Search

Your search keyword '"Berkovic S.F."' showing total 19 results
Start Over Author "Berkovic S.F." Publication Year Range Last 10 years
19 results on '"Berkovic S.F."'

2. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Author

Stamberger, H., Hammer, T.B., Gardella, E., Vlaskamp, D.R.M., Bertelsen, B., Mandelstam, S., Lange, I. de, Zhang, J., Myers, C.T., Fenger, C., Afawi, Z., Fuerte, E.P. Almanza, Andrade, D.M., Balcik, Y., Zeev, B. Ben, Bennett, M.F., Berkovic, S.F., Isidor, B., Bouman, A., Brilstra, E., Ø, L. Busk, Cairns, A., Caumes, R., Chatron, N., Dale, R.C., Geus, C. de, Edery, P., Gill, D., Granild-Jensen, J.B., Gunderson, L., Gunning, B., Heimer, G., Helle, J.R., Hildebrand, M.S., Hollingsworth, G., Kharytonov, V., Klee, E.W., Koeleman, B.P.C., Koolen, D.A., Korff, C., Küry, S., Lesca, G., Lev, D., Leventer, R.J., Mackay, M.T., Macke, E.L., McEntagart, M., Mohammad, S.S., Monin, P., Montomoli, M., Morava, E., Moutton, S., Muir, A.M., Parrini, E., Procopis, P., Ranza, E., Reed, L., Reif, P.S., Rosenow, F., Rossi, M., Sadleir, L.G., Sadoway, T., Schelhaas, H.J., Schneider, A.L., Shah, K., Shalev, R., Sisodiya, S.M., Smol, T., Stumpel, C., Stuurman, K., Symonds, J.D., Mau-Them, F.T., Verbeek, N., Verhoeven, J.S., Wallace, G., Yosovich, K., Zarate, Y.A., Zerem, A., Zuberi, S.M., Guerrini, R., Mefford, H.C., Patel, C., Zhang, Y.H., Møller, R.S., Scheffer, I.E., Stamberger, H., Hammer, T.B., Gardella, E., Vlaskamp, D.R.M., Bertelsen, B., Mandelstam, S., Lange, I. de, Zhang, J., Myers, C.T., Fenger, C., Afawi, Z., Fuerte, E.P. Almanza, Andrade, D.M., Balcik, Y., Zeev, B. Ben, Bennett, M.F., Berkovic, S.F., Isidor, B., Bouman, A., Brilstra, E., Ø, L. Busk, Cairns, A., Caumes, R., Chatron, N., Dale, R.C., Geus, C. de, Edery, P., Gill, D., Granild-Jensen, J.B., Gunderson, L., Gunning, B., Heimer, G., Helle, J.R., Hildebrand, M.S., Hollingsworth, G., Kharytonov, V., Klee, E.W., Koeleman, B.P.C., Koolen, D.A., Korff, C., Küry, S., Lesca, G., Lev, D., Leventer, R.J., Mackay, M.T., Macke, E.L., McEntagart, M., Mohammad, S.S., Monin, P., Montomoli, M., Morava, E., Moutton, S., Muir, A.M., Parrini, E., Procopis, P., Ranza, E., Reed, L., Reif, P.S., Rosenow, F., Rossi, M., Sadleir, L.G., Sadoway, T., Schelhaas, H.J., Schneider, A.L., Shah, K., Shalev, R., Sisodiya, S.M., Smol, T., Stumpel, C., Stuurman, K., Symonds, J.D., Mau-Them, F.T., Verbeek, N., Verhoeven, J.S., Wallace, G., Yosovich, K., Zarate, Y.A., Zerem, A., Zuberi, S.M., Guerrini, R., Mefford, H.C., Patel, C., Zhang, Y.H., Møller, R.S., and Scheffer, I.E.

Abstract

Contains fulltext : 231688.pdf (Publisher’s version ) (Closed access), PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

Published
2021

3. The severe epilepsy syndromes of infancy: A population-based study.

Author

Dabscheck G., McMahon J.M., Mefford H.C., Panetta J., Riseley J., Rodriguez-Casero V., Ryan M.M., Schneider A.L., Smith L.J., Stark Z., Wong F., Yiu E.M., Scheffer I.E., Harvey A.S., Howell K.B., Freeman J.L., Mackay M.T., Fahey M.C., Archer J., Berkovic S.F., Chan E., Eggers S., Hayman M., Holberton J., Hunt R.W., Jacobs S.E., Kornberg A.J., Leventer R.J., Mandelstam S., Dabscheck G., McMahon J.M., Mefford H.C., Panetta J., Riseley J., Rodriguez-Casero V., Ryan M.M., Schneider A.L., Smith L.J., Stark Z., Wong F., Yiu E.M., Scheffer I.E., Harvey A.S., Howell K.B., Freeman J.L., Mackay M.T., Fahey M.C., Archer J., Berkovic S.F., Chan E., Eggers S., Hayman M., Holberton J., Hunt R.W., Jacobs S.E., Kornberg A.J., Leventer R.J., and Mandelstam S.

Abstract

Objective: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. Method(s): A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. Result(s): Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. Significance: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, i

Published
2021

4. The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective.

Author

O'Keefe M., Schneider A., Lynch E., Martyn M., Velakoulis D., Leventer R., Rafehi H., Chong B., Stark Z., Ademi Z., Gaff C., Huq A., Walsh M., James P.A., Krzesinski E.I., Wallis M., Stutterd C.A., Bahlo M., Delatycki M.B., Berkovic S.F., Kwan P., Fahey M., Lunke S., Phelan D.G., Eratne D., Siemering K., West K., Sexton A., Jarmolowicz A., Taylor J.A., Schultz J., Purvis R., Uebergang E., Chalinor H., Creighton B., Gelfand N., Saks T., Prawer Y., Smagarinsky Y., Pan T., Goranitis I., O'Keefe M., Schneider A., Lynch E., Martyn M., Velakoulis D., Leventer R., Rafehi H., Chong B., Stark Z., Ademi Z., Gaff C., Huq A., Walsh M., James P.A., Krzesinski E.I., Wallis M., Stutterd C.A., Bahlo M., Delatycki M.B., Berkovic S.F., Kwan P., Fahey M., Lunke S., Phelan D.G., Eratne D., Siemering K., West K., Sexton A., Jarmolowicz A., Taylor J.A., Schultz J., Purvis R., Uebergang E., Chalinor H., Creighton B., Gelfand N., Saks T., Prawer Y., Smagarinsky Y., Pan T., and Goranitis I.

Abstract

Currently there is no secured ongoing funding in Australia for next generation sequencing (NGS) such as exome sequencing (ES) for adult neurological disorders. Studies have focused on paediatric populations in research or highly specialised settings, utilised standard NGS pipelines focusing only on small insertions, deletions and single nucleotide variants, and not explored impacts on management in detail. This prospective multi-site study performed ES and an extended bioinformatics repeat expansion analysis pipeline, on patients with broad phenotypes (ataxia, dementia, dystonia, spastic paraparesis, motor neuron disease, Parkinson's disease and complex/not-otherwise-specified), with symptom onset between 2 and 60 years. Genomic data analysis was phenotype-driven, using virtual gene panels, reported according to American College of Medical Genetics and Genomics guidelines. One-hundred-and-sixty patients (51% female) were included, median age 52 years (range 14-79) and median 9 years of symptoms. 34/160 (21%) patients received a genetic diagnosis. Highest diagnostic rates were in spastic paraparesis (10/25, 40%), complex/not-otherwise-specified (10/38, 26%) and ataxia (7/28, 25%) groups. Findings were considered 'possible/uncertain' in 21/160 patients. Repeat expansion detection identified an unexpected diagnosis of Huntington disease in an ataxic patient with negative ES. Impacts on management, such as more precise and tailored care, were seen in most diagnosed patients (23/34, 68%). ES and a novel bioinformatics analysis pipepline had a substantial diagnostic yield (21%) and management impacts for most diagnosed patients, in heterogeneous, complex, mainly adult-onset neurological disorders in real-world settings in Australia, providing evidence for NGS and complementary multiple, new technologies as valuable diagnostic tools.Copyright © 2020 Elsevier B.V.

Published
2021

5. SCN1A Variants in vaccine-related febrile seizures: A prospective study.

Author

Hildebrand M.S., Richmond P., Macartney K.K., Scheffer I.E., Berkovic S.F., Wood N., Damiano J.A., Deng L., Li W., Burgess R., Schneider A.L., Crawford N.W., Buttery J., Gold M., Hildebrand M.S., Richmond P., Macartney K.K., Scheffer I.E., Berkovic S.F., Wood N., Damiano J.A., Deng L., Li W., Burgess R., Schneider A.L., Crawford N.W., Buttery J., and Gold M.

Abstract

Objective: Febrile seizures may follow vaccination. Common variants in the sodium channel gene, SCN1A, are associated with febrile seizures, and rare pathogenic variants in SCN1A cause the severe developmental and epileptic encephalopathy Dravet syndrome. Following vaccination, febrile seizures may raise the specter of poor outcome and inappropriately implicate vaccination as the cause. We aimed to determine the prevalence of SCN1A variants in children having their first febrile seizure either proximal to vaccination or unrelated to vaccination compared to controls. Method(s): We performed SCN1A sequencing, blind to clinical category, in a prospective cohort of children presenting with their first febrile seizure as vaccine proximate (n = 69) or as non-vaccine proximate (n = 75), and children with no history of seizures (n = 90) recruited in Australian pediatric hospitals. Result(s): We detected 2 pathogenic variants in vaccine-proximate cases (p.R568X and p.W932R), both of whom developed Dravet syndrome, and 1 in a non-vaccine-proximate case (p.V947L) who had febrile seizures plus from 9 months. All had generalized tonic-clonic seizures lasting >15 minutes. We also found enrichment of a reported risk allele, rs6432860-T, in children with febrile seizures compared to controls (odds ratio = 1.91, 95% confidence interval = 1.31-2.81). Interpretation(s): Pathogenic SCN1A variants may be identified in infants with vaccine-proximate febrile seizures. As early diagnosis of Dravet syndrome is essential for optimal management and outcome, SCN1A sequencing in infants with prolonged febrile seizures, proximate to vaccination, should become routine. ANN NEUROL 2020;87:281-288.Copyright © 2019 American Neurological Association

Published
2020

6. 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., Rootselaar, A.F. van, 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., Maagdenberg, A.M.J.M. van den, Depienne, C., and FAME Consortium

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.

Published
2019

7. Repeat expansion disorders enriched in an Australian and New Zealand Epi25 Year 1 epilepsy cohort

Author

Bennett, M.F., Tankard, R.M., Bennett, C.A., Schneider, A.L., Regan, B.M., Damiano, J.A., Hildebrand, M.S., Sadleir, L.G., Scheffer, I.E., Berkovic, S.F., Bahlo, M., Bennett, M.F., Tankard, R.M., Bennett, C.A., Schneider, A.L., Regan, B.M., Damiano, J.A., Hildebrand, M.S., Sadleir, L.G., Scheffer, I.E., Berkovic, S.F., and Bahlo, M.

Abstract

Meeting abstract: 33rd International Epilepsy Congress Bangkok, Thailand 22 – 26 June 2019

Published
2019

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

Author

Hamdan, F.F., Myers, C.T., Cossette, P., Lemay, P., Spiegelman, D., Laporte, A.D., Nassif, C., Diallo, O., Monlong, J., Cadieux-Dion, M., Dobrzeniecka, S., Meloche, C., Retterer, K., Cho, M.T., Rosenfeld, J.A., Bi, W., Massicotte, C., Miguet, M., Brunga, L., Regan, B.M., Mo, K., Tam, C., Schneider, A., Hollingsworth, G., FitzPatrick, D.R., Donaldson, A., Canham, N., Blair, E., Kerr, B., Fry, A.E., Thomas, R.H., Shelagh, J., Hurst, J.A., Brittain, H., Blyth, M., Lebel, R.R., Gerkes, E.H., Davis-Keppen, L., Stein, Q., Chung, W.K., Dorison, S.J., Benke, P.J., Fassi, E., Corsten-Janssen, N., Kamsteeg, E.J., Mau-Them, F.T., Bruel, A.L., Verloes, A., Ounap, K., Wojcik, M.H., Albert, D.V.F., Venkateswaran, S., Ware, T., Jones, D., Liu, Y.C., Mohammad, S.S., Bizargity, P., Bacino, C.A., Leuzzi, V., Martinelli, S., Dallapiccola, B., Tartaglia, M., Blumkin, L., Wierenga, K.J., Purcarin, G., O'Byrne, J.J., Stockler, S., Lehman, A., Keren, B., Nougues, M.C., Mignot, C., Auvin, S., Nava, C., Hiatt, S.M., Bebin, M., Shao, Y., Scaglia, F., Lalani, S.R., Frye, R.E., Jarjour, I.T., Jacques, S., Boucher, R.M., Riou, E., Srour, M., Carmant, L., Lortie, A., Major, P., Diadori, P., Dubeau, F., D'Anjou, G., Bourque, G., Berkovic, S.F., Sadleir, L.G., Campeau, P.M., Kibar, Z., Lafreniere, R.G., Girard, S.L., Mercimek-Mahmutoglu, S., Boelman, C., Rouleau, G.A., et al., Hamdan, F.F., Myers, C.T., Cossette, P., Lemay, P., Spiegelman, D., Laporte, A.D., Nassif, C., Diallo, O., Monlong, J., Cadieux-Dion, M., Dobrzeniecka, S., Meloche, C., Retterer, K., Cho, M.T., Rosenfeld, J.A., Bi, W., Massicotte, C., Miguet, M., Brunga, L., Regan, B.M., Mo, K., Tam, C., Schneider, A., Hollingsworth, G., FitzPatrick, D.R., Donaldson, A., Canham, N., Blair, E., Kerr, B., Fry, A.E., Thomas, R.H., Shelagh, J., Hurst, J.A., Brittain, H., Blyth, M., Lebel, R.R., Gerkes, E.H., Davis-Keppen, L., Stein, Q., Chung, W.K., Dorison, S.J., Benke, P.J., Fassi, E., Corsten-Janssen, N., Kamsteeg, E.J., Mau-Them, F.T., Bruel, A.L., Verloes, A., Ounap, K., Wojcik, M.H., Albert, D.V.F., Venkateswaran, S., Ware, T., Jones, D., Liu, Y.C., Mohammad, S.S., Bizargity, P., Bacino, C.A., Leuzzi, V., Martinelli, S., Dallapiccola, B., Tartaglia, M., Blumkin, L., Wierenga, K.J., Purcarin, G., O'Byrne, J.J., Stockler, S., Lehman, A., Keren, B., Nougues, M.C., Mignot, C., Auvin, S., Nava, C., Hiatt, S.M., Bebin, M., Shao, Y., Scaglia, F., Lalani, S.R., Frye, R.E., Jarjour, I.T., Jacques, S., Boucher, R.M., Riou, E., Srour, M., Carmant, L., Lortie, A., Major, P., Diadori, P., Dubeau, F., D'Anjou, G., Bourque, G., Berkovic, S.F., Sadleir, L.G., Campeau, P.M., Kibar, Z., Lafreniere, R.G., Girard, S.L., Mercimek-Mahmutoglu, S., Boelman, C., and Rouleau, G.A., et al.

Abstract

Item does not contain fulltext, 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.

Published
2017

9. Familial neonatal seizures in 36 families: Clinical and genetic features correlate with outcome.

Author

Mulley J.C., Malone S., Bassan H., Goldberg-Stern H., Stanley T., Hayman M., Calvert S., Korczyn A.D., Lev D., Lerman-Sagie T., Shevell M., Scheffer I.E., Berkovic S.F., Grinton B.E., Heron S.E., Pelekanos J.T., Zuberi S.M., Kivity S., Afawi Z., Williams T.C., Casalaz D.M., Yendle S., Linder I., Mulley J.C., Malone S., Bassan H., Goldberg-Stern H., Stanley T., Hayman M., Calvert S., Korczyn A.D., Lev D., Lerman-Sagie T., Shevell M., Scheffer I.E., Berkovic S.F., Grinton B.E., Heron S.E., Pelekanos J.T., Zuberi S.M., Kivity S., Afawi Z., Williams T.C., Casalaz D.M., Yendle S., and Linder I.

Abstract

Objective We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions. Methods Detailed clinical data were collected from 36 families comprising two or more individuals with neonatal seizures. The seizure course and occurrence of seizures later in life were analyzed. Families were screened for KCNQ2, KCNQ3, SCN2A, and PRRT2 mutations, and linkage studies were performed in mutation-negative families to exclude known loci. Results Thirty-three families fulfilled clinical criteria for benign familial neonatal epilepsy (BFNE); 27 of these families had KCNQ2 mutations, one had a KCNQ3 mutation, and two had SCN2A mutations. Seizures persisting after age 6 months were reported in 31% of individuals with KCNQ2 mutations; later seizures were associated with frequent neonatal seizures. Linkage mapping in two mutation-negative BFNE families excluded linkage to KCNQ2, KCNQ3, and SCN2A, but linkage to KCNQ2 could not be excluded in the third mutation-negative BFNE family. The three remaining families did not fulfill criteria of BFNE due to developmental delay or intellectual disability; a molecular lesion was identified in two; the other family remains unsolved. Significance Most families in our cohort of familial neonatal seizures fulfill criteria for BFNE; the molecular cause was identified in 91%. Most had KCNQ2 mutations, but two families had SCN2A mutations, which are normally associated with a mixed picture of neonatal and infantile onset seizures. Seizures later in life are more common in BFNE than previously reported and are associated with a greater number of seizures in the neonatal period. Linkage studies in two families excluded known loci, suggesting a further gene is involved in BFNE.Copyright © Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

Published
2015

10. PRIMA1 mutation: A new cause of nocturnal frontal lobe epilepsy

Author

Hildebrand, M.S., Tankard, R., Gazina, E.V., Damiano, J.A., Lawrence, K.M., Dahl, H-H.M., Regan, B.M., Shearer, A.E., Smith, R.J.H., Marini, C., Guerrini, R., Labate, A., Gambardella, A., Tinuper, P., Lichetta, L., Baldassari, S., Bisulli, F., Pippucci, T., Scheffer, I.E., Reid, C.A., Petrou, S., Bahlo, M., Berkovic, S.F., Hildebrand, M.S., Tankard, R., Gazina, E.V., Damiano, J.A., Lawrence, K.M., Dahl, H-H.M., Regan, B.M., Shearer, A.E., Smith, R.J.H., Marini, C., Guerrini, R., Labate, A., Gambardella, A., Tinuper, P., Lichetta, L., Baldassari, S., Bisulli, F., Pippucci, T., Scheffer, I.E., Reid, C.A., Petrou, S., Bahlo, M., and Berkovic, S.F.

Abstract

Objective Nocturnal frontal lobe epilepsy (NFLE) can be sporadic or autosomal dominant; some families have nicotinic acetylcholine receptor subunit mutations. We report a novel autosomal recessive phenotype in a single family and identify the causative gene. Methods Whole exome sequencing data was used to map the family, thereby narrowing exome search space, and then to identify the mutation. Results Linkage analysis using exome sequence data from two affected and two unaffected subjects showed homozygous linkage peaks on chromosomes 7, 8, 13, and 14 with maximum LOD scores between 1.5 and 1.93. Exome variant filtering under these peaks revealed that the affected siblings were homozygous for a novel splice site mutation (c.93+2T>C) in the PRIMA1 gene on chromosome 14. No additional PRIMA1 mutations were found in 300 other NFLE cases. The c.93+2T>C mutation was shown to lead to skipping of the first coding exon of the PRIMA1 mRNA using a minigene system. Interpretation PRIMA1 is a transmembrane protein that anchors acetylcholinesterase (AChE), an enzyme hydrolyzing acetycholine, to membrane rafts of neurons. PRiMA knockout mice have reduction of AChE and accumulation of acetylcholine at the synapse; our minigene analysis suggests that the c.93+2T>C mutation leads to knockout of PRIMA1. Mutations with gain of function effects in acetylcholine receptor subunits cause autosomal dominant NFLE. Thus, enhanced cholinergic responses are the likely cause of the severe NFLE and intellectual disability segregating in this family, representing the first recessive case to be reported and the first PRIMA1 mutation implicated in disease.

Published
2015

11. Postictal Psychosis in Epilepsy: A Clinicogenetic Study

Author

Simona Balestrini, Yvonne G. Weber, Antonio Gambardella, Michael G Doyle, Genevieve Rayner, Vera Braatz, Sanjay M. Sisodiya, Norman Delanty, Stella Calafato, Helena Martins Custodio, J Foong, Francesca Bisulli, Samuel F. Berkovic, Luigi Agrò, Christian Hengsbach, Elvira Bramon, Baihan Wang, Gianpiero L. Cavalleri, Costin Leu, Ingrid E. Scheffer, Braatz V., Martins Custodio H., Leu C., Agro L., Wang B., Calafato S., Rayner G., Doyle M.G., Hengsbach C., Bisulli F., Weber Y.G., Gambardella A., Delanty N., Cavalleri G., Foong J., Scheffer I.E., Berkovic S.F., Bramon E., Balestrini S., and Sisodiya S.M.

Subjects
Adult, Male, medicine.medical_specialty, Psychosis, Psychotic Disorder, Polymorphism, Single Nucleotide, Cohort Studies, Epilepsy, Psychiatric history, Internal medicine, medicine, Humans, Family history, Retrospective Studies, Psychiatric assessment, Electroencephalography, Odds ratio, Middle Aged, medicine.disease, Psychotic Disorders, Neurology, Schizophrenia, Case-Control Studies, Female, Neurology (clinical), Cohort Studie, Case-Control Studie, Human, Cohort study
Abstract

Annals of neurology 90(3), 464-476 (2021). doi:10.1002/ana.26174, Published by Wiley-Blackwell, Hoboken, NJ

Published
2021

12. Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy

Author

Luca Gozzelino, Gaga Kochlamazashvili, Sara Baldassari, Albert Ian Mackintosh, Laura Licchetta, Emanuela Iovino, Yu Chi Liu, Caitlin A Bennett, Mark F Bennett, John A Damiano, Gábor Zsurka, Caterina Marconi, Tania Giangregorio, Pamela Magini, Marijn Kuijpers, Tanja Maritzen, Giuseppe Danilo Norata, Stéphanie Baulac, Laura Canafoglia, Marco Seri, Paolo Tinuper, Ingrid E Scheffer, Melanie Bahlo, Samuel F Berkovic, Michael S Hildebrand, Wolfram S Kunz, Lucio Giordano, Francesca Bisulli, Miriam Martini, Volker Haucke, Emilio Hirsch, Tommaso Pippucci, Gozzelino L., Kochlamazashvili G., Baldassari S., Mackintosh A.I., Licchetta L., Iovino E., Liu Y.-C., Bennett C.A., Bennett M.F., Damiano J.A., Zsurka G., Marconi C., Giangregorio T., Magini P., Kuijpers M., Maritzen T., Norata G.D., Baulac S., Canafoglia L., Seri M., Tinuper P., Scheffer I.E., Bahlo M., Berkovic S.F., Hildebrand M.S., Kunz W.S., Giordano L., Bisulli F., Martini M., Haucke V., Hirsch E., and Pippucci T.

Subjects
PI3K-C2B, class II PI3K, epilepsy, mTOR, variants, Animals, Humans, Lipids, Mechanistic Target of Rapamycin Complex 1, Mice, Mutation, Phosphatidylinositol 3-Kinases, Seizures, Class II Phosphatidylinositol 3-Kinases, Epilepsies, Partial, Epilepsies, Animal, Lipid, Seizure, variant, Class II Phosphatidylinositol 3-Kinase, Settore BIO/14 - Farmacologia, Neurology (clinical), Phosphatidylinositol 3-Kinase, Human, Partial
Abstract

Epilepsy is one of the most frequent neurological diseases, with focal epilepsy accounting for the largest number of cases. The genetic alterations involved in focal epilepsy are far from being fully elucidated.Here, we show that defective lipid signalling caused by heterozygous ultra-rare variants in PIK3C2B, encoding for the class II phosphatidylinositol 3-kinase PI3K-C2β, underlie focal epilepsy in humans. We demonstrate that patients’ variants act as loss-of-function alleles, leading to impaired synthesis of the rare signalling lipid phosphatidylinositol 3,4-bisphosphate, resulting in mTORC1 hyperactivation. In vivo, mutant Pik3c2b alleles caused dose-dependent neuronal hyperexcitability and increased seizure susceptibility, indicating haploinsufficiency as a key driver of disease. Moreover, acute mTORC1 inhibition in mutant mice prevented experimentally induced seizures, providing a potential therapeutic option for a selective group of patients with focal epilepsy.Our findings reveal an unexpected role for class II PI3K-mediated lipid signalling in regulating mTORC1-dependent neuronal excitability in mice and humans.

Published
2022

13. Progressive Myoclonus Epilepsies

Author

Edoardo Ferlazzo, Laura Licchetta, Alessandro Filla, Samuel F. Berkovic, Roberto Michelucci, Paolo Tinuper, Martina Fanella, Silvana Franceschetti, Anna Teresa Giallonardo, Carolina Courage, Federico Zara, Antonio Gambardella, Teresa Anna Cantisani, Patrizia Riguzzi, Barbara Castellotti, Cinzia Gellera, Pasquale Striano, Carlo Di Bonaventura, Tiziana Granata, Melanie Bahlo, Laura Canafoglia, Karen Oliver, Angela La Neve, Anna-Elina Lehesjoki, Adriana Magaudda, HUSLAB, Medicum, Department of Medical and Clinical Genetics, Canafoglia L., Franceschetti S., Gambardella A., Striano P., Giallonardo A.T., Tinuper P., Di Bonaventura C., Michelucci R., Ferlazzo E., Granata T., Magaudda A., Licchetta L., Filla A., la Neve A., Riguzzi P., Cantisani T.A., Fanella M., Castellotti B., Gellera C., Bahlo M., Zara F., Courage C., Lehesjoki A.-E., Oliver K.L., and Berkovic S.F.

Subjects
Biology, DNA sequencing, 3124 Neurology and psychiatry, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Sibling, Gene, myoclonus epilepsy, Genetics (clinical), 030304 developmental biology, Genetic testing, Genetics, 0303 health sciences, medicine.diagnostic_test, 3112 Neurosciences, next generation sequency, Disease gene identification, 3. Good health, CHD2, 3121 General medicine, internal medicine and other clinical medicine, Epilepsy syndromes, Neurology (clinical), medicine.symptom, Myoclonus, 030217 neurology & neurosurgery
Abstract

Background and ObjectivesTo assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort.MethodsOf 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: “Unverricht-Lundborg disease-like PME,” “late-onset PME,” “PME plus developmental delay,” and “PME plus dementia.”ResultsSixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS, CACNA2D2, STUB1, AFG3L2, CLN6, NAXE, and CHD2. Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories.DiscussionThe application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield >80%, PME is one of the best genetically defined epilepsy syndromes.

Published
2021

14. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Joshua E. Motelow, Gundula Povysil, Ryan S. Dhindsa, Kate E. Stanley, Andrew S. Al- len, Yen-Chen Anne Feng, Daniel P. Howrigan, Liam E. Abbott, Ka- therine Tashman, Felecia Cerrato, Caroline Cusick, Tarjinder Singh, Henrike Heyne, Andrea E. Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Namrata Gupta, Benjamin M. Neale, Gianpiero L. Cavalleri, Patrick Cossette, Chris Cotsapas, Peter De Jonghe, Tracy Dixon-Salazar, Renzo Guerrini, Hakon Hakonarson, Erin L. Heinzen, Ingo Helbig, Patrick Kwan, Anthony G. Marson, Slave ? Petrovski, Sitharthan Kamalakaran, Sanjay M. Sisodiya, Randy Stewart, Sarah Weckhuysen, Chantal Depondt, Dennis J. Dlugos, Ingrid E. Scheffer, Pasquale Striano, Catharine Freyer, Roland Krause, Patrick May, Kevin McKenna, Brigid M. Regan, Caitlin A. Bennett, Costin Leu, Stephanie L. Leech, Terence J. O'Brien, Marian Todaro, Hannah Stamberger, Danielle M. Andrade, Quratulain Zulfiqar Ali, Tara R. Sadoway, Heinz Krestel, Andre ? Schaller, Savvas S. Papacostas, Ioanna Kou- siappa, George A. Tanteles, Yiolanda Christou, Katalin Sterbova ?, Marke ? ta Vlckova ?, Lucie Sedlackova, Petra Lassuthova ?, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Bernd A. Neubauer, Friedrich Zimprich, Martha Feucht, Eva M. Reinthaler, Wolfram S. Kunz, Ga ?bor Zsurka, Rainer Surges, Tobias Baumgart- ner, Randi von Wrede, Manuela Pendziwiat, Hiltrud Muhle, An- nika Rademacher, Andreas van Baalen, Sarah von Spiczak, Ulrich Stephani, Zaid Afawi, Amos D. Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Mu ?ller-Schlu ?ter, Gerhard Kluger, Martin Ha ?usler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne G. Weber, Stefan Wolking, Felicitas Becker, Stephan Lauxmann, Christian Boßelmann, Josua Kegele, Christian Hengs- bach, Sarah Rau, Bernhard J. Steinhoff, Andreas Schulze-Bonhage, IngoBorggra ?fe, ChristophJ.Schankin, SusanneSchubert-Bast, Herbert Schreiber, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Markus Wolff, Dieter Dennig, Rene Madeleyn, Reetta Ka ?lvia ?inen, Anni Saarela, Oskari Timonen, Tarja Linnankivi, Anna-Elina Lehesjoki, Sylvain Rheims, Gaetan Lesca, Philippe Ryvlin, Louis Maillard, Luc Valton, Philippe Derambure, Fabrice Bartolomei, Edouard Hirsch, Ve ?ronique Michel, Francine Chas- soux, Mark I. Rees, Seo-Kyung Chung, William O. Pickrell, Robert Powell, Mark D. Baker, Beata Fonferko-Shadrach, Charlotte Law- thom, Joseph Anderson, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R. Johnson, Pauls Auce, Graeme J. Sills, Larry W. Baum, Pak C. Sham, Stacey S. Cherny, Colin H.T. Lui, Norman Delanty, Colin P. Doherty, Arif Shukralla, Hany El-Naggar, Peter Widdess-Walsh, Nina Barisic, Laura 12 The American Journal of Human Genetics 108, 1-18, June 3, 2021 Please cite this article in press as: Epi25 Collaborative, Sub-genic intolerance, ClinVar, the epilepsies: A whole-exome sequencing study of 29, 165 individuals, The American Journal of Human Genetics (2021), https://doi.org/10.1016/j.ajhg.2021.04.009 Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Francesca Ragona, Federico Zara, Michele Iacomino, An- tonella Riva, Francesca Madia, Maria Stella Vari, Vincenzo Salpie- tro, Marcello Scala, Maria Margherita Mancardi, Lino Nobili, Elisa- betta Amadori, Thea Giacomini, Francesca Bisulli, Tommaso Pippucci, Laura Licchetta, Raffaella Minardi, Paolo Tinuper, Lor- enzo Muccioli, Barbara Mostacci, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carmen Barba, Shinichi Hirose, At- sushi Ishii, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Ahmad Beydoun, Wassim Nasreddine, Nathalie Khoueiry Zgheib, Birute Tumiene, Algirdas Utkus, Lynette G. Sadleir, Chontelle King, S. Hande Caglayan, Mutluay Arslan, Zuhal Yap?c?, P?nar To- paloglu, Bulent Kara, Uluc Yis, Dilsad Turkdogan, Asl? Gun- dogdu-Eken, Nerses Bebek, Meng-Han Tsai, Chen-Jui Ho, Chih- Hsiang Lin, Kuang-Lin Lin, I-Jun Chou, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Jeffrey L. Noebels, Alicia Goldman, Robyn M. Busch, Lara Jehi, Imad M. Najm, Lisa Ferguson, Jean Khoury, Tracy A. Glauser, Peggy O. Clark, Russell J. Buono, Thomas N. Ferraro, Michael R. Sperling, Warren Lo, Michael Privitera, Jac- queline A. French, Steven Schachter, Ruben I. Kuzniecky, Orrin Devinsky, Manu Hegde, David A. Greenberg, Colin A. Ellis, Ethan Goldberg, Katherine L. Helbig, Mahgenn Cosico, Priya Vaidis- waran, Eryn Fitch, Samuel F. Berkovic, Holger Lerche, Daniel H. Lowenstein, David B. Goldstein., Motelow J.E., Povysil G., Dhindsa R.S., Stanley K.E., Allen A.S., Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Cusick C., Singh T., Heyne H., Byrnes A.E., Churchhouse C., Watts N., Solomonson M., Lal D., Gupta N., Neale B.M., Cavalleri G.L., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E.L., Helbig I., Kwan P., Marson A.G., Petrovski S., Kamalakaran S., Sisodiya S.M., Stewart R., Weckhuysen S., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B.M., Bennett C.A., Leu C., Leech S.L., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Ali Q.Z., Sadoway T.R., Krestel H., Schaller A., Papacostas S.S., Kousiappa I., Tanteles G.A., Christou Y., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Neubauer B.A., Zimprich F., Feucht M., Reinthaler E.M., Kunz W.S., Zsurka G., Surges R., Baumgartner T., von Wrede R., Pendziwiat M., Muhle H., Rademacher A., van Baalen A., von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Lauxmann S., Bosselmann C., Kegele J., Hengsbach C., Rau S., Steinhoff B.J., Schulze-Bonhage A., Borggrafe I., Schankin C.J., Schubert-Bast S., Schreiber H., Mayer T., Korinthenberg R., Brockmann K., Wolff M., Dennig D., Madeleyn R., Kalviainen R., Saarela A., Timonen O., Linnankivi T., Lehesjoki A.-E., Rheims S., Lesca G., Ryvlin P., Maillard L., Valton L., Derambure P., Bartolomei F., Hirsch E., Michel V., Chassoux F., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Baker M.D., Fonferko-Shadrach B., Lawthom C., Anderson J., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Delanty N., Doherty C.P., Shukralla A., El-Naggar H., Widdess-Walsh P., Barisic N., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Ragona F., Zara F., Iacomino M., Riva A., Madia F., Vari M.S., Salpietro V., Scala M., Mancardi M.M., Nobili L., Amadori E., Giacomini T., Bisulli F., Pippucci T., Licchetta L., Minardi R., Tinuper P., Muccioli L., Mostacci B., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Barba C., Hirose S., Ishii A., Suzuki T., Inoue Y., Yamakawa K., Beydoun A., Nasreddine W., Khoueiry Zgheib N., Tumiene B., Utkus A., Sadleir L.G., King C., Caglayan S.H., Arslan M., Yapici Z., Topaloglu P., Kara B., Yis U., Turkdogan D., Gundogdu-Eken A., Bebek N., Tsai M.-H., Ho C.-J., Lin C.-H., Lin K.-L., Chou I.-J., Poduri A., Shiedley B.R., Shain C., Noebels J.L., Goldman A., Busch R.M., Jehi L., Najm I.M., Ferguson L., Khoury J., Glauser T.A., Clark P.O., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Greenberg D.A., Ellis C.A., Goldberg E., Helbig K.L., Cosico M., Vaidiswaran P., Fitch E., Berkovic S.F., Lerche H., Lowenstein D.H., Goldstein D.B., Epi25 Collaborative, Institut de Neurosciences des Systèmes (INS), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, focal epilepsy, Whole Exome Sequencing, Cohort Studies, Epilepsy, 0302 clinical medicine, Genetic Marker, Missense mutation, Exome, whole-exome sequencing, generalized epilepsy, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Exome sequencing, seizures, Genetics, ClinVar, Phenotype, epileptic encephalopathy, Epi25, intolerance, Case-Control Studie, Human, Genetic Markers, seizure, Disease Association, Biology, Article, 03 medical and health sciences, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Generalized epilepsy, Gene, Louvain, [SCCO.NEUR]Cognitive science/Neuroscience, Correction, Genetic Variation, medicine.disease, epilepsy, Human genetics, 030104 developmental biology, Case-Control Studies, Human medicine, Cohort Studie, Genetic generalized epilepsy, 030217 neurology & neurosurgery
Abstract

Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Published
2021

15. Polygenic burden in focal and generalized epilepsies

Author

Leu C., Stevelink R., Smith A. W., Goleva S. B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S. M., Cavalleri G. L., Koeleman B. P. C., Lerche H., Jehi L., Davis L. K., Najm I. M., Palotie A., Daly M. J., Busch R. M., Lal D., Feng Y. -C. A., Howrigan D. P., Abbott L. E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B. M., Berkovic S. F., Goldstein D. B., Lowenstein D. H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E. L., Helbig I., Kwan P., Marson A. G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D. J., Scheffer I. E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B. M., Bellows S. T., Bennett C. A., Johns E. M. C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T. J., Todaro M., Stamberger H., Andrade D. M., Sadoway T. R., Mo K., Krestel H., Gallati S., Papacostas S. S., Kousiappa I., Tanteles G. A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K. M., Rosenow F., Reif P. S., Knake S., Kunz W. S., Zsurka G., Elger C. E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A. D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J. R., Krey I., Weber Y. G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A. F., Steinhoff B. J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C. J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A. -E., Rees M. I., Chung S. -K., Pickrell W. O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M. R., Auce P., Sills G. J., Baum L. W., Sham P. C., Cherny S. S., Lui C. H. T., Barisic N., Delanty N., Doherty C. P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M. S., Mancardi M. M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L. G., King C., Mountier E., Caglayan S. H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B. R., Shain C., Poduri A., Buono R. J., Ferraro T. N., Sperling M. R., Lo W., Privitera M., French J. A., Schachter S., Kuzniecky R. I., Devinsky O., Hegde M., Khankhanian P., Helbig K. L., Ellis C. A., Spalletta G., Piras F., Gili T., Ciullo V., Leu C., Stevelink R., Smith A.W., Goleva S.B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S.M., Cavalleri G.L., Koeleman B.P.C., Lerche H., Jehi L., Davis L.K., Najm I.M., Palotie A., Daly M.J., Busch R.M., Lal D., Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B.M., Berkovic S.F., Goldstein D.B., Lowenstein D.H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E.L., Helbig I., Kwan P., Marson A.G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B.M., Bellows S.T., Bennett C.A., Johns E.M.C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Sadoway T.R., Mo K., Krestel H., Gallati S., Papacostas S.S., Kousiappa I., Tanteles G.A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Kunz W.S., Zsurka G., Elger C.E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A.F., Steinhoff B.J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C.J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A.-E., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Barisic N., Delanty N., Doherty C.P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M.S., Mancardi M.M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L.G., King C., Mountier E., Caglayan S.H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B.R., Shain C., Poduri A., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Khankhanian P., Helbig K.L., Ellis C.A., Spalletta G., Piras F., Gili T., Ciullo V., Commission of the European Communities, Medical Research Council (MRC), Tumienė, Birutė, Mameniškienė, Rūta, Utkus, Algirdas, Praninskienė, Rūta, Grikinienė, Jurgita, Samaitienė-Aleknienė, Rūta, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Helsinki Institute of Life Science HiLIFE, and Department of Medical and Clinical Genetics

Subjects
0301 basic medicine, Male, Multifactorial Inheritance, Epi25 Consortium, Databases, Factual, FEATURES, Genome-wide association study, Epilepsies, 3124 Neurology and psychiatry, Cohort Studies, Epilepsy, 0302 clinical medicine, Cost of Illness, 1ST SEIZURE, HISTORY, genetics, POPULATION, 11 Medical and Health Sciences, education.field_of_study, medicine.diagnostic_test, SCORES, Single Nucleotide, Biobank, 3. Good health, 17 Psychology and Cognitive Sciences, Genetic generalized epilepsy, Epilepsy, Generalized, Female, Partial, Cohort study, Human, medicine.medical_specialty, Population, European Continental Ancestry Group, Clinical Neurology, BIOBANK, Polymorphism, Single Nucleotide, epilepsy, genetic generalized epilepsy, common variant risk, Databases, 03 medical and health sciences, Genetic, Internal medicine, medicine, Journal Article, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, Generalized epilepsy, education, SEIZURE RECURRENCE, Factual, METAANALYSIS, Genetic testing, Neurology & Neurosurgery, RISK PREDICTION, Generalized, business.industry, 3112 Neurosciences, Common variant risk, Genetic Variation, Original Articles, medicine.disease, Comorbidity, Cost of Illne, Epilepsies, Partial, Genome-Wide Association Study, 030104 developmental biology, Neurology (clinical), Cohort Studie, business, 030217 neurology & neurosurgery
Abstract

See Hansen and Møller (doi:10.1093/brain/awz318) for a scientific commentary on this article. Using polygenic risk scores from a genome-wide association study in generalized and focal epilepsy, Leu et al. reveal a significantly higher genetic burden for epilepsy in multiple cohorts of people with epilepsy compared to population controls. Quantification of common variant burden may be valuable for epilepsy prognosis and treatment., Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10−15; Cleveland: P = 2.85×10−4; Finnish-ancestry Epi25: P = 1.80×10−4) or population controls (Epi25: P = 2.35×10−70; Cleveland: P = 1.43×10−7; Finnish-ancestry Epi25: P = 3.11×10−4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10−4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10−19; Cleveland: P = 1.69×10−6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10−15; Cleveland: P = 1.39×10−2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls—in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.

Published
2019

16. 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

17. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Author

Yen-Chen Anne Feng, Daniel P. Howrigan, Liam E. Abbott, Katherine Tashman, Felecia Cerrato, Tarjinder Singh, Henrike Heyne, Andrea Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Erin L. Heinzen, Ryan S. Dhindsa, Kate E. Stanley, Gianpiero L. Cavalleri, Hakon Hakonarson, Ingo Helbig, Roland Krause, Patrick May, Sarah Weckhuysen, Slavé Petrovski, Sitharthan Kamalakaran, Sanjay M. Sisodiya, Patrick Cossette, Chris Cotsapas, Peter De Jonghe, Tracy Dixon-Salazar, Renzo Guerrini, Patrick Kwan, Anthony G. Marson, Randy Stewart, Chantal Depondt, Dennis J. Dlugos, Ingrid E. Scheffer, Pasquale Striano, Catharine Freyer, Kevin McKenna, Brigid M. Regan, Susannah T. Bellows, Costin Leu, Caitlin A. Bennett, Esther M.C. Johns, Alexandra Macdonald, Hannah Shilling, Rosemary Burgess, Dorien Weckhuysen, Melanie Bahlo, Terence J. O’Brien, Marian Todaro, Hannah Stamberger, Danielle M. Andrade, Tara R. Sadoway, Kelly Mo, Heinz Krestel, Sabina Gallati, Savvas S. Papacostas, Ioanna Kousiappa, George A. Tanteles, Katalin Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Wolfram S. Kunz, Gábor Zsurka, Christian E. Elger, Jürgen Bauer, Michael Rademacher, Manuela Pendziwiat, Hiltrud Muhle, Annika Rademacher, Andreas van Baalen, Sarah von Spiczak, Ulrich Stephani, Zaid Afawi, Amos D. Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Müller-Schlüter, Gerhard Kluger, Martin Häusler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne G. Weber, Stefan Wolking, Felicitas Becker, Christian Hengsbach, Sarah Rau, Ana F. Maisch, Bernhard J. Steinhoff, Andreas Schulze-Bonhage, Susanne Schubert-Bast, Herbert Schreiber, Ingo Borggräfe, Christoph J. Schankin, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Dieter Dennig, Rene Madeleyn, Reetta Kälviäinen, Pia Auvinen, Anni Saarela, Tarja Linnankivi, Anna-Elina Lehesjoki, Mark I. Rees, Seo-Kyung Chung, William O. Pickrell, Robert Powell, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R. Johnson, Pauls Auce, Graeme J. Sills, Larry W. Baum, Pak C. Sham, Stacey S. Cherny, Colin H.T. Lui, Nina Barišić, Norman Delanty, Colin P. Doherty, Arif Shukralla, Mark McCormack, Hany El-Naggar, Laura Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Federico Zara, Michele Iacomino, Francesca Madia, Maria Stella Vari, Maria Margherita Mancardi, Vincenzo Salpietro, Francesca Bisulli, Paolo Tinuper, Laura Licchetta, Tommaso Pippucci, Carlotta Stipa, Raffaella Minardi, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carla Marini, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Birute Tumiene, Lynette G. Sadleir, Chontelle King, Emily Mountier, S. Hande Caglayan, Mutluay Arslan, Zuhal Yapıcı, Uluc Yis, Pınar Topaloglu, Bulent Kara, Dilsad Turkdogan, Aslı Gundogdu-Eken, Nerses Bebek, Sibel Uğur-İşeri, Betül Baykan, Barış Salman, Garen Haryanyan, Emrah Yücesan, Yeşim Kesim, Çiğdem Özkara, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Russell J. Buono, Thomas N. Ferraro, Michael R. Sperling, Warren Lo, Michael Privitera, Jacqueline A. French, Steven Schachter, Ruben I. Kuzniecky, Orrin Devinsky, Manu Hegde, Pouya Khankhanian, Katherine L. Helbig, Colin A. Ellis, Gianfranco Spalletta, Fabrizio Piras, Federica Piras, Tommaso Gili, Valentina Ciullo, Andreas Reif, Andrew McQuillin, Nick Bass, Andrew McIntosh, Douglas Blackwood, Mandy Johnstone, Aarno Palotie, Michele T. Pato, Carlos N. Pato, Evelyn J. Bromet, Celia Barreto Carvalho, Eric D. Achtyes, Maria Helena Azevedo, Roman Kotov, Douglas S. Lehrer, Dolores Malaspina, Stephen R. Marder, Helena Medeiros, Christopher P. Morley, Diana O. Perkins, Janet L. Sobell, Peter F. Buckley, Fabio Macciardi, Mark H. Rapaport, James A. Knowles, Ayman H. Fanous, Steven A. McCarroll, Namrata Gupta, Stacey B. Gabriel, Mark J. Daly, Eric S. Lander, Daniel H. Lowenstein, David B. Goldstein, Holger Lerche, Samuel F. Berkovic, Benjamin M. Neale, Wellcome Trust, Department of Health, Institute of Neurology, UCL, Imperial College Healthcare NHS Trust- BRC Funding, Commission of the European Communities, Medical Research Council (MRC), Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Singh T., Heyne H., Byrnes A., Churchhouse C., Watts N., Solomonson M., Lal D., Heinzen E.L., Dhindsa R.S., Stanley K.E., Cavalleri G.L., Hakonarson H., Helbig I., Krause R., May P., Weckhuysen S., Petrovski S., Kamalakaran S., Sisodiya S.M., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Kwan P., Marson A.G., Stewart R., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., McKenna K., Regan B.M., Bellows S.T., Leu C., Bennett C.A., Johns E.M.C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Sadoway T.R., Mo K., Krestel H., Gallati S., Papacostas S.S., Kousiappa I., Tanteles G.A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Kunz W.S., Zsurka G., Elger C.E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., van Baalen A., von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A.F., Steinhoff B.J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C.J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A.-E., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Barisic N., Delanty N., Doherty C.P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M.S., Mancardi M.M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Tumiene B., Sadleir L.G., King C., Mountier E., Caglayan S.H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Poduri A., Shiedley B.R., Shain C., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Khankhanian P., Helbig K.L., Ellis C.A., Spalletta G., Piras F., Gili T., Ciullo V., Reif A., McQuillin A., Bass N., McIntosh A., Blackwood D., Johnstone M., Palotie A., Pato M.T., Pato C.N., Bromet E.J., Carvalho C.B., Achtyes E.D., Azevedo M.H., Kotov R., Lehrer D.S., Malaspina D., Marder S.R., Medeiros H., Morley C.P., Perkins D.O., Sobell J.L., Buckley P.F., Macciardi F., Rapaport M.H., Knowles J.A., Fanous A.H., McCarroll S.A., Gupta N., Gabriel S.B., Daly M.J., Lander E.S., Lowenstein D.H., Goldstein D.B., Lerche H., Berkovic S.F., Neale B.M., Epi25 Collaborative, YÜCESAN, EMRAH, Institute for Molecular Medicine Finland, Children's Hospital, HUS Children and Adolescents, Department of Medical and Clinical Genetics, University Management, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, and Genomics of Neurological and Neuropsychiatric Disorders

Subjects
s.berkovic@unimelb.edu.au [Epi25 Collaborative. Electronic address], 0301 basic medicine, GAMMA-2-SUBUNIT, burden analysi, DNA Mutational Analysis, PROTEIN, Neurodegenerative, VARIANTS, SUSCEPTIBILITY, Medical and Health Sciences, Epilepsy, 0302 clinical medicine, 2.1 Biological and endogenous factors, EPIDEMIOLOGY, Missense mutation, Exome, Aetiology, Genetics (clinical), Exome sequencing, 11 Medical and Health Sciences, seizures, GABRG2, Genetics, Genetics & Heredity, 0303 health sciences, biology, COMMON EPILEPSIES, 1184 Genetics, developmental biology, physiology, sequencing, Biological Sciences, Epi25 Collaborative, Phenotype, GENOME, epileptic encephalopathy, burden analysis, Neurological, Biotechnology, Genetic Markers, seizure, EEF1A2, Burden analysis, epilepsy, exome, Article, 03 medical and health sciences, Clinical Research, Exome Sequencing, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Gene, EPILEPTIC SEIZURES, METAANALYSIS, 030304 developmental biology, Human Genome, Neurosciences, Genetic Variation, 06 Biological Sciences, medicine.disease, Brain Disorders, 030104 developmental biology, Genetic marker, DE-NOVO MUTATIONS, Case-Control Studies, biology.protein, 3111 Biomedicine, Human medicine, 030217 neurology & neurosurgery
Abstract

Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of European ancestry. We focused on three phenotypic groups; the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.

Published
2019

18. PRIMA1 mutation: a new cause of nocturnal frontal lobe epilepsy

Author

Antonio Gambardella, Brigid M. Regan, Aiden Eliot Shearer, Samuel F. Berkovic, Francesca Bisulli, Sara Baldassari, Carla Marini, Renzo Guerrini, Hans Henrik M. Dahl, Tommaso Pippucci, Richard J.H. Smith, Ingrid E. Scheffer, Laura Lichetta, Rick M. Tankard, Christopher A. Reid, Steven Petrou, Angelo Labate, Kate M. Lawrence, Melanie Bahlo, Michael S. Hildebrand, John A. Damiano, Paolo Tinuper, Elena V. Gazina, Hildebrand M.S., Tankard R., Gazina E.V., Damiano J.A., Lawrence K.M., Dahl H-H. M., Regan B.M., Shearer A.E., Smith R.J.H., Marini C., Guerrini R., Labate A., Gambardella A., Tinuper P., Licchetta L., Baldassari S., Bisulli F., Pippucci T., Scheffer I.E., Reid C.A., Petrou S., Bahlo M., and Berkovic S.F.

Subjects
Genetics, Mutation, Splice site mutation, Autosomal recessive nocturnal frontal lobe epilepsy, General Neuroscience, Nocturnal frontal lobe epilepsy, Biology, medicine.disease_cause, PRIMA1, NFLE, Exon, Genetic linkage, intellectual disability, Autosomal Dominant, medicine, Neurology (clinical), Exome, Exome sequencing, Research Articles, Minigene
Abstract

OBJECTIVE: Nocturnal frontal lobe epilepsy (NFLE) can be sporadic or autosomal dominant; some families have nicotinic acetylcholine receptor subunit mutations. We report a novel autosomal recessive phenotype in a single family and identify the causative gene. METHODS: Whole exome sequencing data was used to map the family, thereby narrowing exome search space, and then to identify the mutation. RESULTS: Linkage analysis using exome sequence data from two affected and two unaffected subjects showed homozygous linkage peaks on chromosomes 7, 8, 13, and 14 with maximum LOD scores between 1.5 and 1.93. Exome variant filtering under these peaks revealed that the affected siblings were homozygous for a novel splice site mutation (c.93+2T>C) in the PRIMA1 gene on chromosome 14. No additional PRIMA1 mutations were found in 300 other NFLE cases. The c.93+2T>C mutation was shown to lead to skipping of the first coding exon of the PRIMA1 mRNA using a minigene system. INTERPRETATION: PRIMA1 is a transmembrane protein that anchors acetylcholinesterase (AChE), an enzyme hydrolyzing acetycholine, to membrane rafts of neurons. PRiMA knockout mice have reduction of AChE and accumulation of acetylcholine at the synapse; our minigene analysis suggests that the c.93+2T>C mutation leads to knockout of PRIMA1. Mutations with gain of function effects in acetylcholine receptor subunits cause autosomal dominant NFLE. Thus, enhanced cholinergic responses are the likely cause of the severe NFLE and intellectual disability segregating in this family, representing the first recessive case to be reported and the first PRIMA1 mutation implicated in disease.

Published
2015

19. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy

Author

Steven Petrou, Aarno Palotie, Danielle M. Andrade, Marta A. Bayly, Laura Licchetta, Ingrid E. Scheffer, Rikke S. Møller, Frederick Andermann, Laura Canafoglia, Arielle Crespel, Silvana Franceschetti, Veronica Saletti, Michael Duchowny, Michael S. Hildebrand, Ebba Lohmann, Antonio Gambardella, Eva Andermann, Chiara Criscuolo, Salla Markkinen, Bernt A. Engelsen, Cigdem Ozkara, Meral Topçu, Adeel Ahmad, Edoardo Ferlazzo, Holger Lerche, João Massano, Edith Said, Mary D. King, Paolo Tinuper, Alessandro Filla, Mikko Muona, Samuel F. Berkovic, Betül Baykan, Alberto J. Espay, Karen Oliver, Matthias Lindenau, Michael Privitera, Zaid Afawi, Tarja Joensuu, Leanne M. Dibbens, Bruria Ben-Zeev, Snezana Maljevic, Patrizia Riguzzi, Kaitlin E. Samocha, Birgit Kauffmann, Mark J. Daly, Roberto Michelucci, Rachel Straussberg, Sarah E. Heron, Anna-Elina Lehesjoki, Jamil Ahmad, Muona, Mikko, Berkovic, Samuel F, Dibbens, Leanne M, Oliver, Karen L, Bayly, Marta A, Heron, Sarah E, Lehesjoki, Anna-Elina, Muona, M., Berkovic, S.F., Dibbens, L.M., Oliver, K.L., Maljevic, S., Bayly, M.A., Joensuu, T., Canafoglia, L., Franceschetti, S., Michelucci, R., Markkinen, S., Heron, S.E., Hildebrand, M.S., Andermann, E., Andermann, F., Gambardella, A., Tinuper, P., Licchetta, L., Scheffer, I.E., Criscuolo, C., Filla, A., Ferlazzo, E., Ahmad, J., Ahmad, A., Baykan, B., Said, E., Topcu, M., Riguzzi, P., King, M.D., Ozkara, C., Andrade, D.M., Engelsen, B.A., Crespel, A., Lindenau, M., Lohmann, E., Saletti, V., Massano, J., Privitera, M., Espay, A.J., Kauffmann, B., Duchowny, M., Moller, R.S., Straussberg, R., Afawi, Z., Ben-Zeev, B., Samocha, K.E., Daly, M.J., Petrou, S., Lerche, H., Palotie, A., Lehesjoki, A.-E., Çocuk Sağlığı ve Hastalıkları, Maljevic, Snezana, Joensuu, Tarja, Canafoglia, Laura, Franceschetti, Silvana, Michelucci, Roberto, Markkinen, Salla, Hildebrand, Michael S, Andermann, Eva, Andermann, Frederick, Gambardella, Antonio, Tinuper, Paolo, Licchetta, Laura, Scheffer, Ingrid E, Criscuolo, Chiara, Filla, Alessandro, Ferlazzo, Edoardo, Ahmad, Jamil, Ahmad, Adeel, Baykan, Betul, Said, Edith, Topcu, Meral, Riguzzi, Patrizia, King, Mary D, Ozkara, Cigdem, Andrade, Danielle M, Engelsen, Bernt A, Crespel, Arielle, Lindenau, Matthia, Lohmann, Ebba, Saletti, Veronica, Massano, João, Privitera, Michael, Espay, Alberto J, Kauffmann, Birgit, Duchowny, Michael, Møller, Rikke S, Straussberg, Rachel, Afawi, Zaid, Ben Zeev, Bruria, Samocha, Kaitlin E, Daly, Mark J, Petrou, Steven, Lerche, Holger, Palotie, Aarno, and Lehesjoki, Anna Elina

Subjects
Male, Protein Conformation, PRNP protein, human, SACS protein, human, medicine.disease_cause, genetics [Carrier Proteins], Epilepsy, 0302 clinical medicine, genetics [Heat-Shock Proteins], Missense mutation, Exome, Conserved Sequence, Heat-Shock Proteins, Genes, Dominant, Genetics & Heredity, Genetics, 0303 health sciences, Mutation, GTPase-Activating Proteins, Heat-Shock Protein, genetics [Myoclonic Epilepsies, Progressive], KCNC1 protein, human, 3. Good health, Pedigree, Shaw Potassium Channels, Prion, Female, medicine.symptom, Human, Ataxia, Prions, Molecular Sequence Data, Mutation, Missense, Nerve Tissue Proteins, Progressive myoclonus epilepsy, Biology, Article, Prion Proteins, 03 medical and health sciences, Species Specificity, physiology [Shaw Potassium Channels], ddc:570, medicine, Animals, Humans, Point Mutation, Shaw Potassium Channel, Amino Acid Sequence, 030304 developmental biology, genetics [Shaw Potassium Channels], Base Sequence, Sequence Homology, Amino Acid, Animal, genetics [Prions], Point mutation, Membrane Proteins, medicine.disease, Myoclonic Epilepsies, Progressive, Molecular biology, SHAKER K+ CHANNEL DNA-SEQUENCING DATA ATAXIA TYPE 13 POTASSIUM CHANNEL S4 SEGMENT CYSTATIN-B DISEASE FREQUENCY FRAMEWORK ONSET, Amino Acid Substitution, KCNC1, epilepsy, TBC1D24 protein, human, mutation, Carrier Protein, Carrier Proteins, Myoclonus, Sequence Alignment, 030217 neurology & neurosurgery
Abstract

Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31 %). Remarkably, a recurrent de novo mutation, c. 959G>A (p.Arg320His), in KCNC1 was identified as a new major cause for PME. Eleven unrelated exome-sequenced (13%) and two affected individuals in a secondary cohort (7%) had this mutation. KCNC1 encodes KV3.1, a subunit of the KV3 voltage-gated potassium ion channels, which are major determinants of high-frequency neuronal firing. Functional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect. Ten cases had pathogenic mutations in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6 and SERPINI1). Identification of mutations in PRNP, SACS and TBC1D24 expand their phenotypic spectra to PME. These findings provide insights into the molecular genetic basis of PME and show the role of de novo mutations in this disease entity. Refereed/Peer-reviewed

Published
2015

Catalog

Books, media, physical & digital resources
See catalog results