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2. Statement in Support of: 'Virology under the Microscope-a Call for Rational Discourse'.

Author

Speck, P, Mackenzie, J, Bull, RA, Slobedman, B, Drummer, H, Fraser, J, Herrero, L, Helbig, K, Londrigan, S, Moseley, G, Prow, N, Hansman, G, Edwards, R, Ahlenstiel, C, Abendroth, A, Tscharke, D, Hobson-Peters, J, Kriiger-Loterio, R, Parry, R, Marsh, G, Harding, E, Jacques, DA, Gartner, MJ, Lee, WS, McAuley, J, Vaz, P, Sainsbury, F, Tate, MD, Sinclair, J, Imrie, A, Rawlinson, S, Harman, A, Carr, JM, Monson, EA, Hibma, M, Mahony, TJ, Tu, T, Center, RJ, Shrestha, LB, Hall, R, Warner, M, Ward, V, Anderson, DE, Eyre, NS, Netzler, NE, Peel, AJ, Revill, P, Beard, M, Legione, AR, Spencer, AJ, Idris, A, Forwood, J, Sarker, S, Purcell, DFJ, Bartlett, N, Deerain, JM, Brew, BJ, Asgari, S, Farrell, H, Khromykh, A, Enosi Tuipulotu, D, Anderson, D, Mese, S, Tayyar, Y, Edenborough, K, Uddin, JM, Hussain, A, Daymond, CJI, Agius, J, Johnson, KN, Shirmast, P, Abedinzadeshahri, M, MacDiarmid, R, Ashley, CL, Laws, J, Furfaro, LL, Burton, TD, Johnson, SMR, Telikani, Z, Petrone, M, Roby, JA, Samer, C, Suhrbier, A, Van Der Kamp, A, Cunningham, A, Donato, C, Mahar, J, Black, WD, Vasudevan, S, Lenchine, R, Spann, K, Rawle, DJ, Rudd, P, Neil, J, Kingston, R, Newsome, TP, Kim, KW, Mak, J, Lowry, K, Bryant, N, Meers, J, Roberts, JA, McMillan, N, Labzin, LI, Slonchak, A, Hugo, LE, Henzeler, B, Newton, ND, David, CT, Reading, PC, Esneau, C, Briody, T, Nasr, N, McNeale, D, McSharry, B, Fakhri, O, Horsburgh, BA, Logan, G, Howley, P, Young, P, Speck, P, Mackenzie, J, Bull, RA, Slobedman, B, Drummer, H, Fraser, J, Herrero, L, Helbig, K, Londrigan, S, Moseley, G, Prow, N, Hansman, G, Edwards, R, Ahlenstiel, C, Abendroth, A, Tscharke, D, Hobson-Peters, J, Kriiger-Loterio, R, Parry, R, Marsh, G, Harding, E, Jacques, DA, Gartner, MJ, Lee, WS, McAuley, J, Vaz, P, Sainsbury, F, Tate, MD, Sinclair, J, Imrie, A, Rawlinson, S, Harman, A, Carr, JM, Monson, EA, Hibma, M, Mahony, TJ, Tu, T, Center, RJ, Shrestha, LB, Hall, R, Warner, M, Ward, V, Anderson, DE, Eyre, NS, Netzler, NE, Peel, AJ, Revill, P, Beard, M, Legione, AR, Spencer, AJ, Idris, A, Forwood, J, Sarker, S, Purcell, DFJ, Bartlett, N, Deerain, JM, Brew, BJ, Asgari, S, Farrell, H, Khromykh, A, Enosi Tuipulotu, D, Anderson, D, Mese, S, Tayyar, Y, Edenborough, K, Uddin, JM, Hussain, A, Daymond, CJI, Agius, J, Johnson, KN, Shirmast, P, Abedinzadeshahri, M, MacDiarmid, R, Ashley, CL, Laws, J, Furfaro, LL, Burton, TD, Johnson, SMR, Telikani, Z, Petrone, M, Roby, JA, Samer, C, Suhrbier, A, Van Der Kamp, A, Cunningham, A, Donato, C, Mahar, J, Black, WD, Vasudevan, S, Lenchine, R, Spann, K, Rawle, DJ, Rudd, P, Neil, J, Kingston, R, Newsome, TP, Kim, KW, Mak, J, Lowry, K, Bryant, N, Meers, J, Roberts, JA, McMillan, N, Labzin, LI, Slonchak, A, Hugo, LE, Henzeler, B, Newton, ND, David, CT, Reading, PC, Esneau, C, Briody, T, Nasr, N, McNeale, D, McSharry, B, Fakhri, O, Horsburgh, BA, Logan, G, Howley, P, and Young, P

Published
2023

4. Male patients affected by mosaic PCDH19 mutations: five new cases

Author

de Lange, I. M., Rump, P., Neuteboom, R. F., Augustijn, P. B., Hodges, K., Kistemaker, A. I., Brouwer, O. F., Mancini, G. M. S., Newman, H. A., Vos, Y. J., Helbig, K. L., Peeters-Scholte, C., Kriek, M., Knoers, N. V., Lindhout, D., Koeleman, B. P. C., van Kempen, M. J. A., and Brilstra, E. H.

Published
2017
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7. Seroprevalence of Coxiella burnetii antibodies in wild deer populations in eastern Australia.

Author

Voss, L, Huaman, J, Pacioni, C, Tolpinrud, A, Helbig, K, Carvalho, TG, and Firestone, SM

Subjects
DEER populations, COXIELLA burnetii, Q fever, SEROPREVALENCE, LIVESTOCK losses, IMMUNOGLOBULINS
Abstract

Coxiella burnetii causes significant reproduction losses in livestock and the disease Q fever in humans. Transmission of C. burnetii is facilitated by the stability of the bacterium in the environment and the susceptibility of a variety of host species to infection. Consequently, inter‐species transmission occurs frequently through either direct or indirect contact. Wildlife may represent reservoirs of C. burnetii and could therefore be a source of infection for domestic animals. Understanding the prevalence of C. burnetii infections at the wildlife‐livestock interface is important for disease control. This study aimed to investigate the extent of C. burnetii exposure in wild deer in eastern Australia. Serum samples were obtained from 413 wild deer from seven regions in four eastern Australian states from 2017 to 2020. Antibodies were detected using a commercial Q fever antibody kit validated for ruminants. Seroprevalence of C. burnetii antibodies in deer was determined and true prevalence estimated, for each region. The overall seroprevalence of C. burnetii antibodies in wild deer was 3.4% (14 seropositive of 413 deer sampled) with true prevalence estimated to be 4.3% (95% credible interval: 0.6%, 10.9%). Seropositive deer were identified only in Queensland (7/108 seropositive) and northern New South Wales (7/120 seropositive). This geospatial distribution is consistent with seropositivity in other animal species and indicative of the level of C. burnetii in the environment. The low seroprevalence suggests that wild deer are unlikely to be a major reservoir species for C. burnetii in eastern Australia but may still be implicated in inter‐species transmission cycles. [ABSTRACT FROM AUTHOR]

Published
2023
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8. A Formalism for the Consistent Description of Non-Linear Elasticity of Anisotropic Media Formalisme pour une description cohérente de l'élasticité non linéaire des milieux anisotropes

Author

Helbig K.

Subjects
Chemical technology, TP1-1185, Energy industries. Energy policy. Fuel trade, HD9502-9502.5
Abstract

The propagation of elastic waves is generally treated under four assumptions: - that the medium is isotropic,- that the medium is homogeneous, - that there is a one-to-one relationship between stress and strain, - that stresses are linearly related to strains (equivalently, that strains are linearly related to stresses). Real media generally violate at least some-and often all-of these assumptions. A valid theoretical description of wave propagation in real media thus depends on the qualitative and quantitative description of the relevant inhomogeneity, anisotropy, and non-linearity: one either has to assume (or show) that the deviation from the assumption can - for the problem at hand - be neglected, or develop a theoretical description that is valid even under the deviation. While the effect of a single deviation from the ideal state is rather well understood, difficulties arise in the combination of several such deviations. Non-linear elasticity of anisotropic (triclinic) rock samples has been reported, e. g. by P. Rasolofosaon and H. Yin at the 6th IWSA in Trondheim (Rasolofosaon and Yin, 1996). Non-linear anisotropic elasticity matters only for non-infinitesimalamplitudes, i. e. , at least in the vicinity of the source. How large this vicinity is depends on the accuracy of observation and interpretation one tries to maintain, on the source intensity, and on the level of non-linearity. This paper is concerned with the last aspect, i. e. , with the meaning of the numbers beyond the fact that they are the results of measurements. As a measure of the non-linearity of the material, one can use the strain level at which the effective stiffness tensor deviates significantly from the zero-strain stiffness tensor. Particularly useful for this evaluation is the eigensystem (six eigenstiffnesses and six eigenstrains) of the stiffness tensor : the eigenstrains provide suitable strain typesfor the calculation of the effective stiffness tensor, and the deviation can be expressed by the relative change of the eigenstiffnesses and by the variation in the direction of the eigenstrains (expressed as vectors in six-dimensional strain space). The suggested procedure is applied to the two materials discussed by Rasolofosaon and Yin (1996). The results allow a heuristic evaluation of the meaning of the reference strain , the square root of the ratio of the norms of the fourth-rank and sixth-rank stiffness tensors. It is stressed that this is not a new theory of non-linearity, but only a different way of viewing the existing theory and results. La propagation des ondes élastiques est généralement traitée sous quatre hypothèses : - le milieu est isotrope, - le milieu est homogène, - il y a une relation biunivoque entre la tension et la déformation, - les tensions sont reliées d'une façon linéaire aux déformations (et de manière équivalente, les déformations sont reliées d'une façon linéaire aux tensions). En général au moins une de ces hypothèses - et souvent toutes - n'est pas vérifiée dans les milieux réels. Une description théorique valide de la propagation des ondes dans les milieux réels dépend ainsi de la description à la fois qualitative et quantitative de l'hétérogénéité, de l'anisotropie et de la non-linéarité : soit on doit supposer (ou montrer) que l'écart par rapport à l'hypothèse de départ peut être - pour le problème considéré - négligé, soit on doit développer une description théorique, valide même en présence de ces écarts. Alors que l'effet d'un seul écart par rapport à un état idéal est relativement bien connu, les difficultés surviennent quand on veut combiner plusieurs de ces écarts. Les propriétés élastiques non linéaires d'échantillons de roche anisotropes (tricliniques) ont été étudiées, par P. Rasolofosaon et H. Yin au 6e IWSA à Trondheim (Rasolofosaon et Yin, 1996). L'élasticité anisotrope non linéaire est importante seulement pour les amplitudes non infinitésimales , c'est-à-dire dans un certain voisinage de la source. L'étendue de ce voisinage dépend de la précision de l'observation et de l'interprétation que l'on tente de maintenir, de l'intensité de la source, et du degré de non-linéarité. Cet article traite du dernier aspect, c'est-à-dire de la signification des nombres au-delà du fait qu'ils sont le résultat de mesures. Pour la mesure de la non-linéarité des matériaux, on peut utiliser le seuil de déformation au niveau duquel le tenseur de rigidité effective s'écarte sensiblement du tenseur de rigidité à déformation nulle. Il est particulièrement utile de prendre en compte le système propre du tenseur de rigidité (six rigidités propres et six déformations propres) : les déformations propres fournissent des types de déformationadaptés au calcul du tenseur de rigidité effective, et la perturbation peut être exprimée par le changement relatif des rigidités propres et par la variation des directions propres associées aux déformations propres (exprimées en tant que vecteurs dans un espace à six dimensions). La méthode suggérée est appliquée aux deux matériaux étudiés par Rasolofosaon et Yin (1996). Les résultats permettent une évaluation heuristique de la signification de la déformation de référence , définie comme la racine carrée du rapport des normes des tenseurs de rigidité du quatrième et du sixième rang. Il est à signaler qu'il ne s'agit pas d'une nouvelle théorie de la non-linéarité, mais d'une nouvelle approche de la théorie existante et des résultats.

Published
2006
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9. Conditions for the Occurrence of Decoupling Planes in Anisotropic Elastic Materials Conditions pour la présence de plans de découplage dans les matériaux élastiques anisotropes

Author

Helbig K.

Subjects
Chemical technology, TP1-1185, Energy industries. Energy policy. Fuel trade, HD9502-9502.5
Abstract

Planes of symmetry are often identified by the existence of pure cross-plane polarization. However, this type of polarization can occur without the plane being a plane of symmetry. Planes that support cross-plane polarization are called decoupling planes , since the system of three coupled linear equations in the direction cosines of the polarization vector decouples into a single cross-plane equation and a coupled pair of in-plane equations. Only if the direction perpendicular to a decoupling plane is a longitudinal direction(i. e. , if in the direction there are pure P- and S-waves), it is a plane of symmetry. Without the observation of the associated longitudinal direction, a rawdecoupling plane might be mis-interpreted as a plane of symmetry. The plane perpendicular to the i-direction is a decoupling plane if in four-subscript notation all stiffnesses with a single subscript i vanish; the i-direction is a longitudinal di-rection if all stiffnesses with three subscripts i vanish. In media of orthorhombic or higher symmetry all stiffnesses with any single or triple subscript vanish; therefore raw decoupling planes can occur only in media of monoclinic or triclinic symmetry. In triclinic symmetry, two mutually perpendicular raw decoupling planes can occur. Decoupling planes intersecting under an oblique angle are possible if the stiffnesses satisfy a number of constraints. Les plans de symétrie sont souvent identifiés par l'existence d'une polarisation pure perpendiculaire à ces plans. Cependant, ce type de polarisation peut apparaître sans que le plan soit un plan de symétrie. Les plans qui présentent une polarisation pure suivant leurs normales sont appelés plans de découplage , car le système de trois équations linéaires couplées par les cosinus directeurs du vecteur de polarisation se découple en une seule équation relative à la polarisation normale au plan et en deux équations couplées relatives aux polarisations dans le plan. C'est un plan de symétrie uniquement dans le cas où la direction perpendiculaire à un plan de découplageest une direction longitudinale(c'est-à-dire, si dans cette direction, il y a des ondes P et des ondes S pures). Sans la présence de la direction purement longitudinale associée, un plan de découplage brutpourrait être interprété faussement comme un plan de symétrie. Le plan perpendiculaire à la direction i est un plan de découplage si, en notation à quatre indices, toutes les rigidités avec un seul indice i disparaissent ; la direction i est une direction longitudinale si toutes les rigidités avec trois indices i disparaissent. Dans les milieux de symétrie orthorhombique ou supérieure, toutes les rigidités ayant un indice simple ou triple disparaissent ; par conséquent, les plans de découplage peuvent apparaître uniquement dans les milieux ayant une symétrie monoclinique ou triclinique. Dans la symétrie triclinique, deux plans de découplage brut perpendiculaires peuvent apparaître. Des plans de découplage qui se croisent avec un angle oblique sont possibles si les rigidités satisfont un certain nombre de contraintes.

Published
2006
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11. Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

Author

Lal, D., May, P., Perez-Palma, E., Samocha, K. E., Kosmicki, J. A., Robinson, E. B., Moller, R. S., Krause, R., Nurnberg, P., Weckhuysen, S., De Jonghe, P., Guerrini, R., Niestroj, L. M., Du, J., Marini, C., Balling, R., Barisic, N., Baulac, S., Caglayan, H., Craiu, D. C., Depienne, C., Helbig, I., Hjalgrim, H., Hoffman-Zacharska, D., Jahn, J., Klein, K. M., Koeleman, B. P. C., Komarek, V., Leguern, E., Lehesjoki, A. -E., Lemke, J. R., Lerche, H., Linnankivi, T., Muhle, H., Pal, D. K., Palotie, A., Rosenow, F., Schubert-Bast, S., Selmer, K., Serratosa, J. M., Stephani, U., Sterbova, K., Striano, P., Suls, A., Talvik, T., Von Spiczak, S., Weber, Y. G., Zara, F., Ware, J. S., Kurki, M., Gormley, P., Tang, S., Wu, S., Biskup, S., Poduri, A., Neubauer, B. A., Helbig, K. L., Majithia, A. R., Daly, M. J., EuroEPINOMICS-RES Consortium, 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, Department of Medical and Clinical Genetics, Medicum, HUS Helsinki and Uusimaa Hospital District, and Wellcome Trust

Subjects
Candidate gene, lcsh:QH426-470, Developmental Disabilities, Mutation, Missense, Sequence Homology, lcsh:Medicine, ORTHOLOGS, Computational biology, Conservation, Gene family, Missense variants, Neurodevelopmental disorders, Paralogs, Biology, 03 medical and health sciences, MULTIPLE SEQUENCE ALIGNMENT, PHYLOGENETIC TREES, Genetics, Missense mutation, Ensembl, Molecular Biology, Gene, Genetics (clinical), Phylogeny, 030304 developmental biology, 0303 health sciences, 0604 Genetics, Phylogenetic tree, Research, 030305 genetics & heredity, lcsh:R, 1184 Genetics, developmental biology, physiology, 1103 Clinical Sciences, EuroEPINOMICS-RES Consortium, Human genetics, lcsh:Genetics, Genetic Loci, DE-NOVO MUTATIONS, Multigene Family, Molecular Medicine, Human medicine, Orthologous Gene, Genome-Wide Association Study
Abstract

Background Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs. Methods Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families. Results We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint. Conclusion This study represents the first method to incorporate gene family information into a statistical framework to interpret variant data for NDDs and to discover new NDD-associated genes.

Published
2020
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12. Whole-exome and HLA sequencing in Febrile infection-related epilepsy syndrome

Author

Helbig, I, Barcia, G, Pendziwiat, M, Ganesan, S, Mueller, S, Helbig, K, Vaidiswaran, P, Xian, J, Galer, PD, Afawi, Zaid, Specchio, N, Kluger, G, Kuhlenbäumer, G, Appenzeller, S, Wittig, M, Kramer, U, van Baalen, A, Nabbout, R, Helbig, I, Barcia, G, Pendziwiat, M, Ganesan, S, Mueller, S, Helbig, K, Vaidiswaran, P, Xian, J, Galer, PD, Afawi, Zaid, Specchio, N, Kluger, G, Kuhlenbäumer, G, Appenzeller, S, Wittig, M, Kramer, U, van Baalen, A, and Nabbout, R

Published
2020

13. De novo variants in neurodevelopmental disorders with epilepsy

Author

Heyne, H. O., Singh, T., Stamberger, H., Abou Jamra, R., Caglayan, H., Craiu, D., De Jonghe, P., Guerrini, R., Helbig, K. L., Koeleman, B. P. C., Kosmicki, J. A., Linnankivi, T., May, P., Muhle, H., Moller, R. S., Neubauer, B. A., Palotie, A., Pendziwiat, M., Striano, P., Tang, S., Wu, S., Afawi, Z., De Kovel, C., Dimova, P., Djemie, T., Endziniene, M., Hoffman-Zacharska, D., Jahn, J., Korff, C., Lehesjoki, A. -E., Marini, C., Muller, S. H., Pal, D., Schwarz, N., Selmer, K., Serratosa, J., Stephani, U., Sterbova, K., Suls, A., Syrbe, S., Talvik, I., Von Spiczak, S., Zara, F., Poduri, A., Weber, Y. G., Weckhuysen, S., Sisodiya, S. M., Daly, M. J., Helbig, I., Lal, D., Lemke, J. R., Children's Hospital, Lastenneurologian yksikkö, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Research Programme for Molecular Neurology, Neuroscience Center, HUS Children and Adolescents, Genomics of Neurological and Neuropsychiatric Disorders, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], University of Luxembourg: High Performance Computing - ULHPC [research center], Korff, Christian, and EuroEPINOMICS RES Consortium

Subjects
Exome/genetics, Male, 0301 basic medicine, ILAE COMMISSION, Joint analysis, Neurodevelopmental Disorders/genetics, Bioinformatics, Epilepsy/genetics, Epilepsy, 0302 clinical medicine, Intellectual disability, SEQUENCE VARIANTS, Missense mutation, Epilepsy is a frequent feature, Exome, TERMINOLOGY, Disease gene, 0303 health sciences, ddc:618, medicine.diagnostic_test, Genetic Predisposition to Disease/genetics, Neurodevelopmental disorders, 1184 Genetics, developmental biology, physiology, HUMAN-DISEASE, PREVALENCE, 3. Good health, Genetic Variation/genetics, De novo variants, Female, Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], Genetic Testing/methods, Disease Association, Biology, CLASSIFICATION, 03 medical and health sciences, Intellectual Disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Limited evidence, 030304 developmental biology, Genetic testing, business.industry, MUTATIONS, AUTISM SPECTRUM DISORDER, Genetic Variation, medicine.disease, Intellectual Disability/genetics, 030104 developmental biology, Neurodevelopmental Disorders, epilepsy, KCNQ2 ENCEPHALOPATHY, Human medicine, 3111 Biomedicine, business, Genetic diagnosis, 030217 neurology & neurosurgery
Abstract

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

Published
2018
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16. 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
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20. Characterization of the first mitochondrial genome of a little Corella (Cacatua sanguinea) and its phylogenetic implications

Author

Sarker, S, Talukder, S, Sutherland, M, Forwood, JK, Helbig, K, Raidal, SR, Sarker, S, Talukder, S, Sutherland, M, Forwood, JK, Helbig, K, and Raidal, SR

Abstract

This study was designed to sequence the first complete mitochondrial genome from a little corella (Cacatua sanguinea). The mitogenome sequence was circular and 16,695 bp in length. In comparison to other available mitogenome sequences belongs to Psittacidae species, this mitogenome encoded a conserved structure consisting of 13 protein-coding genes (PCGs), two rRNA genes, 22 tRNA genes. The lengths of 12S and 16S ribosomal RNA were 975 bp and 1582 bp, respectively. The overall base composition of the mitogenome of C. sanguinea was dominated by higher AT (53.0%) than GC (47.0%) content. The complete mitogenome sequence determined in this study is useful for understanding the more profound evolutionary history and the conservation of C. sanguinea.

Published
2019

21. The first complete mitogenome of Indian ringneck (Psittacula krameri) demonstrates close phylogenetic relationship with Eclectus parrot.

Author

Sarker, S, Sutherland, M, Talukder, S, Das, S, Forwood, JK, Helbig, K, Raidal, SR, Sarker, S, Sutherland, M, Talukder, S, Das, S, Forwood, JK, Helbig, K, and Raidal, SR

Abstract

This study was aimed to sequence the first complete mitochondrial genome from an Indian ringneck parrot (Psittacula krameri). The mitogenome sequence was circular and 16,413 bp in length. In comparison to other available mitogenome sequences belonging to Psittacidae species, this mitogenome encoded a conserved structure consisting of 13 protein-coding genes (PCGs), two rRNA genes, 21 tRNA genes and a control region; however, this mitogenome missing a tRNA-Glu. The lengths of 12S and 16S ribosomal RNA were 975 bp and 1582 bp, respectively. The overall base composition of the mitogenome of P. krameri was dominated by higher AT (53.5%) than GC (46.5%) content. The complete mitogenome sequence determined in this study would be useful to track the more profound evolutionary history and the conservation of P. krameri.

Published
2019

23. De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder

Author

Reijnders, MRF, Miller, KA, Alvi, M, Goos, JAC, Lees, MM, de Burca, A, Henderson, A, Kraus, A, Mikat, B, de Vries, BBA, Isidor, B, Kerr, B, Marcelis, C, Schluth-Bolard, C, Deshpande, C, Ruivenkamp, CAL, Wieczorek, D, Deciphering Developmental Disorders Study, Baralle, D, Blair, EM, Engels, H, Lüdecke, H-J, Eason, J, Santen, GWE, Clayton-Smith, J, Chandler, K, Tatton-Brown, K, Payne, K, Helbig, K, Radtke, K, Nugent, KM, Cremer, K, Strom, TM, Bird, LM, Sinnema, M, Bitner-Glindzicz, M, van Dooren, MF, Alders, M, Koopmans, M, Brick, L, Kozenko, M, Harline, ML, Klaassens, M, Steinraths, M, Cooper, NS, Edery, P, Yap, P, Terhal, PA, van der Spek, PJ, Lakeman, P, Taylor, RL, Littlejohn, RO, Pfundt, R, Mercimek-Andrews, S, Stegmann, APA, Kant, SG, McLean, S, Joss, S, Swagemakers, SMA, Douzgou, S, Wall, SA, Küry, S, Calpena, E, Koelling, N, McGowan, SJ, Twigg, SRF, Mathijssen, IMJ, Nellaker, C, Brunner, HG, and Wilkie, AOM

Subjects
Adult, Male, Adolescent, kinase, Messenger, Inheritance Patterns, Translocation, Medical and Health Sciences, Cell Line, Young Adult, Genetic, Clinical Research, Loss of Function Mutation, Genetics, 2.1 Biological and endogenous factors, Humans, Aetiology, Child, Preschool, Genetic Association Studies, Genetics & Heredity, Tousled-like, Base Sequence, Human Genome, Neurosciences, Facies, Infant, Deciphering Developmental Disorders Study, Biological Sciences, Brain Disorders, haploinsufficiency, Neurodevelopmental Disorders, intellectual disability, RNA, Female, Protein Kinases, facial averaging, Biotechnology
Abstract

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

Published
2018

24. De Novo and Inherited Loss-of-Function Variants in TLK2 : Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder

Author

Reijnders, M.R.F., Miller, K.A., Alvi, M., Goos, J.A.C., Lees, M.M., Burca, A. de, Henderson, A., Kraus, A., Mikat, B., Vries, B.B.A. de, Isidor, B., Kerr, B., Marcelis, C.L.M., Schluth-Bolard, C., Deshpande, C., Ruivenkamp, C.A.L., Wieczorek, D., Baralle, D., Blair, E.M., Engels, H., Ludecke, H.J., Eason, J., Santen, G.W.E., Clayton-Smith, J., Chandler, K., Tatton-Brown, K., Payne, K., Helbig, K., Radtke, K., Nugent, K.M., Cremer, K., Strom, T.M., Bird, L.M., Sinnema, M., Bitner-Glindzicz, M., Dooren, M.F. van, Alders, M., Koopmans, M., Brick, L., Kozenko, M., Harline, M.L., Klaassens, M., Steinraths, M., Cooper, N.S., Edery, P., Yap, P., Terhal, P.A., Spek, P.J. van der, Lakeman, P., Taylor, R.L., Littlejohn, R.O., Pfundt, R.P., Mercimek-Andrews, S., Stegmann, A.P.A., Kant, S.G., McLean, S., Joss, S., Swagemakers, S.M.A., Douzgou, S., Wall, S.A., Kury, S., Calpena, E., Koelling, N., McGowan, S.J., Twigg, S.R.F., Mathijssen, I.M.J., Nellaker, C., Brunner, H.G., Wilkie, A.O.M., Plastic and Reconstructive Surgery and Hand Surgery, Clinical Genetics, and Pathology

Subjects
Tousled-like, Facial Averaging, Haploinsufficiency, Intellectual Disability, Kinase, Adult, Male, Adolescent, kinase, viruses, Inheritance Patterns, Medizin, Translocation, Genetic, Cell Line, Young Adult, Loss of Function Mutation, Report, Humans, RNA, Messenger, Child, Genetic Association Studies, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Base Sequence, Facies, Infant, haploinsufficiency, Neurodevelopmental Disorders, intellectual disability, Child, Preschool, Female, Protein Kinases, facial averaging, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Human adenovirus (HAdV) E1B-55K is a multifunctional regulator of productive viral replication and oncogenic transformation in nonpermissive mammalian cells. These functions depend on E1B-55K's posttranslational modification with the SUMO protein and its binding to HAdV E4orf6. Both early viral proteins recruit specific host factors to form an E3 ubiquitin ligase complex that targets antiviral host substrates for proteasomal degradation. Recently, we reported that the PML-NB associated factor Daxx represses efficient HAdV productive infection and is proteasomally degraded via a SUMO-E1B-55K-dependent, E4orf6-independent pathway, the details of which remained to be established. RNF4, a cellular SUMO-targeted ubiquitin ligase (STUbL), induces ubiquitinylation of specific SUMOy lated proteins and plays an essential role during DNA repair. Here, we show that E1B-55K recruits RNF4 to the insoluble nuclear matrix fraction of the infected cell to support RNF4/Daxx association, promoting Daxx PTM and thus inhibiting this antiviral factor. Removing RNF4 from infected cells using RNA interference resulted in blocking the proper establishment of viral replication centers and significantly diminished viral gene expression. These results provide a model for how HAdV antagonize the antiviral host responses by exploiting the functional capacity of cellular STUbLs. Thus, RNF4 and its STUbL function represent a positive factor during lytic infection and a novel candidate for future therapeutic antiviral intervention strategies.IMPORTANCE Daxx is a PML-NB-associated transcription factor that was recently shown to repress efficient HAdV productive infection. To counteract this antiviral measurement during infection, Daxx is degraded via a novel pathway including viral E1B-55K and host proteasomes. This virus-mediated degradation is independent of the classical HAdV E3 ubiquitin ligase complex, which is essential during viral infection to target other host antiviral substrates. To maintain a productive viral life cycle, HAdV E1B-55K early viral protein inhibits the chromatin-remodeling factor Daxx in a SUMO-dependent manner. In addition, viral E1B-55K protein recruits the STUbL RNF4 and sequesters it into the insoluble fraction of the infected cell. E1B-55K promotes complex formation between RNF4-and E1B-55K-targeted Daxx protein, supporting Daxx posttranslational modification prior to functional inhibition. Hence, RNF4 represents a novel host factor that is beneficial for HAdV gene expression by supporting Daxx counteraction. In this regard, RNF4 and other STUbL proteins might represent novel targets for therapeutic intervention.

Published
2018

25. HCN1 mutation spectrum: From neonatal epileptic encephalopathy to benign generalized epilepsy and beyond

Author

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, Depienne, C, Innes, AM, Mancardi, MM, Clark, DR, Helbig, KL, Lemke, JR, DiFrancesco, D, LeGuern, E, Di Francesco, JC, 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, Depienne, C, Innes, AM, Mancardi, MM, Clark, DR, Helbig, KL, Lemke, JR, DiFrancesco, D, LeGuern, E, and Di Francesco, JC

Abstract

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 volta

Published
2018

26. De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder

Author

Reijnders, M R F, Miller, KA, Alvi, M, Goos, Jacqueline, Lees, MM, de Burca, A, Henderson, A, Kraus, A, Mikat, B, de Vries, BBA, Isidor, B, Kerr, B, Marcelis, C, Schluth-Bolard, C, Deshpande, C, Ruivenkamp, CAL, Wieczorek, D, Baralle, D, Blair, EM, Engels, H, Ludecke, HJ, Eason, J, Santen, GWE, Clayton-Smith, J, Chandler, K, Tatton-Brown, K, Payne, K, Helbig, K, Radtke, K, Nugent, KM, Cremer, K, Strom, TM, Bird, LM, Sinnema, M, Bitner-Glindzicz, M, van Dooren, Marieke, Alders, M, Koopmans, M, Brick, L, Kozenko, M, Harline, ML, Klaassens, M, Steinraths, M, Cooper, NS, Edery, P, Yap, P, Terhal, PA, van der Spek, Peter, Lakeman, P, Taylor, RL, Littlejohn, RO, Pfundt, R, Mercimek-Andrews, S, Stegmann, APA, Kant, SG, McLean, S, Joss, S, Swagemakers, Sigrid, Douzgou, S, Wall, SA, Kury, S, Calpena, E, Koelling, N, McGowan, SJ, Twigg, SRF, Mathijssen, Irene, Nellaker, C, Brunner, HG, Wilkie, AOM, Reijnders, M R F, Miller, KA, Alvi, M, Goos, Jacqueline, Lees, MM, de Burca, A, Henderson, A, Kraus, A, Mikat, B, de Vries, BBA, Isidor, B, Kerr, B, Marcelis, C, Schluth-Bolard, C, Deshpande, C, Ruivenkamp, CAL, Wieczorek, D, Baralle, D, Blair, EM, Engels, H, Ludecke, HJ, Eason, J, Santen, GWE, Clayton-Smith, J, Chandler, K, Tatton-Brown, K, Payne, K, Helbig, K, Radtke, K, Nugent, KM, Cremer, K, Strom, TM, Bird, LM, Sinnema, M, Bitner-Glindzicz, M, van Dooren, Marieke, Alders, M, Koopmans, M, Brick, L, Kozenko, M, Harline, ML, Klaassens, M, Steinraths, M, Cooper, NS, Edery, P, Yap, P, Terhal, PA, van der Spek, Peter, Lakeman, P, Taylor, RL, Littlejohn, RO, Pfundt, R, Mercimek-Andrews, S, Stegmann, APA, Kant, SG, McLean, S, Joss, S, Swagemakers, Sigrid, Douzgou, S, Wall, SA, Kury, S, Calpena, E, Koelling, N, McGowan, SJ, Twigg, SRF, Mathijssen, Irene, Nellaker, C, Brunner, HG, and Wilkie, AOM

Published
2018

27. PATIENTS AFFECTED BY MOSAIC PCDH19 MUTATIONS: 5 NEW CASES

Author

Lange, I. de, Rump, P., Neuteboom, R., Augustijn, P., Hodges, K., Kistemaker, A., Brouwer, O., Mancini, G., Newman, H., Vos, Y., Helbig, K., Peeters-Scholte, C., Kriek, M., Knoers, N., Lindhout, D., Koeleman, B., Kempen, M. van, and Brilstra, E.

Published
2017

28. Multimodale Bildungsangebote für pflegende Angehörige von älteren Menschen mit Demenz – qualitative Bedarfsanalyse hinsichtlich digitaler und technischer Pflegeassistenz in Sachsen-Anhalt

Author

Paulicke, D, Helbig, K, Voigt, J, Stoevesandt, D, and Jahn, P

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Hintergrund: Der von der OECD verfolgte „Ageing in Place“-Ansatz stellt eine Lösungsstrategie zum Umgang mit den Herausforderungen des demografischen Wandels sowie des Fachkräftemangels dar. Der Schlüssel zur Umsetzung dieses Ansatzes ist die Kombination adäquate Qualifizierung[zum vollständigen Text gelangen Sie über die oben angegebene URL], 16. Deutscher Kongress für Versorgungsforschung (DKVF)

Published
2017
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37. CLINICAL HETEROGENEITY AND ITS POTENTIAL THERAPEUTIC IMPLICATIONS IN CHILDREN WITH SCN2A-RELATED DISORDERS

Author

Ceulemans, B., Lederer, D., Dorn, T., Helbig, K. L., Hardies, K., Stamberger, H., de Jonghe, P., Weckhuysen, S., Lemke, J. R., Helbig, I, Kluger, G., Moller, R. S., Johannesen, K. M., Wolf, M., Masnada, S., Rubboli, G., Gardella, E., Milh, M., Villard, L., Mignot, C., Lardennois, C., Bourel-Ponchel, Emilie, Nava, C., Lesca, G., Gerard, M., Perrin, L., Doummar, D., Auvin, S., Miranda, M. J., Brilstra, E., Knoers, N., Doecker, M., Bast, T., Loddenkemper, T., Wong-Kisiel, L., Baumeister, F. M., Fazeli, W., Striano, P., Kurlemann, G., Klepper, J., Thoene, J. G., Arndt, D. H., Schmitt-Mechelke, T., Maier, O., Muhle, H., Wical, B., Finetti, C., Brueckner, R., Pietz, J., Golla, G., Jillella, D., Afenjar, A., Linnet, K. M., Charles, P., Oiglane-Slik, E., Mantovani, J. F., Deprez, M., Scalais, E., Lagae, L., Nikanorova, M., Hjalgrim, H., Depienne, C., Scheidecker, S., Kremer, V, Doray, B., Alembik, y., University of British Columbia (UBC), Pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) - Hôpital de la Timone, Ecole Polytechnique Fédérale de Lausanne (EPFL), Université de Strasbourg (UNISTRA), Centre National de la Recherche Scientifique (CNRS), Groupe de Recherche sur l'Analyse Multimodale de la Fonction Cérébrale - UMR INSERM_S 1105 (GRAMFC), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-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), 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), Laboratoire Insulaire du Vivant et de l'Environnement (LIVE), Université de la Nouvelle-Calédonie (UNC), Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Department of Child Neurology, Development and Rehabilitation [Hospital of Eastern Switzerland], Children's Hospital of Eastern Switzerland St.Gallen, Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de médecine interne et centre de référence des maladies rares [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], IMEC (IMEC), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Statens seruminstitut, and Les Hôpitaux Universitaires de Strasbourg (HUS)

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2016

40. Genome sequence of an Australian strain of <italic>canid alphaherpesvirus 1</italic>.

Author

Sarker, S., Das, S., Helbig, K., Peters, A., and Raidal, S. R.

Subjects
CANIDAE, NUCLEOTIDE sequencing, NUCLEOTIDE sequence, VETERINARY medicine, POLYMERASE chain reaction, DISEASES
Abstract

Objective: Characterisation of a complete genome sequence of an Australian strain of canid alphaherpesvirus 1 (CHV‐1) and its phylogenetic relationship with other varicellovirus species. Methods: Standard pathology and PCR methods were used to initially detect herpesvirus in hepatic tissue from an infected 4‐week‐old Labrador Retriever puppy. The complete CHV‐1 genome was sequenced using next‐generation sequencing technology followed by de novo and reference assembly, and genome annotation. Results: The CHV‐1 genome was 125 kbp in length and contained 74 predicted open reading frames encoding functional proteins, all of which have counterparts in other alphaherpesviruses. Phylogenetic analysis using the DNA polymerase gene revealed that the newly sequenced CHV‐1 clustered with canid alphaherpesvirus isolated from the UK and shared a 99% overall nucleotide sequence similarity. Conclusion: This is the first complete genome of an Australian strain of CHV‐1, which will contribute to our understanding of the genetics and evolution of herpesvirus. [ABSTRACT FROM AUTHOR]

Published
2018
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43. Male patients affected by mosaic PCDH19 mutations: five new cases.

Author

Lange, I., Rump, P., Neuteboom, R., Augustijn, P., Hodges, K., Kistemaker, A., Brouwer, O., Mancini, G., Newman, H., Vos, Y., Helbig, K., Peeters-Scholte, C., Kriek, M., Knoers, N., Lindhout, D., Koeleman, B., Kempen, M., and Brilstra, E.

Abstract

Pathogenic variants in the PCDH19 gene are associated with epilepsy, intellectual disability (ID) and behavioural disturbances. Only heterozygous females and mosaic males are affected, likely due to a disease mechanism named cellular interference. Until now, only four affected mosaic male patients have been described in literature. Here, we report five additional male patients, of which four are older than the oldest patient reported so far. All reported patients were selected for genetic testing because of developmental delay and/or epilepsy. Custom-targeted next generation sequencing gene panels for epilepsy genes were used. Clinical data were collected from medical records. All patients were mosaic in blood for likely pathogenic variants in the PCDH19 gene. In most, clinical features were very similar to the female phenotype, with normal development before seizure onset, which occurred between 5 and 10 months of age, clustering of seizures and sensitivity to fever. Four out of five patients had mild to severe ID and behavioural problems. We reaffirm the similarity between male and female PCDH19-related phenotypes, now also in a later phase of the disorder (ages 10-14 years). [ABSTRACT FROM AUTHOR]

Published
2017
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45. A novel assay for detection of hepatitis C virus-specific effector CD4(+) T cells via co-expression of CD25 and CD134

Author

Keoshkerian, E, Helbig, K, Beard, M, Zaunders, J, Seddiki, N, Kelleher, AD, Hampartzoumian, T, Zekry, A, Lloyd, AR, Keoshkerian, E, Helbig, K, Beard, M, Zaunders, J, Seddiki, N, Kelleher, AD, Hampartzoumian, T, Zekry, A, and Lloyd, AR

Abstract

Hepatitis C virus (HCV)-specific CD4+ effector T cell responses are likely to play a key role inthe immunopathogenesis of HCV infection by promoting viral clearance and maintainingcontrol of viraemia. As the precursor frequency of HCV-specific CD4+ T cells in peripheralblood is low, favoured assay systems such as intracellular cytokine (ICC) or tetramer staininghave limited utility for ex vivo analyses. Accordingly, the traditional lymphocyte proliferationassay (LPA) remains the gold standard, despite detecting responses in only a minority ofinfected subjects. Recently, we reported development and validation of a novel whole bloodCD4+ effector T cell assay based on ex vivo antigen stimulation followed by co-expression ofCD25 and CD134 on CD4+ T cells. Here we report adaptation of this assay to assessment ofHCV-specific responses in cryopreserved peripheral blood mononuclear cells using standardisedantigens, including peptide pools, viral supernatants and recombinant viral proteins. The assayallowed detection of HCV-specific CD4 responses in donors with both resolved and chronic infection. Responses were highly correlated with those revealed by LPA. Application of this assay willfurther define the role of CD4+ T cells in the immunopathogenesis of HCV infection.

Published
2012

46. CD4 + T-cell deficiency in HIV patients responding to antiretroviral therapy is associated with increased expression of interferon-stimulated genes in CD4 + T cells

Author

Fernandez, S., Tanaskovic, S., Helbig, K., Rajasuriar, R., Kramski, M., Murray, J., Beard, M., Purcell, D., Lewin, S., Price, Patricia, French, M., Fernandez, S., Tanaskovic, S., Helbig, K., Rajasuriar, R., Kramski, M., Murray, J., Beard, M., Purcell, D., Lewin, S., Price, Patricia, and French, M.

Abstract

Most patients with human immunodeficiency virus (HIV) who remain CD4 + T-cell deficient on antiretroviral therapy (ART) exhibit marked immune activation. As CD4 + T-cell activation may be mediated by microbial translocation or interferon-alpha (IFN-a), we examined these factors in HIV patients with good or poor CD4 + T-cell recovery on long-term ART. Messenger RNA levels for 3 interferon-stimulated genes were increased in CD4 + T cells of patients with poor CD4 + T-cell recovery, whereas levels in patients with good recovery did not differ from those in healthy controls. Poor CD4 + T-cell recovery was also associated with CD4 + T-cell expression of markers of activation, senescence, and apoptosis, and with increased serum levels of the lipopolysaccharide receptor and soluble CD14, but these were not significantly correlated with expression of the interferon-stimulated genes. Therefore, CD4 + T-cell recovery may be adversely affected by the effects of IFN-a, which may be amenable to therapeutic intervention. © 2011 The Author.

Published
2011

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