction, Infant, Repressor Protein, Cortical dysplasia, medicine.disease, ddc:616.8, Repressor Proteins, 030104 developmental biology, Frontal lobe seizures, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Multiprotein Complexes, Multiprotein Complexe, Signal Transduction/genetics, Human medicine, business
Abstract: Purpose:\ud \ud To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway.\ud \ud Methods:\ud \ud We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants.\ud \ud Results:\ud \ud The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign.\ud \ud Conclusion:\ud \ud Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.
Published: 2018

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22 results on '"Nava, C."'

1. Patients with KCNH1 -related intellectual disability without distinctive features of Zimmermann-Laband/Temple-Baraitser syndrome.

2. The EPIGENE network: A French initiative to harmonize and improve the nationwide diagnosis of monogenic epilepsies.

3. GM3 synthase deficiency in non-Amish patients.

4. KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum.

5. Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy.

6. De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy.

7. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

8. Novel GABRA2 variants in epileptic encephalopathy and intellectual disability with seizures.

9. De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy.

10. The landscape of epilepsy-related GATOR1 variants.

11. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.

12. Early-onset encephalopathy with paroxysmal movement disorders and epileptic seizures without hemiplegic attacks: About three children with novel ATP1A3 mutations.

13. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.

14. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.

15. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

16. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy

17. Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2

18. Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy

19. KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum

20. Damaging de novo missense variants in EEF1A2lead to a developmental and degenerative epileptic-dyskinetic encephalopathy

21. HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond

22. The landscape of epilepsy-related GATOR1 variants

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