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1. Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement

Author

Kaiyrzhanov, R., Mohammed, S.E.M., Maroofian, R., Husain, R.A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Grønborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., Baptista, J., Haider, S., Feichtinger, R.G., Bernardi, P., Zulian, A., Gusic, M., Efthymiou, S., Bai, R., Bibi, F., Horga, A., Martinez-Agosto, J.A., Lam, A., Manole, A, Rodriguez, D.P., Durigon, R., Pyle, A., Albash, B., Dionisi-Vici, C., Murphy, D., Martinelli, D., Bugiardini, E., Allis, K., Lamperti, C., Reipert, S., Risom, L., Laugwitz, L., Nottia, M. Di, McFarland, R., Vilarinho, L., Hanna, M., Prokisch, H., Mayr, J.A., Bertini, E.S., Ghezzi, D., Østergaard, E., Wortmann, S.B., Carrozzo, R., Haack, T.B., Taylor, R.W., Spinazzola, A., Nowikovsky, K., Houlden, H., Kaiyrzhanov, R., Mohammed, S.E.M., Maroofian, R., Husain, R.A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Grønborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., Baptista, J., Haider, S., Feichtinger, R.G., Bernardi, P., Zulian, A., Gusic, M., Efthymiou, S., Bai, R., Bibi, F., Horga, A., Martinez-Agosto, J.A., Lam, A., Manole, A, Rodriguez, D.P., Durigon, R., Pyle, A., Albash, B., Dionisi-Vici, C., Murphy, D., Martinelli, D., Bugiardini, E., Allis, K., Lamperti, C., Reipert, S., Risom, L., Laugwitz, L., Nottia, M. Di, McFarland, R., Vilarinho, L., Hanna, M., Prokisch, H., Mayr, J.A., Bertini, E.S., Ghezzi, D., Østergaard, E., Wortmann, S.B., Carrozzo, R., Haack, T.B., Taylor, R.W., Spinazzola, A., Nowikovsky, K., and Houlden, H.

Abstract

Contains fulltext : 283148.pdf (Publisher’s version ) (Open Access), Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K(+)/H(+) exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K(+) efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial patholog

Published
2022

2. Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement

Author

Kaiyrzhanov, R., Mohammed, S.E.M., Maroofian, R., Husain, R.A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Grønborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., Baptista, J., Haider, S., Feichtinger, R.G., Bernardi, P., Zulian, A., Gusic, M., Efthymiou, S., Bai, R., Bibi, F., Horga, A., Martinez-Agosto, J.A., Lam, A., Manole, A, Rodriguez, D.P., Durigon, R., Pyle, A., Albash, B., Dionisi-Vici, C., Murphy, D., Martinelli, D., Bugiardini, E., Allis, K., Lamperti, C., Reipert, S., Risom, L., Laugwitz, L., Nottia, M. Di, McFarland, R., Vilarinho, L., Hanna, M., Prokisch, H., Mayr, J.A., Bertini, E.S., Ghezzi, D., Østergaard, E., Wortmann, S.B., Carrozzo, R., Haack, T.B., Taylor, R.W., Spinazzola, A., Nowikovsky, K., Houlden, H., Kaiyrzhanov, R., Mohammed, S.E.M., Maroofian, R., Husain, R.A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Grønborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., Baptista, J., Haider, S., Feichtinger, R.G., Bernardi, P., Zulian, A., Gusic, M., Efthymiou, S., Bai, R., Bibi, F., Horga, A., Martinez-Agosto, J.A., Lam, A., Manole, A, Rodriguez, D.P., Durigon, R., Pyle, A., Albash, B., Dionisi-Vici, C., Murphy, D., Martinelli, D., Bugiardini, E., Allis, K., Lamperti, C., Reipert, S., Risom, L., Laugwitz, L., Nottia, M. Di, McFarland, R., Vilarinho, L., Hanna, M., Prokisch, H., Mayr, J.A., Bertini, E.S., Ghezzi, D., Østergaard, E., Wortmann, S.B., Carrozzo, R., Haack, T.B., Taylor, R.W., Spinazzola, A., Nowikovsky, K., and Houlden, H.

Abstract

Contains fulltext : 283148.pdf (Publisher’s version ) (Open Access), Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K(+)/H(+) exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K(+) efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial patholog

Published
2022

3. The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications

Author

Brunklaus, A, Bruenger, T, Feng, T, Fons, C, Lehikoinen, A, Panagiotakaki, E, Vintan, M-A, Symonds, J, Andrew, J, Arzimanoglou, A, Delima, S, Gallois, J, Hanrahan, D, Lesca, G, MacLeod, S, Marjanovic, D, McTague, A, Nunez-Enamorado, N, Perez-Palma, E, Scott Perry, M, Pysden, K, Russ-Hall, SJ, Scheffer, IE, Sully, K, Syrbe, S, Vaher, U, Velayutham, M, Vogt, J, Weiss, S, Wirrell, E, Zuberi, SM, Lal, D, Moller, RS, Mantegazza, M, Cestele, S, Brunklaus, A, Bruenger, T, Feng, T, Fons, C, Lehikoinen, A, Panagiotakaki, E, Vintan, M-A, Symonds, J, Andrew, J, Arzimanoglou, A, Delima, S, Gallois, J, Hanrahan, D, Lesca, G, MacLeod, S, Marjanovic, D, McTague, A, Nunez-Enamorado, N, Perez-Palma, E, Scott Perry, M, Pysden, K, Russ-Hall, SJ, Scheffer, IE, Sully, K, Syrbe, S, Vaher, U, Velayutham, M, Vogt, J, Weiss, S, Wirrell, E, Zuberi, SM, Lal, D, Moller, RS, Mantegazza, M, and Cestele, S

Abstract

Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4-69.3; P = 1.3 × 10-7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexc

Published
2022

4. Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Author

Schirwani, S., Albaba, S., Carere, D.A., Sacoto, M.J. Guillen, Zamora, F. Milan, Si, Y., Rabin, R., Pappas, J., Renaud, D.L., Hauser, N., Reid, E., Blanchet, P., Foulds, N., Dixit, A., Fisher, R., Armstrong, R., Isidor, B., Cogne, B., Vergano, S. Schrier, Demirdas, S., Dykzeul, N., Cohen, J.S., Grand, K., Morel, D., Slavotinek, A., Albassam, H.F., Naik, S., Dean, J., Ragge, N., Cinzia, C., Tedesco, M.G., Harrison, R.E., Bouman, A., Palen, E., Challman, T.D., Willemsen, M.H., Vogt, J., Cunniff, C., Bergstrom, K., Walia, J.S., Bruel, A.L., Kini, U., Alkuraya, F.S., Slegesky, V., Meeks, N., Girotto, P., Johnson, D., Newbury-Ecob, R., Ockeloen, C.W., Prontera, P., Lynch, S.A., Li, D., Graham, J.M., Balasubramanian, M., Schirwani, S., Albaba, S., Carere, D.A., Sacoto, M.J. Guillen, Zamora, F. Milan, Si, Y., Rabin, R., Pappas, J., Renaud, D.L., Hauser, N., Reid, E., Blanchet, P., Foulds, N., Dixit, A., Fisher, R., Armstrong, R., Isidor, B., Cogne, B., Vergano, S. Schrier, Demirdas, S., Dykzeul, N., Cohen, J.S., Grand, K., Morel, D., Slavotinek, A., Albassam, H.F., Naik, S., Dean, J., Ragge, N., Cinzia, C., Tedesco, M.G., Harrison, R.E., Bouman, A., Palen, E., Challman, T.D., Willemsen, M.H., Vogt, J., Cunniff, C., Bergstrom, K., Walia, J.S., Bruel, A.L., Kini, U., Alkuraya, F.S., Slegesky, V., Meeks, N., Girotto, P., Johnson, D., Newbury-Ecob, R., Ockeloen, C.W., Prontera, P., Lynch, S.A., Li, D., Graham, J.M., and Balasubramanian, M.

Abstract

Item does not contain fulltext, The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

Published
2021

6. Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Author

Schirwani, S., Albaba, S., Carere, D.A., Sacoto, M.J. Guillen, Zamora, F. Milan, Si, Y., Rabin, R., Pappas, J., Renaud, D.L., Hauser, N., Reid, E., Blanchet, P., Foulds, N., Dixit, A., Fisher, R., Armstrong, R., Isidor, B., Cogne, B., Vergano, S. Schrier, Demirdas, S., Dykzeul, N., Cohen, J.S., Grand, K., Morel, D., Slavotinek, A., Albassam, H.F., Naik, S., Dean, J., Ragge, N., Cinzia, C., Tedesco, M.G., Harrison, R.E., Bouman, A., Palen, E., Challman, T.D., Willemsen, M.H., Vogt, J., Cunniff, C., Bergstrom, K., Walia, J.S., Bruel, A.L., Kini, U., Alkuraya, F.S., Slegesky, V., Meeks, N., Girotto, P., Johnson, D., Newbury-Ecob, R., Ockeloen, C.W., Prontera, P., Lynch, S.A., Li, D., Graham, J.M., Balasubramanian, M., Schirwani, S., Albaba, S., Carere, D.A., Sacoto, M.J. Guillen, Zamora, F. Milan, Si, Y., Rabin, R., Pappas, J., Renaud, D.L., Hauser, N., Reid, E., Blanchet, P., Foulds, N., Dixit, A., Fisher, R., Armstrong, R., Isidor, B., Cogne, B., Vergano, S. Schrier, Demirdas, S., Dykzeul, N., Cohen, J.S., Grand, K., Morel, D., Slavotinek, A., Albassam, H.F., Naik, S., Dean, J., Ragge, N., Cinzia, C., Tedesco, M.G., Harrison, R.E., Bouman, A., Palen, E., Challman, T.D., Willemsen, M.H., Vogt, J., Cunniff, C., Bergstrom, K., Walia, J.S., Bruel, A.L., Kini, U., Alkuraya, F.S., Slegesky, V., Meeks, N., Girotto, P., Johnson, D., Newbury-Ecob, R., Ockeloen, C.W., Prontera, P., Lynch, S.A., Li, D., Graham, J.M., and Balasubramanian, M.

Abstract

Item does not contain fulltext, The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

Published
2021

7. Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Author

Schirwani, S., Albaba, S., Carere, D.A., Sacoto, M.J. Guillen, Zamora, F. Milan, Si, Y., Rabin, R., Pappas, J., Renaud, D.L., Hauser, N., Reid, E., Blanchet, P., Foulds, N., Dixit, A., Fisher, R., Armstrong, R., Isidor, B., Cogne, B., Vergano, S. Schrier, Demirdas, S., Dykzeul, N., Cohen, J.S., Grand, K., Morel, D., Slavotinek, A., Albassam, H.F., Naik, S., Dean, J., Ragge, N., Cinzia, C., Tedesco, M.G., Harrison, R.E., Bouman, A., Palen, E., Challman, T.D., Willemsen, M.H., Vogt, J., Cunniff, C., Bergstrom, K., Walia, J.S., Bruel, A.L., Kini, U., Alkuraya, F.S., Slegesky, V., Meeks, N., Girotto, P., Johnson, D., Newbury-Ecob, R., Ockeloen, C.W., Prontera, P., Lynch, S.A., Li, D., Graham, J.M., Balasubramanian, M., Schirwani, S., Albaba, S., Carere, D.A., Sacoto, M.J. Guillen, Zamora, F. Milan, Si, Y., Rabin, R., Pappas, J., Renaud, D.L., Hauser, N., Reid, E., Blanchet, P., Foulds, N., Dixit, A., Fisher, R., Armstrong, R., Isidor, B., Cogne, B., Vergano, S. Schrier, Demirdas, S., Dykzeul, N., Cohen, J.S., Grand, K., Morel, D., Slavotinek, A., Albassam, H.F., Naik, S., Dean, J., Ragge, N., Cinzia, C., Tedesco, M.G., Harrison, R.E., Bouman, A., Palen, E., Challman, T.D., Willemsen, M.H., Vogt, J., Cunniff, C., Bergstrom, K., Walia, J.S., Bruel, A.L., Kini, U., Alkuraya, F.S., Slegesky, V., Meeks, N., Girotto, P., Johnson, D., Newbury-Ecob, R., Ockeloen, C.W., Prontera, P., Lynch, S.A., Li, D., Graham, J.M., and Balasubramanian, M.

Abstract

Item does not contain fulltext, The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

Published
2021

9. Temperature drives variation in flying insect biomass across a German malaise trap network

Author

Welti, E.A.R., Zajicek, P., Frenzel, Mark, Ayasse, M., Bornholdt, T., Buse, J., Classen, A., Dziock, F., Engelmann, R.A., Englmeier, J., Fellendorf, M., Förschler, M.I., Fricke, U., Ganuza, C., Hippke, M., Hoenselaar, G., Kaus-Thiel, A., Kerner, J., Kilian, D., Mandery, K., Marten, A., Monaghan, M.T., Morkel, C., Müller, J., Puffpaff, S., Redlich, S., Richter, R., Rojas-Botero, S., Scharnweber, T., Scheiffarth, G., Schmidt Yáñez, P., Schumann, R., Seibold, S., Steffan-Dewenter, I., Stoll, S., Tobisch, C., Twietmeyer, S., Uhler, J., Vogt, J., Weis, D., Weisser, W.W., Wilmking, M., Haase, P., Welti, E.A.R., Zajicek, P., Frenzel, Mark, Ayasse, M., Bornholdt, T., Buse, J., Classen, A., Dziock, F., Engelmann, R.A., Englmeier, J., Fellendorf, M., Förschler, M.I., Fricke, U., Ganuza, C., Hippke, M., Hoenselaar, G., Kaus-Thiel, A., Kerner, J., Kilian, D., Mandery, K., Marten, A., Monaghan, M.T., Morkel, C., Müller, J., Puffpaff, S., Redlich, S., Richter, R., Rojas-Botero, S., Scharnweber, T., Scheiffarth, G., Schmidt Yáñez, P., Schumann, R., Seibold, S., Steffan-Dewenter, I., Stoll, S., Tobisch, C., Twietmeyer, S., Uhler, J., Vogt, J., Weis, D., Weisser, W.W., Wilmking, M., and Haase, P.

Abstract

Among the many concerns for biodiversity in the Anthropocene, recent reports of flying insect loss are particularly alarming, given their importance as pollinators, pest control agents, and as a food source. Few insect monitoring programmes cover the large spatial scales required to provide more generalizable estimates of insect responses to global change drivers.We ask how climate and surrounding habitat affect flying insect biomass using data from the first year of a new monitoring network at 84 locations across Germany comprising a spatial gradient of land cover types from protected to urban and crop areas.Flying insect biomass increased linearly with temperature across Germany. However, the effect of temperature on flying insect biomass flipped to negative in the hot months of June and July when local temperatures most exceeded long-term averages.Land cover explained little variation in insect biomass, but biomass was lowest in forests. Grasslands, pastures, and orchards harboured the highest insect biomass. The date of peak biomass was primarily driven by surrounding land cover, with grasslands especially having earlier insect biomass phenologies.Standardised, large-scale monitoring provides key insights into the underlying processes of insect decline and is pivotal for the development of climate-adapted strategies to promote insect diversity. In a temperate climate region, we find that the positive effects of temperature on flying insect biomass diminish in a German summer at locations where temperatures most exceeded long-term averages. Our results highlight the importance of local adaptation in climate change-driven impacts on insect communities.

Published
2021

10. Contrasting responses of above- and belowground diversity to multiple components of land-use intensity

Author

Le Provost, G., Thiele, J., Westphal, C., Penone, C., Allan, E., Neyret, M., van der Plas, F., Ayasse, M., Bardgett, R.D., Birkhofer, K., Boch, S., Bonkowski, M., Buscot, Francois, Feldhaar, H., Gaulton, R., Goldmann, Kezia, Gossner, M.M., Klaus, V.H., Kleinebecker, T., Krauss, J., Renner, S., Scherreiks, P., Sikorski, J., Baulechner, D., Blüthgen, N., Bolliger, R., Börschig, C., Busch, V., Chisté, M., Fiore-Donno, A.M., Fischer, M., Arndt, H., Hoelzel, N., John, K., Jung, K., Lange, M., Marzini, C., Overmann, J., Paŝalić, E., Perović, D.J., Prati, D., Schäfer, D., Schöning, I., Schrumpf, M., Sonnemann, I., Steffan-Dewenter, I., Tschapka, M., Türke, M., Vogt, J., Wehner, K., Weiner, C., Weisser, W., Wells, K., Werner, M., Wolters, V., Wubet, Tesfaye, Wurst, S., Zaitsev, A.S., Manning, P., Le Provost, G., Thiele, J., Westphal, C., Penone, C., Allan, E., Neyret, M., van der Plas, F., Ayasse, M., Bardgett, R.D., Birkhofer, K., Boch, S., Bonkowski, M., Buscot, Francois, Feldhaar, H., Gaulton, R., Goldmann, Kezia, Gossner, M.M., Klaus, V.H., Kleinebecker, T., Krauss, J., Renner, S., Scherreiks, P., Sikorski, J., Baulechner, D., Blüthgen, N., Bolliger, R., Börschig, C., Busch, V., Chisté, M., Fiore-Donno, A.M., Fischer, M., Arndt, H., Hoelzel, N., John, K., Jung, K., Lange, M., Marzini, C., Overmann, J., Paŝalić, E., Perović, D.J., Prati, D., Schäfer, D., Schöning, I., Schrumpf, M., Sonnemann, I., Steffan-Dewenter, I., Tschapka, M., Türke, M., Vogt, J., Wehner, K., Weiner, C., Weisser, W., Wells, K., Werner, M., Wolters, V., Wubet, Tesfaye, Wurst, S., Zaitsev, A.S., and Manning, P.

Abstract

Land-use intensification is a major driver of biodiversity loss. However, understanding how different components of land use drive biodiversity loss requires the investigation of multiple trophic levels across spatial scales. Using data from 150 agricultural grasslands in central Europe, we assess the influence of multiple components of local- and landscape-level land use on more than 4,000 above- and belowground taxa, spanning 20 trophic groups. Plot-level land-use intensity is strongly and negatively associated with aboveground trophic groups, but positively or not associated with belowground trophic groups. Meanwhile, both above- and belowground trophic groups respond to landscape-level land use, but to different drivers: aboveground diversity of grasslands is promoted by diverse surrounding land-cover, while belowground diversity is positively related to a high permanent forest cover in the surrounding landscape. These results highlight a role of landscape-level land use in shaping belowground communities, and suggest that revised agroecosystem management strategies are needed to conserve whole-ecosystem biodiversity.

Published
2021

11. The BepiColombo Planetary Magnetometer MPO-MAG: What Can We Learn from the Hermean Magnetic Field?

Author

Heyner, D., Auster, H. U., Fornaçon, K. H., Carr, C., Richter, I., Mieth, J. Z.D., Kolhey, P., Exner, W., Motschmann, U., Baumjohann, W., Matsuoka, A., Magnes, W., Berghofer, G., Fischer, D., Plaschke, F., Nakamura, R., Narita, Y., Delva, M., Volwerk, M., Balogh, A., Dougherty, M., Horbury, T., Langlais, B., Mandea, M., Masters, A., Oliveira, J. S., Sánchez-Cano, B., Slavin, J. A., Vennerstrøm, S., Vogt, J., Wicht, J., Glassmeier, K. H., Heyner, D., Auster, H. U., Fornaçon, K. H., Carr, C., Richter, I., Mieth, J. Z.D., Kolhey, P., Exner, W., Motschmann, U., Baumjohann, W., Matsuoka, A., Magnes, W., Berghofer, G., Fischer, D., Plaschke, F., Nakamura, R., Narita, Y., Delva, M., Volwerk, M., Balogh, A., Dougherty, M., Horbury, T., Langlais, B., Mandea, M., Masters, A., Oliveira, J. S., Sánchez-Cano, B., Slavin, J. A., Vennerstrøm, S., Vogt, J., Wicht, J., and Glassmeier, K. H.

Abstract

The magnetometer instrument MPO-MAG on-board the Mercury Planetary Orbiter (MPO) of the BepiColombo mission en-route to Mercury is introduced, with its instrument design, its calibration and scientific targets. The instrument is comprised of two tri-axial fluxgate magnetometers mounted on a 2.9 m boom and are 0.8 m apart. They monitor the magnetic field with up to 128 Hz in a ± 2048 nT range. The MPO will be injected into an initial 480 × 1500 km polar orbit (2.3 h orbital period). At Mercury, we will map the planetary magnetic field and determine the dynamo generated field and constrain the secular variation. In this paper, we also discuss the effect of the instrument calibration on the ability to improve the knowledge on the internal field. Furthermore, the study of induced magnetic fields and field-aligned currents will help to constrain the interior structure in concert with other geophysical instruments. The orbit is also well-suited to study dynamical phenomena at the Hermean magnetopause and magnetospheric cusps. Together with its sister instrument Mio-MGF on-board the second satellite of the BepiColombo mission, the magnetometers at Mercury will study the reaction of the highly dynamic magnetosphere to changes in the solar wind. In the extreme case, the solar wind might even collapse the entire dayside magnetosphere. During cruise, MPO-MAG will contribute to studies of solar wind turbulence and transient phenomena.

Published
2021

12. Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

Author

Cheng, H, Capponi, S, Wakeling, E, Marchi, E, Li, Q, Zhao, M, Weng, C, Stefan, PG, Ahlfors, H, Kleyner, R, Rope, A, Lumaka, A, Lukusa, P, Devriendt, K, Vermeesch, J, Posey, JE, Palmer, EE, Murray, L, Leon, E, Diaz, J, Worgan, L, Mallawaarachchi, A, Vogt, J, de Munnik, SA, Dreyer, L, Baynam, G, Ewans, L, Stark, Z, Lunke, S, Gonçalves, AR, Soares, G, Oliveira, J, Fassi, E, Willing, M, Waugh, JL, Faivre, L, Riviere, JB, Moutton, S, Mohammed, S, Payne, K, Walsh, L, Begtrup, A, Guillen Sacoto, MJ, Douglas, G, Alexander, N, Buckley, MF, Mark, PR, Adès, LC, Sandaradura, SA, Lupski, JR, Roscioli, T, Agrawal, PB, Kline, AD, Wang, K, Timmers, HTM, Lyon, GJ, Cheng, H, Capponi, S, Wakeling, E, Marchi, E, Li, Q, Zhao, M, Weng, C, Stefan, PG, Ahlfors, H, Kleyner, R, Rope, A, Lumaka, A, Lukusa, P, Devriendt, K, Vermeesch, J, Posey, JE, Palmer, EE, Murray, L, Leon, E, Diaz, J, Worgan, L, Mallawaarachchi, A, Vogt, J, de Munnik, SA, Dreyer, L, Baynam, G, Ewans, L, Stark, Z, Lunke, S, Gonçalves, AR, Soares, G, Oliveira, J, Fassi, E, Willing, M, Waugh, JL, Faivre, L, Riviere, JB, Moutton, S, Mohammed, S, Payne, K, Walsh, L, Begtrup, A, Guillen Sacoto, MJ, Douglas, G, Alexander, N, Buckley, MF, Mark, PR, Adès, LC, Sandaradura, SA, Lupski, JR, Roscioli, T, Agrawal, PB, Kline, AD, Wang, K, Timmers, HTM, and Lyon, GJ

Abstract

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability [ID] syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TATA-box binding protein associated factor 1 (TAF1), which participates in RNA polymerase II transcription. The initial study reported 11 families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into ID and/or autism spectrum disorder. We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modeling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of the TAF1/MRXS33 ID syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for a gene mapping to chromosome X.

Published
2020

13. Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

Author

Cheng, H, Capponi, S, Wakeling, E, Marchi, E, Li, Q, Zhao, M, Weng, C, Stefan, PG, Ahlfors, H, Kleyner, R, Rope, A, Lumaka, A, Lukusa, P, Devriendt, K, Vermeesch, J, Posey, JE, Palmer, EE, Murray, L, Leon, E, Diaz, J, Worgan, L, Mallawaarachchi, A, Vogt, J, de Munnik, SA, Dreyer, L, Baynam, G, Ewans, L, Stark, Z, Lunke, S, Goncalves, AR, Soares, G, Oliveira, J, Fassi, E, Willing, M, Waugh, JL, Faivre, L, Riviere, J-B, Moutton, S, Mohammed, S, Payne, K, Walsh, L, Begtrup, A, Sacoto, MJG, Douglas, G, Alexander, N, Buckley, MF, Mark, PR, Ades, LC, Sandaradura, SA, Lupski, JR, Roscioli, T, Agrawal, PB, Kline, AD, Wang, K, Timmers, HTM, Lyon, GJ, Cheng, H, Capponi, S, Wakeling, E, Marchi, E, Li, Q, Zhao, M, Weng, C, Stefan, PG, Ahlfors, H, Kleyner, R, Rope, A, Lumaka, A, Lukusa, P, Devriendt, K, Vermeesch, J, Posey, JE, Palmer, EE, Murray, L, Leon, E, Diaz, J, Worgan, L, Mallawaarachchi, A, Vogt, J, de Munnik, SA, Dreyer, L, Baynam, G, Ewans, L, Stark, Z, Lunke, S, Goncalves, AR, Soares, G, Oliveira, J, Fassi, E, Willing, M, Waugh, JL, Faivre, L, Riviere, J-B, Moutton, S, Mohammed, S, Payne, K, Walsh, L, Begtrup, A, Sacoto, MJG, Douglas, G, Alexander, N, Buckley, MF, Mark, PR, Ades, LC, Sandaradura, SA, Lupski, JR, Roscioli, T, Agrawal, PB, Kline, AD, Wang, K, Timmers, HTM, and Lyon, GJ

Abstract

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved.

Published
2020

14. Cannabinoid Receptor 2 Modulates Maturation of Dendritic Cells and Their Capacity to Induce Hapten-Induced Contact Hypersensitivity

Author

Gaffal, E, Kemter, AM, Scheu, S, Dantas, RL, Vogt, J, Baune, B, Tueting, T, Zimmer, A, Alferink, J, Gaffal, E, Kemter, AM, Scheu, S, Dantas, RL, Vogt, J, Baune, B, Tueting, T, Zimmer, A, and Alferink, J

Abstract

Contact hypersensitivity (CHS) is an established animal model for allergic contact dermatitis. Dendritic cells (DCs) play an important role in the sensitization phase of CHS by initiating T cell responses to topically applied haptens. The cannabinoid receptors 1 (CB1) and 2 (CB2) modulate DC functions and inflammatory skin responses, but their influence on the capacity of haptenized DCs to induce CHS is still unknown. We found lower CHS responses to 2,4-dinitro-1-fluorobenzene (DNFB) in wild type (WT) mice after adoptive transfer of haptenized Cnr2-/- and Cnr1-/-/Cnr2-/- bone marrow (BM) DCs as compared to transfer of WT DCs. In contrast, induction of CHS was not affected in WT recipients after transfer of Cnr1-/- DCs. In vitro stimulated Cnr2-/- DCs showed lower CCR7 and CXCR4 expression when compared to WT cells, while in vitro migration towards the chemokine ligands was not affected by CB2. Upregulation of MHC class II and co-stimulatory molecules was also reduced in Cnr2-/- DCs. This study demonstrates that CB2 modulates the maturation phenotype of DCs but not their chemotactic capacities in vitro. These findings and the fact that CHS responses mediated by Cnr2-/- DCs are reduced suggest that CB2 is a promising target for the treatment of inflammatory skin conditions.

Published
2020

15. A reference map of potential determinants for the human serum metabolome

Author

Bar, N., Korem, T., Weissbrod, O., Zeevi, D., Rothschild, D., Leviatan, S., Kosower, N., Lotan-Pompan, M., Weinberger, A., Le Roy, C. I., Menni, C., Visconti, A., Falchi, M., Spector, T. D., Vestergaard, H., Arumugam, M., Hansen, T., Allin, K., Hong, Mun-Gwan, Schwenk, Jochen M., Häussler, Ragna S., Dale, Matilda, Giorgino, T., Rodriquez, M., Perry, M., Nice, R., McDonald, T., Hattersley, A., Jones, A., Graefe-Mody, U., Baum, P., Grempler, R., Thomas, C. E., Masi, F. D., Brorsson, C. A., Mazzoni, G., Allesøe, R., Rasmussen, S., Gudmundsdóttir, V., Nielsen, A. M., Banasik, K., Tsirigos, K., Nilsson, B., Pedersen, H., Brunak, S., Karaderi, T., Lundgaard, A. T., Johansen, J., Gupta, R., Sackett, P. W., Tillner, J., Lehr, T., Scherer, N., Dings, C., Sihinevich, I., Loftus, H., Cabrelli, L., McEvoy, D., Mari, A., Bizzotto, R., Tura, A., ’t Hart, L., Dekkers, K., Leeuwen, N., Slieker, R., Rutters, F., Beulens, J., Nijpels, G., Koopman, A., Oort, S., Groeneveld, L., Groop, L., Elders, P., Viñuela, A., Ramisch, A., Dermitzakis, E., Ehrhardt, B., Jennison, C., Froguel, P., Canouil, M., Boneford, A., McVittie, I., Wake, D., Frau, F., Staerfeldt, H. -H, Adragni, K., Thomas, M., Wu, H., Pavo, I., Steckel-Hamann, B., Thomsen, H., Giordano, G. N., Fitipaldi, H., Ridderstråle, M., Kurbasic, A., Pasdar, N. A., Pomares-Millan, H., Mutie, P., Koivula, R., McRobert, N., McCarthy, M., Wesolowska-Andersen, A., Mahajan, A., Abdalla, M., Fernandez, J., Holl, R., Heggie, A., Deshmukh, H., Hennige, A., Bianzano, S., Thorand, B., Sharma, S., Grallert, H., Adam, J., Troll, M., Fritsche, A., Hill, A., Thorne, C., Hudson, M., Kuulasmaa, T., Vangipurapu, J., Laakso, M., Cederberg, H., Kokkola, T., Jiao, Y., Gough, S., Robertson, N., Verkindt, H., Raverdi, V., Caiazzo, R., Pattou, F., White, M., Donnelly, L., Brown, A., Palmer, C., Davtian, D., Dawed, A., Forgie, I., Pearson, E., Ruetten, H., Musholt, P., Bell, J., Thomas, E. L., Whitcher, B., Haid, M., Nicolay, C., Mourby, M., Kaye, J., Shah, N., Teare, H., Frost, G., Jablonka, B., Uhlen, M., Eriksen, R., Vogt, J., Dutta, A., Jonsson, A., Engelbrechtsen, L., Forman, A., Sondertoft, N., de Preville, N., Baltauss, T., Walker, M., Gassenhuber, J., Klintenberg, M., Bergstrom, M., Ferrer, J., Adamski, J., Franks, P. W., Pedersen, O., Segal, E., consortium, The IMI DIRECT, Bar, N., Korem, T., Weissbrod, O., Zeevi, D., Rothschild, D., Leviatan, S., Kosower, N., Lotan-Pompan, M., Weinberger, A., Le Roy, C. I., Menni, C., Visconti, A., Falchi, M., Spector, T. D., Vestergaard, H., Arumugam, M., Hansen, T., Allin, K., Hong, Mun-Gwan, Schwenk, Jochen M., Häussler, Ragna S., Dale, Matilda, Giorgino, T., Rodriquez, M., Perry, M., Nice, R., McDonald, T., Hattersley, A., Jones, A., Graefe-Mody, U., Baum, P., Grempler, R., Thomas, C. E., Masi, F. D., Brorsson, C. A., Mazzoni, G., Allesøe, R., Rasmussen, S., Gudmundsdóttir, V., Nielsen, A. M., Banasik, K., Tsirigos, K., Nilsson, B., Pedersen, H., Brunak, S., Karaderi, T., Lundgaard, A. T., Johansen, J., Gupta, R., Sackett, P. W., Tillner, J., Lehr, T., Scherer, N., Dings, C., Sihinevich, I., Loftus, H., Cabrelli, L., McEvoy, D., Mari, A., Bizzotto, R., Tura, A., ’t Hart, L., Dekkers, K., Leeuwen, N., Slieker, R., Rutters, F., Beulens, J., Nijpels, G., Koopman, A., Oort, S., Groeneveld, L., Groop, L., Elders, P., Viñuela, A., Ramisch, A., Dermitzakis, E., Ehrhardt, B., Jennison, C., Froguel, P., Canouil, M., Boneford, A., McVittie, I., Wake, D., Frau, F., Staerfeldt, H. -H, Adragni, K., Thomas, M., Wu, H., Pavo, I., Steckel-Hamann, B., Thomsen, H., Giordano, G. N., Fitipaldi, H., Ridderstråle, M., Kurbasic, A., Pasdar, N. A., Pomares-Millan, H., Mutie, P., Koivula, R., McRobert, N., McCarthy, M., Wesolowska-Andersen, A., Mahajan, A., Abdalla, M., Fernandez, J., Holl, R., Heggie, A., Deshmukh, H., Hennige, A., Bianzano, S., Thorand, B., Sharma, S., Grallert, H., Adam, J., Troll, M., Fritsche, A., Hill, A., Thorne, C., Hudson, M., Kuulasmaa, T., Vangipurapu, J., Laakso, M., Cederberg, H., Kokkola, T., Jiao, Y., Gough, S., Robertson, N., Verkindt, H., Raverdi, V., Caiazzo, R., Pattou, F., White, M., Donnelly, L., Brown, A., Palmer, C., Davtian, D., Dawed, A., Forgie, I., Pearson, E., Ruetten, H., Musholt, P., Bell, J., Thomas, E. L., Whitcher, B., Haid, M., Nicolay, C., Mourby, M., Kaye, J., Shah, N., Teare, H., Frost, G., Jablonka, B., Uhlen, M., Eriksen, R., Vogt, J., Dutta, A., Jonsson, A., Engelbrechtsen, L., Forman, A., Sondertoft, N., de Preville, N., Baltauss, T., Walker, M., Gassenhuber, J., Klintenberg, M., Bergstrom, M., Ferrer, J., Adamski, J., Franks, P. W., Pedersen, O., Segal, E., and consortium, The IMI DIRECT

Abstract

The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites., QC 20211001

Published
2020
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16. ESA field-aligned currents:methodology inter-comparison exercise

Author

Trenchi, L. (Lorenzo), T. F. (The FAC-MICE Team), Kauristie, K. (K.), Käki, S. (S.), Vanhamäki, H. (Heikki), Juusola, L. (L.), Blagau, A. (Adrian), Vogt, J. (Joachim), Marghitu, O. (Octav), Dunlop, M. W. (M. W.), Yang, Y.-Y. (Y.-Y.), Yang, J.-Y. (J.-Y.), Lühr, H. (Hermann), Kervalishvili, G. (Guram), Rauberg, J. (Jan), Stolle, C. (Claudia), Pakhotin, I. P. (Ivan P.), Mann, I. R. (Ian R.), Forsyth, C. (C.), Rae, I. J. (I. J.), Wu, J. (Jiashu), Gjerloev, J. (J.), Ohtani, S. (S.), Friel, M. (M.), Trenchi, L. (Lorenzo), T. F. (The FAC-MICE Team), Kauristie, K. (K.), Käki, S. (S.), Vanhamäki, H. (Heikki), Juusola, L. (L.), Blagau, A. (Adrian), Vogt, J. (Joachim), Marghitu, O. (Octav), Dunlop, M. W. (M. W.), Yang, Y.-Y. (Y.-Y.), Yang, J.-Y. (J.-Y.), Lühr, H. (Hermann), Kervalishvili, G. (Guram), Rauberg, J. (Jan), Stolle, C. (Claudia), Pakhotin, I. P. (Ivan P.), Mann, I. R. (Ian R.), Forsyth, C. (C.), Rae, I. J. (I. J.), Wu, J. (Jiashu), Gjerloev, J. (J.), Ohtani, S. (S.), and Friel, M. (M.)

Abstract

Various ESA projects and several proposals to first Swarm DISC Call for Ideas (May 2016) suggested possible evolution for the current Swarm Level 2 FAC products, and the implementation of quality flags for the FAC products. The Field-Aligned Currents—Methodology Inter-Comparison Exercise (FAC-MICE) consisted in comparison of the various methods to determine the FAC from Swarm data, with a test dataset of 28 Swarm auroral crossings delivered to participants last June. Eight groups performed the FAC-MICE analysis. The results of this exercise, discussed in the dedicated ‘Swarm Ionospheric Currents Products workshop’ in ESTEC on September 2017, highlighted the strengths of the various methods/approaches. Following discussion with the participants to this workshop, we are now working to develop an open source platform for user-definable FAC calculation.

Published
2020

17. Distribution of medically relevant antibiotic resistance genes and mobile genetic elements in soils of temperate forests and grasslands varying in land use

Author

Willms, I.M., Yuan, J., Penone, C., Goldmann, Kezia, Vogt, J., Wubet, Tesfaye, Schöning, I., Schrumpf, M., Buscot, Francois, Nacke, H., Willms, I.M., Yuan, J., Penone, C., Goldmann, Kezia, Vogt, J., Wubet, Tesfaye, Schöning, I., Schrumpf, M., Buscot, Francois, and Nacke, H.

Abstract

Antibiotic-resistant pathogens claim the lives of thousands of people each year and are currently considered as one of the most serious threats to public health. Apart from clinical environments, soil ecosystems also represent a major source of antibiotic resistance determinants, which can potentially disseminate across distinct microbial habitats and be acquired by human pathogens via horizontal gene transfer. Therefore, it is of global importance to retrieve comprehensive information on environmental factors, contributing to an accumulation of antibiotic resistance genes and mobile genetic elements in these ecosystems. Here, medically relevant antibiotic resistance genes, class 1 integrons and IncP-1 plasmids were quantified via real time quantitative PCR in soils derived from temperate grasslands and forests, varying in land use over a large spatial scale. The generated dataset allowed an analysis, decoupled from regional influences, and enabled the identification of land use practices and soil characteristics elevating the abundance of antibiotic resistance genes and mobile genetic elements. In grassland soils, the abundance of the macrolide resistance gene mefA as well as the sulfonamide resistance gene sul2 was positively correlated with organic fertilization and the abundance of aac(6’)-lb, conferring resistance to different aminoglycosides, increased with mowing frequency. With respect to forest soils, the beta-lactam resistance gene blaIMP-12 was significantly correlated with fungal diversity which might be due to the fact that different fungal species can produce beta-lactams. Furthermore, except blaIMP-5 and blaIMP-12, the analyzed antibiotic resistance genes as well as IncP-1 plasmids and class-1 integrons were detected less frequently in forest soils than in soils derived from grassland that are commonly in closer proximity to human activities.

Published
2020

18. Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Author

Wilman, H. R., Parisinos, C. A., Atabaki-Pasdar, N., Kelly, M., Thomas, E. L., Neubauer, S., Jennison, C., Ehrhardt, B., Baum, P., Schoelsch, C., Freijer, J., Grempler, R., Graefe-Mody, U., Hennige, A., Dings, C., Lehr, T., Scherer, N., Sihinecich, I., Pattou, F., Raverdi, V., Caiazzo, R., Torres, F., Verkindt, H., Mari, A., Tura, A., Giorgino, T., Bizzotto, Froguel, P., Bonneford, A., Canouil, M., Dhennin, V., Brorsson, C., Brunak, S., De Masi, F., Gudmundsdóttir, V., Pedersen, H., Banasik, K., Thomas, C., Sackett, P., Staerfeldt, H. -H, Lundgaard, A., Nilsson, B., Nielsen, A., Mazzoni, G., Karaderi, T., Rasmussen, S., Johansen, J., Allesøe, R., Fritsche, A., Thorand, B., Adamski, J., Grallert, H., Haid, M., Sharma, S., Troll, M., Adam, J., Ferrer, J., Eriksen, H., Frost, G., Häussler, Ragna S., Hong, Mun-Gwan, Schwenk, Jochen M., Uhlén, Mathias, Nicolay, C., Pavo, I., Steckel-Hamann, B., Thomas, M., Adragni, K., Wu, H., Hart, L., Roderick, S., van Leeuwen, N., Dekkers, K., Frau, F., Gassenhuber, J., Jablonka, B., Musholt, P., Ruetten, H., Tillner, J., Baltauss, T., Bernard Poenaru, O., de Preville, N., Rodriquez, M., Arumugam, M., Allin, K., Engelbrechtsen, L., Hansen, T., Forman, A., Jonsson, A., Pedersen, O., Dutta, A., Vogt, J., Vestergaard, H., Laakso, M., Kokkola, T., Kuulasmaa, T., Franks, P., Giordano, N., Pomares-Millan, H., Fitipaldi, H., Mutie, P., Klintenberg, M., Bergstrom, M., Groop, L., Ridderstrale, M., Atabaki Pasdar, N., Deshmukh, H., Heggie, A., Wake, D., McEvoy, D., McVittie, I., Walker, M., Hattersley, A., Hill, A., Jones, A., McDonald, T., Perry, M., Nice, R., Hudson, M., Thorne, C., Dermitzakis, E., Viñuela, A., Cabrelli, L., Loftus, H., Dawed, A., Donnelly, L., Forgie, I., Pearson, E., Palmer, C., Brown, A., Koivula, R., Wesolowska-Andersen, A., Abdalla, M., McRobert, N., Fernandez, J., Jiao, Y., Robertson, N., Gough, S., Kaye, J., Mourby, M., Mahajan, A., McCarthy, M., Shah, N., Teare, H., Holl, R., Koopman, A., Rutters, F., Beulens, J., Groeneveld, L., Bell, J., Thomas, L., Whitcher, B., Hingorani, A. D., Patel, R. S., Hemingway, H., Franks, P. W., Bell, J. D., Banerjee, R., Yaghootkar, H., Wilman, H. R., Parisinos, C. A., Atabaki-Pasdar, N., Kelly, M., Thomas, E. L., Neubauer, S., Jennison, C., Ehrhardt, B., Baum, P., Schoelsch, C., Freijer, J., Grempler, R., Graefe-Mody, U., Hennige, A., Dings, C., Lehr, T., Scherer, N., Sihinecich, I., Pattou, F., Raverdi, V., Caiazzo, R., Torres, F., Verkindt, H., Mari, A., Tura, A., Giorgino, T., Bizzotto, Froguel, P., Bonneford, A., Canouil, M., Dhennin, V., Brorsson, C., Brunak, S., De Masi, F., Gudmundsdóttir, V., Pedersen, H., Banasik, K., Thomas, C., Sackett, P., Staerfeldt, H. -H, Lundgaard, A., Nilsson, B., Nielsen, A., Mazzoni, G., Karaderi, T., Rasmussen, S., Johansen, J., Allesøe, R., Fritsche, A., Thorand, B., Adamski, J., Grallert, H., Haid, M., Sharma, S., Troll, M., Adam, J., Ferrer, J., Eriksen, H., Frost, G., Häussler, Ragna S., Hong, Mun-Gwan, Schwenk, Jochen M., Uhlén, Mathias, Nicolay, C., Pavo, I., Steckel-Hamann, B., Thomas, M., Adragni, K., Wu, H., Hart, L., Roderick, S., van Leeuwen, N., Dekkers, K., Frau, F., Gassenhuber, J., Jablonka, B., Musholt, P., Ruetten, H., Tillner, J., Baltauss, T., Bernard Poenaru, O., de Preville, N., Rodriquez, M., Arumugam, M., Allin, K., Engelbrechtsen, L., Hansen, T., Forman, A., Jonsson, A., Pedersen, O., Dutta, A., Vogt, J., Vestergaard, H., Laakso, M., Kokkola, T., Kuulasmaa, T., Franks, P., Giordano, N., Pomares-Millan, H., Fitipaldi, H., Mutie, P., Klintenberg, M., Bergstrom, M., Groop, L., Ridderstrale, M., Atabaki Pasdar, N., Deshmukh, H., Heggie, A., Wake, D., McEvoy, D., McVittie, I., Walker, M., Hattersley, A., Hill, A., Jones, A., McDonald, T., Perry, M., Nice, R., Hudson, M., Thorne, C., Dermitzakis, E., Viñuela, A., Cabrelli, L., Loftus, H., Dawed, A., Donnelly, L., Forgie, I., Pearson, E., Palmer, C., Brown, A., Koivula, R., Wesolowska-Andersen, A., Abdalla, M., McRobert, N., Fernandez, J., Jiao, Y., Robertson, N., Gough, S., Kaye, J., Mourby, M., Mahajan, A., McCarthy, M., Shah, N., Teare, H., Holl, R., Koopman, A., Rutters, F., Beulens, J., Groeneveld, L., Bell, J., Thomas, L., Whitcher, B., Hingorani, A. D., Patel, R. S., Hemingway, H., Franks, P. W., Bell, J. D., Banerjee, R., and Yaghootkar, H.

Abstract

Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10−8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Lay summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart di, QC 20191128

Published
2019
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19. Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

Author

Cheng, H., Capponi, S., Wakeling, E., Marchi, E., Li, Q., Zhao, M., Weng, C., Stefan, P.G., Ahlfors, H., Kleyner, R., Rope, A., Lumaka, A., Lukusa, P., Devriendt, K., Vermeesch, J., Posey, J.E., Palmer, E.E., Murray, L., Leon, E., Diaz, J., Worgan, L., Mallawaarachchi, A., Vogt, J., Munnik, S.A., Dreyer, L., Baynam, G., Ewans, L., Stark, Z., Lunke, S., Gonçalves, A.R., Soares, G., Oliveira, J., Fassi, E., Willing, M., Waugh, J.L., Faivre, L., Riviere, J‐B, Moutton, S., Mohammed, S., Payne, K., Walsh, L., Begtrup, A., Guillen Sacoto, M.J., Douglas, G., Alexander, N., Buckley, M.F., Mark, P.R., Adès, L.C., Sandaradura, S.A., Lupski, J.R., Roscioli, T., Agrawal, P.B., Kline, A.D., Wang, K., Timmers, H.T.M., Lyon, G.J., Cheng, H., Capponi, S., Wakeling, E., Marchi, E., Li, Q., Zhao, M., Weng, C., Stefan, P.G., Ahlfors, H., Kleyner, R., Rope, A., Lumaka, A., Lukusa, P., Devriendt, K., Vermeesch, J., Posey, J.E., Palmer, E.E., Murray, L., Leon, E., Diaz, J., Worgan, L., Mallawaarachchi, A., Vogt, J., Munnik, S.A., Dreyer, L., Baynam, G., Ewans, L., Stark, Z., Lunke, S., Gonçalves, A.R., Soares, G., Oliveira, J., Fassi, E., Willing, M., Waugh, J.L., Faivre, L., Riviere, J‐B, Moutton, S., Mohammed, S., Payne, K., Walsh, L., Begtrup, A., Guillen Sacoto, M.J., Douglas, G., Alexander, N., Buckley, M.F., Mark, P.R., Adès, L.C., Sandaradura, S.A., Lupski, J.R., Roscioli, T., Agrawal, P.B., Kline, A.D., Wang, K., Timmers, H.T.M., and Lyon, G.J.

Abstract

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability [ID] syndrome) (MIM# 300966) caused by pathogenic variants involving the X‐linked gene TATA‐box binding protein associated factor 1 (TAF1), which participates in RNA polymerase II transcription. The initial study reported 11 families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into ID and/or autism spectrum disorder. We have now identified an additional 27 families through a genotype‐first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modeling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of the TAF1/MRXS33 ID syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for a gene mapping to chromosome X.

Published
2019

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

Author

O'Donnell-Luria, A.H., Pais, L.S., Faundes, V., Wood, J.C., Sveden, A., Luria, V., Jamra, R. Abou, Accogli, A., Amburgey, K., Anderlid, B.M., Azzarello-Burri, S., Basinger, A.A., Bianchini, C., Bird, L.M., Buchert, R., Carre, W., Ceulemans, S., Charles, P., Cox, H., Culliton, L., Curro, A., Demurger, F., Dowling, J.J., Duban-Bedu, B., Dubourg, C., Eiset, S.E., Escobar, L.F., Ferrarini, A., Haack, T.B., Hashim, M., Heide, S. van der, Helbig, K.L., Helbig, I., Heredia, R., Heron, D., Isidor, B., Jonasson, A.R., Joset, P., Keren, B., Kok, F., Kroes, H.Y., Lavillaureix, A., Lu, X., Maas, S.M., Maegawa, G.H., Marcelis, C.L.M., Mark, P.R., Masruha, M.R., McLaughlin, H.M., McWalter, K., Melchinger, E.U., Mercimek-Andrews, S., Nava, C., Pendziwiat, M., Person, R., Ramelli, G.P., Ramos, L.L.P., Rauch, A., Reavey, C., Renieri, A., Riess, A., Sanchez-Valle, A., Sattar, S., Saunders, C., Schwarz, N., Smol, T., Srour, M., Steindl, K., Syrbe, S., Taylor, J.C., Telegrafi, A., Thiffault, I., Trauner, D.A., Linden, H., Jr. van der, Koningsbruggen, S. van, Villard, L., Vogel, I., Vogt, J., Weber, Y.G., Wentzensen, I.M., Widjaja, E., Zak, J., Baxter, S., Banka, S., Rodan, L.H., O'Donnell-Luria, A.H., Pais, L.S., Faundes, V., Wood, J.C., Sveden, A., Luria, V., Jamra, R. Abou, Accogli, A., Amburgey, K., Anderlid, B.M., Azzarello-Burri, S., Basinger, A.A., Bianchini, C., Bird, L.M., Buchert, R., Carre, W., Ceulemans, S., Charles, P., Cox, H., Culliton, L., Curro, A., Demurger, F., Dowling, J.J., Duban-Bedu, B., Dubourg, C., Eiset, S.E., Escobar, L.F., Ferrarini, A., Haack, T.B., Hashim, M., Heide, S. van der, Helbig, K.L., Helbig, I., Heredia, R., Heron, D., Isidor, B., Jonasson, A.R., Joset, P., Keren, B., Kok, F., Kroes, H.Y., Lavillaureix, A., Lu, X., Maas, S.M., Maegawa, G.H., Marcelis, C.L.M., Mark, P.R., Masruha, M.R., McLaughlin, H.M., McWalter, K., Melchinger, E.U., Mercimek-Andrews, S., Nava, C., Pendziwiat, M., Person, R., Ramelli, G.P., Ramos, L.L.P., Rauch, A., Reavey, C., Renieri, A., Riess, A., Sanchez-Valle, A., Sattar, S., Saunders, C., Schwarz, N., Smol, T., Srour, M., Steindl, K., Syrbe, S., Taylor, J.C., Telegrafi, A., Thiffault, I., Trauner, D.A., Linden, H., Jr. van der, Koningsbruggen, S. van, Villard, L., Vogel, I., Vogt, J., Weber, Y.G., Wentzensen, I.M., Widjaja, E., Zak, J., Baxter, S., Banka, S., and Rodan, L.H.

Abstract

Contains fulltext : 206572.pdf (publisher's version ) (Open Access), We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Published
2019

21. The phenotype of Sotos syndrome in adulthood: A review of 44 individuals

Author

Foster, A, Zachariou, A, Loveday, C, Ashraf, T, Blair, E, Clayton-Smith, J, Dorkins, H, Fryer, A, Gener, B, Goudie, D, Henderson, A, Irving, M, Joss, S, Keeley, V, Lahiri, N, Lynch, SA, Mansour, S, McCann, E, Morton, J, Motton, N, Murray, A, Riches, K, Shears, D, Stark, Z, Thompson, E, Vogt, J, Wright, M, Cole, T, Tatton-Brown, K, Foster, A, Zachariou, A, Loveday, C, Ashraf, T, Blair, E, Clayton-Smith, J, Dorkins, H, Fryer, A, Gener, B, Goudie, D, Henderson, A, Irving, M, Joss, S, Keeley, V, Lahiri, N, Lynch, SA, Mansour, S, McCann, E, Morton, J, Motton, N, Murray, A, Riches, K, Shears, D, Stark, Z, Thompson, E, Vogt, J, Wright, M, Cole, T, and Tatton-Brown, K

Abstract

Sotos syndrome is an overgrowth-intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the published Sotos syndrome clinical descriptions are based on studies of children; the phenotype in adults with Sotos syndrome is not yet well described. Given that it is now 17 years since disruption of NSD1 was shown to cause Sotos syndrome, many of the children first reported are now adults. It is therefore timely to investigate the phenotype of 44 adults with Sotos syndrome and NSD1 pathogenic variants. We have shown that adults with Sotos syndrome display a wide spectrum of intellectual ability with functioning ranging from fully independent to fully dependent. Reproductive rates are low. In our cohort, median height in adult women is +1.9 SD and men +0.5 SD. There is a distinctive facial appearance in adults with a tall, square, prominent chin. Reassuringly, adults with Sotos syndrome are generally healthy with few new medical issues; however, lymphedema, poor dentition, hearing loss, contractures and tremor have developed in a small number of individuals.

Published
2019

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

Author

O'Donnell-Luria, A.H., Pais, L.S., Faundes, V., Wood, J.C., Sveden, A., Luria, V., Jamra, R. Abou, Accogli, A., Amburgey, K., Anderlid, B.M., Azzarello-Burri, S., Basinger, A.A., Bianchini, C., Bird, L.M., Buchert, R., Carre, W., Ceulemans, S., Charles, P., Cox, H., Culliton, L., Curro, A., Demurger, F., Dowling, J.J., Duban-Bedu, B., Dubourg, C., Eiset, S.E., Escobar, L.F., Ferrarini, A., Haack, T.B., Hashim, M., Heide, S. van der, Helbig, K.L., Helbig, I., Heredia, R., Heron, D., Isidor, B., Jonasson, A.R., Joset, P., Keren, B., Kok, F., Kroes, H.Y., Lavillaureix, A., Lu, X., Maas, S.M., Maegawa, G.H., Marcelis, C.L.M., Mark, P.R., Masruha, M.R., McLaughlin, H.M., McWalter, K., Melchinger, E.U., Mercimek-Andrews, S., Nava, C., Pendziwiat, M., Person, R., Ramelli, G.P., Ramos, L.L.P., Rauch, A., Reavey, C., Renieri, A., Riess, A., Sanchez-Valle, A., Sattar, S., Saunders, C., Schwarz, N., Smol, T., Srour, M., Steindl, K., Syrbe, S., Taylor, J.C., Telegrafi, A., Thiffault, I., Trauner, D.A., Linden, H., Jr. van der, Koningsbruggen, S. van, Villard, L., Vogel, I., Vogt, J., Weber, Y.G., Wentzensen, I.M., Widjaja, E., Zak, J., Baxter, S., Banka, S., Rodan, L.H., O'Donnell-Luria, A.H., Pais, L.S., Faundes, V., Wood, J.C., Sveden, A., Luria, V., Jamra, R. Abou, Accogli, A., Amburgey, K., Anderlid, B.M., Azzarello-Burri, S., Basinger, A.A., Bianchini, C., Bird, L.M., Buchert, R., Carre, W., Ceulemans, S., Charles, P., Cox, H., Culliton, L., Curro, A., Demurger, F., Dowling, J.J., Duban-Bedu, B., Dubourg, C., Eiset, S.E., Escobar, L.F., Ferrarini, A., Haack, T.B., Hashim, M., Heide, S. van der, Helbig, K.L., Helbig, I., Heredia, R., Heron, D., Isidor, B., Jonasson, A.R., Joset, P., Keren, B., Kok, F., Kroes, H.Y., Lavillaureix, A., Lu, X., Maas, S.M., Maegawa, G.H., Marcelis, C.L.M., Mark, P.R., Masruha, M.R., McLaughlin, H.M., McWalter, K., Melchinger, E.U., Mercimek-Andrews, S., Nava, C., Pendziwiat, M., Person, R., Ramelli, G.P., Ramos, L.L.P., Rauch, A., Reavey, C., Renieri, A., Riess, A., Sanchez-Valle, A., Sattar, S., Saunders, C., Schwarz, N., Smol, T., Srour, M., Steindl, K., Syrbe, S., Taylor, J.C., Telegrafi, A., Thiffault, I., Trauner, D.A., Linden, H., Jr. van der, Koningsbruggen, S. van, Villard, L., Vogel, I., Vogt, J., Weber, Y.G., Wentzensen, I.M., Widjaja, E., Zak, J., Baxter, S., Banka, S., and Rodan, L.H.

Abstract

Contains fulltext : 206572.pdf (publisher's version ) (Open Access), We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Published
2019

23. Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

Author

Cheng, H., Capponi, S., Wakeling, E., Marchi, E., Li, Q., Zhao, M., Weng, C., Stefan, P.G., Ahlfors, H., Kleyner, R., Rope, A., Lumaka, A., Lukusa, P., Devriendt, K., Vermeesch, J., Posey, J.E., Palmer, E.E., Murray, L., Leon, E., Diaz, J., Worgan, L., Mallawaarachchi, A., Vogt, J., Munnik, S.A., Dreyer, L., Baynam, G., Ewans, L., Stark, Z., Lunke, S., Gonçalves, A.R., Soares, G., Oliveira, J., Fassi, E., Willing, M., Waugh, J.L., Faivre, L., Riviere, J‐B, Moutton, S., Mohammed, S., Payne, K., Walsh, L., Begtrup, A., Guillen Sacoto, M.J., Douglas, G., Alexander, N., Buckley, M.F., Mark, P.R., Adès, L.C., Sandaradura, S.A., Lupski, J.R., Roscioli, T., Agrawal, P.B., Kline, A.D., Wang, K., Timmers, H.T.M., Lyon, G.J., Cheng, H., Capponi, S., Wakeling, E., Marchi, E., Li, Q., Zhao, M., Weng, C., Stefan, P.G., Ahlfors, H., Kleyner, R., Rope, A., Lumaka, A., Lukusa, P., Devriendt, K., Vermeesch, J., Posey, J.E., Palmer, E.E., Murray, L., Leon, E., Diaz, J., Worgan, L., Mallawaarachchi, A., Vogt, J., Munnik, S.A., Dreyer, L., Baynam, G., Ewans, L., Stark, Z., Lunke, S., Gonçalves, A.R., Soares, G., Oliveira, J., Fassi, E., Willing, M., Waugh, J.L., Faivre, L., Riviere, J‐B, Moutton, S., Mohammed, S., Payne, K., Walsh, L., Begtrup, A., Guillen Sacoto, M.J., Douglas, G., Alexander, N., Buckley, M.F., Mark, P.R., Adès, L.C., Sandaradura, S.A., Lupski, J.R., Roscioli, T., Agrawal, P.B., Kline, A.D., Wang, K., Timmers, H.T.M., and Lyon, G.J.

Abstract

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability [ID] syndrome) (MIM# 300966) caused by pathogenic variants involving the X‐linked gene TATA‐box binding protein associated factor 1 (TAF1), which participates in RNA polymerase II transcription. The initial study reported 11 families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into ID and/or autism spectrum disorder. We have now identified an additional 27 families through a genotype‐first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modeling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of the TAF1/MRXS33 ID syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for a gene mapping to chromosome X.

Published
2019

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

Author

O'Donnell-Luria, A.H., Pais, L.S., Faundes, V., Wood, J.C., Sveden, A., Luria, V., Jamra, R. Abou, Accogli, A., Amburgey, K., Anderlid, B.M., Azzarello-Burri, S., Basinger, A.A., Bianchini, C., Bird, L.M., Buchert, R., Carre, W., Ceulemans, S., Charles, P., Cox, H., Culliton, L., Curro, A., Demurger, F., Dowling, J.J., Duban-Bedu, B., Dubourg, C., Eiset, S.E., Escobar, L.F., Ferrarini, A., Haack, T.B., Hashim, M., Heide, S. van der, Helbig, K.L., Helbig, I., Heredia, R., Heron, D., Isidor, B., Jonasson, A.R., Joset, P., Keren, B., Kok, F., Kroes, H.Y., Lavillaureix, A., Lu, X., Maas, S.M., Maegawa, G.H., Marcelis, C.L.M., Mark, P.R., Masruha, M.R., McLaughlin, H.M., McWalter, K., Melchinger, E.U., Mercimek-Andrews, S., Nava, C., Pendziwiat, M., Person, R., Ramelli, G.P., Ramos, L.L.P., Rauch, A., Reavey, C., Renieri, A., Riess, A., Sanchez-Valle, A., Sattar, S., Saunders, C., Schwarz, N., Smol, T., Srour, M., Steindl, K., Syrbe, S., Taylor, J.C., Telegrafi, A., Thiffault, I., Trauner, D.A., Linden, H., Jr. van der, Koningsbruggen, S. van, Villard, L., Vogel, I., Vogt, J., Weber, Y.G., Wentzensen, I.M., Widjaja, E., Zak, J., Baxter, S., Banka, S., Rodan, L.H., O'Donnell-Luria, A.H., Pais, L.S., Faundes, V., Wood, J.C., Sveden, A., Luria, V., Jamra, R. Abou, Accogli, A., Amburgey, K., Anderlid, B.M., Azzarello-Burri, S., Basinger, A.A., Bianchini, C., Bird, L.M., Buchert, R., Carre, W., Ceulemans, S., Charles, P., Cox, H., Culliton, L., Curro, A., Demurger, F., Dowling, J.J., Duban-Bedu, B., Dubourg, C., Eiset, S.E., Escobar, L.F., Ferrarini, A., Haack, T.B., Hashim, M., Heide, S. van der, Helbig, K.L., Helbig, I., Heredia, R., Heron, D., Isidor, B., Jonasson, A.R., Joset, P., Keren, B., Kok, F., Kroes, H.Y., Lavillaureix, A., Lu, X., Maas, S.M., Maegawa, G.H., Marcelis, C.L.M., Mark, P.R., Masruha, M.R., McLaughlin, H.M., McWalter, K., Melchinger, E.U., Mercimek-Andrews, S., Nava, C., Pendziwiat, M., Person, R., Ramelli, G.P., Ramos, L.L.P., Rauch, A., Reavey, C., Renieri, A., Riess, A., Sanchez-Valle, A., Sattar, S., Saunders, C., Schwarz, N., Smol, T., Srour, M., Steindl, K., Syrbe, S., Taylor, J.C., Telegrafi, A., Thiffault, I., Trauner, D.A., Linden, H., Jr. van der, Koningsbruggen, S. van, Villard, L., Vogel, I., Vogt, J., Weber, Y.G., Wentzensen, I.M., Widjaja, E., Zak, J., Baxter, S., Banka, S., and Rodan, L.H.

Abstract

Contains fulltext : 206572.pdf (publisher's version ) (Open Access), We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Published
2019

25. Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Author

Wilman, Henry R., Parisinos, Constantinos A., Atabaki-Pasdar, Naeimeh, Kelly, Matt, Thomas, E. Louise, Neubauer, Stefan, Jennison, Christopher, Ehrhardt, B., Baum, Patrick, Schoelsch, Corinna, Freijer, Jan, Grempler, Rolf, Graefe-Mody, Ulrike, Hennige, A., Dings, Christiane, Lehr, Thorsten, Scherer, Nina, Sihinecich, I., Pattou, Francois, Raverdi, Violeta, Caiazzo, Robert, Torres, Fanelly, Verkindt, Helene, Mari, Andrea, Tura, Andrea, Giorgino, Toni, Bizzotto, Froguel, Philippe, Brorsson, Caroline, Brunak, S., De Masi, Federico, Pedersen, H., Banasik, Karina, Thomas, Cecilia, Lundgaard, Agnete, Nielsen, A., Mazzoni, Gianluca, Karaderi, T., Rasmussen, S., Johansen, Joachim, Allesøe, Rosa, Arumugam, Manimozhiyan, Allin, Kristine, Hansen, Torben, Hansen, Tue, Jonsson, Anna, Pedersen, Oluf, Dutta, Avirup, Vogt, J., Vestergaard, Henrik, Wilman, Henry R., Parisinos, Constantinos A., Atabaki-Pasdar, Naeimeh, Kelly, Matt, Thomas, E. Louise, Neubauer, Stefan, Jennison, Christopher, Ehrhardt, B., Baum, Patrick, Schoelsch, Corinna, Freijer, Jan, Grempler, Rolf, Graefe-Mody, Ulrike, Hennige, A., Dings, Christiane, Lehr, Thorsten, Scherer, Nina, Sihinecich, I., Pattou, Francois, Raverdi, Violeta, Caiazzo, Robert, Torres, Fanelly, Verkindt, Helene, Mari, Andrea, Tura, Andrea, Giorgino, Toni, Bizzotto, Froguel, Philippe, Brorsson, Caroline, Brunak, S., De Masi, Federico, Pedersen, H., Banasik, Karina, Thomas, Cecilia, Lundgaard, Agnete, Nielsen, A., Mazzoni, Gianluca, Karaderi, T., Rasmussen, S., Johansen, Joachim, Allesøe, Rosa, Arumugam, Manimozhiyan, Allin, Kristine, Hansen, Torben, Hansen, Tue, Jonsson, Anna, Pedersen, Oluf, Dutta, Avirup, Vogt, J., and Vestergaard, Henrik

Abstract

Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10−8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Lay summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and he

Published
2019

26. Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Author

Wilman, Henry R., Parisinos, Constantinos A., Atabaki-Pasdar, Naeimeh, Kelly, Matt, Thomas, E. Louise, Neubauer, Stefan, Jennison, Christopher, Ehrhardt, B., Baum, Patrick, Schoelsch, Corinna, Freijer, Jan, Grempler, Rolf, Graefe-Mody, Ulrike, Hennige, A., Dings, Christiane, Lehr, Thorsten, Scherer, Nina, Sihinecich, I., Pattou, Francois, Raverdi, Violeta, Caiazzo, Robert, Torres, Fanelly, Verkindt, Helene, Mari, Andrea, Tura, Andrea, Giorgino, Toni, Bizzotto, Froguel, Philippe, Brorsson, Caroline, Brunak, S., De Masi, Federico, Pedersen, H., Banasik, Karina, Thomas, Cecilia, Lundgaard, Agnete, Nielsen, A., Mazzoni, Gianluca, Karaderi, T., Rasmussen, S., Johansen, Joachim, Allesøe, Rosa, Arumugam, Manimozhiyan, Allin, Kristine, Hansen, Torben, Hansen, Tue, Jonsson, Anna, Pedersen, Oluf, Dutta, Avirup, Vogt, J., Vestergaard, Henrik, Wilman, Henry R., Parisinos, Constantinos A., Atabaki-Pasdar, Naeimeh, Kelly, Matt, Thomas, E. Louise, Neubauer, Stefan, Jennison, Christopher, Ehrhardt, B., Baum, Patrick, Schoelsch, Corinna, Freijer, Jan, Grempler, Rolf, Graefe-Mody, Ulrike, Hennige, A., Dings, Christiane, Lehr, Thorsten, Scherer, Nina, Sihinecich, I., Pattou, Francois, Raverdi, Violeta, Caiazzo, Robert, Torres, Fanelly, Verkindt, Helene, Mari, Andrea, Tura, Andrea, Giorgino, Toni, Bizzotto, Froguel, Philippe, Brorsson, Caroline, Brunak, S., De Masi, Federico, Pedersen, H., Banasik, Karina, Thomas, Cecilia, Lundgaard, Agnete, Nielsen, A., Mazzoni, Gianluca, Karaderi, T., Rasmussen, S., Johansen, Joachim, Allesøe, Rosa, Arumugam, Manimozhiyan, Allin, Kristine, Hansen, Torben, Hansen, Tue, Jonsson, Anna, Pedersen, Oluf, Dutta, Avirup, Vogt, J., and Vestergaard, Henrik

Abstract

Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10−8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Lay summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and he

Published
2019

29. Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer

Author

Jarzabek, M.A. (Monika A.), Proctor, W.R. (William R.), Vogt, J. (Jennifer), Desai, R. (Rupal), Dicker, P. (Patrick), Cain, G. (Gary), Raja, R. (Rajiv), Brodbeck, J. (Jens), Stevens, D. (Dale), Stok, E.P. van der, Martens, J.W.M. (John), Verhoef, C. (Kees), Hegde, P.S. (Priti S.), Byrne, A.T. (Annette T.), Tarrant, J.M. (Jacqueline M.), Jarzabek, M.A. (Monika A.), Proctor, W.R. (William R.), Vogt, J. (Jennifer), Desai, R. (Rupal), Dicker, P. (Patrick), Cain, G. (Gary), Raja, R. (Rajiv), Brodbeck, J. (Jens), Stevens, D. (Dale), Stok, E.P. van der, Martens, J.W.M. (John), Verhoef, C. (Kees), Hegde, P.S. (Priti S.), Byrne, A.T. (Annette T.), and Tarrant, J.M. (Jacqueline M.)

Abstract

Drug-related sinusoidal dilatation (SD) is a common form of hepatotoxicity associated with oxaliplatin-based chemotherapy used prior to resection of colorectal liver metastases (CRLM). Recently, hepatic SD has also been associated with anti-delta like 4 (DLL4) cancer therapies targeting the NOTCH pathway. To investigate the hypothesis that NOTCH signaling plays an important role in drug-induced SD, gene expression changes were examined in livers from anti-DLL4 and oxaliplatin-induced SD in non-human primate (NHP) and patients, respectively. Putative mechanistic biomarkers of bevacizumab (bev)-mediated protection against oxaliplatin-induced SD were also investigated. RNA was extracted from whole liver sections or centrilobular regions by laser-capture microdissection (LCM) obtained from NHP administered anti-DLL4 fragment antigen-binding (F(ab’)2 or patients with CRLM receiving oxaliplatin-based chemotherapy with or without bev. mRNA expression was quantified using high-throughput real-time quantitative PCR. Significance analysis was used to identify genes with differential expression patterns (false discovery rate (FDR) < 0.05). Eleven (CCL2, CCND1, EFNB2, ERG, ICAM1, IL16, LFNG, NOTCH1, NOTCH4, PRDX1, and TGFB1) and six (CDH5, EFNB2, HES1, IL16, MIK67, HES1 and VWF) candidate genes were differentially expressed in the liver of anti-DLL4- and oxaliplatin-induced SD, respectively. Addition of bev to oxaliplatin-based chemotherapy resulted in differential changes in hepatic CDH5, HEY1, IL16, JAG1, MMP9, NOTCH4 and TIMP1 expression. This work implicates NOTCH and IL16 pathways in the pathogenesis of drug-induced SD and further explains the hepato-protective effect of bev in oxaliplatin-induced SD observed in CRLM patients.

Published
2018
Full Text
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30. Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer

Author

Jarzabek, MA, Proctor, WR, Vogt, J, Desai, R, Dicker, P, Cain, G, Raja, R, Brodbeck, J, Stevens, D, Stok, Eric, Martens, John, Verhoef, Kees, Hegde, PS, Byrne, AT, Tarrant, JM, Jarzabek, MA, Proctor, WR, Vogt, J, Desai, R, Dicker, P, Cain, G, Raja, R, Brodbeck, J, Stevens, D, Stok, Eric, Martens, John, Verhoef, Kees, Hegde, PS, Byrne, AT, and Tarrant, JM

Published
2018

31. Posters display III clinical outcome and PET

Author

Baliño, N., Masoli, O., Traverso, S., Grynberg, L., Rappallo, C., Redruello, M., Rosa, D., Cragnolino, D., Meretta, A., Vidal, L., Graf, S., Khorsand, A., Gyongyosi, M., Karanikas, G., Eidherr, H., Kletter, K., Porenta, G., Glogar, D., Sochor, H., Beheshti, M., Poetzi, C., Wadsak, W., Maurer, G., Wolfram, J., Winter, O., Velghe, A., Veire, N., Bondt, P., Buyzere, M., Wiele, C., Backer, G., Gillebert, T., Dierckx, R., Sutter, J., Bernard, D., Langlois, M., Duarte, P., Mastrocolla, L., Sampaio, C., Rossi, J., Smanio, P., Lima, E., Oliveira, C., Pereira, J., Beraldo, P., Rodrigues, F., Thom, A., Yoshinaga, K., Ukkonen, H., Burwash, I., DeKemp, R., Dafoe, W., Davies, R., Haddad, H., Ruddy, T., DaSilva, J., Beanlands, R., Chow, B., Williams, K., Garrard, L., Szeto, A., Aung, M., Sondergaard, H., Bottcher, M., Madsen, M., Schmitz, O., Nielsen, T., Botker, H., Høilund-Carlsen, P., Johansen, A., Christensen, H., Vach, W., Møldrup, M., Haghfelt, T., Kristensen, J., Maeng, M., Mortensen, U., Berg, J., Rehling, M., Elsaban, K., El-Kady, T., El-Gabaly, M., Yehia, A., El-Sayed, M., Naum, A., Laaksonen, M., Tuunanen, H., Oikonen, V., Kemppainen, J., Järvisalo, M., Nuutila, P., Knuuti, J., Vanzetto, G., Jacon, P., Fagret, D., Machecourt, J., Lindner, O., Vogt, J., Kammeier, A., Fricke, E., Wielepp, P., Baller, D., Lamp, B., Holzinger, J., Horstkotte, D., Burchert, W., Nekolla, S., Souvatzoglou, M., Hausleiter, J., Henke, N., Kruschke, K., Bengel, F., Schwaiger, M., Sundaram, P., Padma, S., Haridas, K., Kumar, S., Zachariah, M., Livschitz, S., Zornitzki, T., Vered, S., Oettinger, M., Levy, R., Caspi, A., Faraggi, D., Knobler, H., Mats, I., Solodky, A., Ben-Gal, T., Battler, A., Zafrir, N., Varani, E., Balducelli, M., Severi, S., Patroncini, A., Vecchi, G., Gatti, C., Corbelli, C., Casanova, R., Maresta, A., Cittanti, C., Valgimigli, M., Giganti, M., Malagutti, P., Percoco, G., Bagatin, E., Panareo, S., Avigni, N., Ferrari, R., Feggi, L., Filardi, P., Cuocolo, A., Storto, G., Brevetti, G., Dellegrottaglie, S., Corrado, L., Cafiero, M., Polimeno, M., Zarrilli, A., Chiariello, M., Marcassa, C., Campini, R., Calza, P., Giannuzzi, P., Galassi, A., Grasso, C., Azzarelli, S., Leotta, E., Moshiri, S., Tamburino, C., Acampa, W., Ferro, A., Petretta, M., Salvatore, M., Pieri, P., Berta, R., Moscatelli, G., Buccoliero, F., Inglese, E., Medolago, G., Imperiale, A., Rimini, M., Bertagna, F., Sullo, P., Lupo, M., Cappagli, M., Fukuda, H., Kunimasa, T., Furuhashi, T., Moroi, M., Yasuhi, W., Akihiro, S., Akio, Y., Ryou, K., Kimio, T., Yasunori, W., Yasuhiko, T., Nariaki, E., Watabe, H., Teramoto, N., Ohta, Y., Kou, Y., Hayashi, T., Iida, H., Bom, H., Song, H., Min, J., Heo, Y., Seo, J., Lee, J., Bae, J., Jeong, S., Ahn, B., Chae, S., Lee, K., Popiel, M., Grajek, S., Czepczynski, R., Breborowicz, P., Lesiak, M., Czyz, A., Sawinski, K., Komarnicki, M., Cieslinski, A., Sowinski, J., Ferreira, A., Ventosa, A., Gil, V., Calqueiro, J., Lima, S., Aguiar, C., Couto, R., Raposo, L., Seabra-Gomes, R., Vasconcelos, M., Martins, E., Faria, T., Oliveira, A., Garcia, M., Rocha-Gonçalves, F., Lourenço, C., Roque, C., Ferrer-Antunes, A., Ferreira, M., Providência, L., Lima, J., Medrea, C., Bogdan, R., Lazar, A., Mot, S., Capilneanu, R., Kozulin, V., Berkovich, O., Ivashchenko, T., Larionova, V., Esipovich, I., Gordeev, M., Panov, A., Shlyakhto, E., Burova, N., Baranov, D., Timoshin, V., Chuprova, S., Shkolnikova, M., Zaklyazminskaya, E., Poliakov, A., Sazonova, S., Romero-Farina, G., Arenillas, J., Candell-Riera, J., Aguadè-Bruix, S., Leon, G., Molina, C., Chacon, P., Montaner, J., Rovira, A., Alvarez-Sabin, J., Namdar, M., Siegrist, P., Grathwohl, R., Delaloye, R., Koepfli, P., Wyss, C., Kaufmann, P., Bartenstein, N., Hellermann, J., Pollack, C., Schurr, U., Zellweger, M., Burger, P., Mueller-Brand, J., Pfisterer, M., Gordon, L., Epps, A., Chiarameda, S., Navare, S., Ahlberg, A., Cyr, G., Katten, D., Ausef, A., Heller, G., Darrow, B., Thomas, G., Ip, T., Thompson, R., Kramer, D., Rice, D., Thomas, J., Miyamoto, M., Druz, R., Nichols, K., Akinboboye, O., Reichek, N., Podrasky, E., Tuttle, R., Shaw, L., Hanson, M., Borges-Neto, S., Lundbye, J., Werden, S., Kazi, F., Whalen, A., Noble, G., O'Sullivan, D., Boden, W., Danias, P., Papaioannou, G., Leka, I., Beretta, M., Viňas, S., Gonzalez, A., Vidal, I., Rener, A., Baliño, N., Masoli, O., Traverso, S., Grynberg, L., Rappallo, C., Redruello, M., Rosa, D., Cragnolino, D., Meretta, A., Vidal, L., Graf, S., Khorsand, A., Gyongyosi, M., Karanikas, G., Eidherr, H., Kletter, K., Porenta, G., Glogar, D., Sochor, H., Beheshti, M., Poetzi, C., Wadsak, W., Maurer, G., Wolfram, J., Winter, O., Velghe, A., Veire, N., Bondt, P., Buyzere, M., Wiele, C., Backer, G., Gillebert, T., Dierckx, R., Sutter, J., Bernard, D., Langlois, M., Duarte, P., Mastrocolla, L., Sampaio, C., Rossi, J., Smanio, P., Lima, E., Oliveira, C., Pereira, J., Beraldo, P., Rodrigues, F., Thom, A., Yoshinaga, K., Ukkonen, H., Burwash, I., DeKemp, R., Dafoe, W., Davies, R., Haddad, H., Ruddy, T., DaSilva, J., Beanlands, R., Chow, B., Williams, K., Garrard, L., Szeto, A., Aung, M., Sondergaard, H., Bottcher, M., Madsen, M., Schmitz, O., Nielsen, T., Botker, H., Høilund-Carlsen, P., Johansen, A., Christensen, H., Vach, W., Møldrup, M., Haghfelt, T., Kristensen, J., Maeng, M., Mortensen, U., Berg, J., Rehling, M., Elsaban, K., El-Kady, T., El-Gabaly, M., Yehia, A., El-Sayed, M., Naum, A., Laaksonen, M., Tuunanen, H., Oikonen, V., Kemppainen, J., Järvisalo, M., Nuutila, P., Knuuti, J., Vanzetto, G., Jacon, P., Fagret, D., Machecourt, J., Lindner, O., Vogt, J., Kammeier, A., Fricke, E., Wielepp, P., Baller, D., Lamp, B., Holzinger, J., Horstkotte, D., Burchert, W., Nekolla, S., Souvatzoglou, M., Hausleiter, J., Henke, N., Kruschke, K., Bengel, F., Schwaiger, M., Sundaram, P., Padma, S., Haridas, K., Kumar, S., Zachariah, M., Livschitz, S., Zornitzki, T., Vered, S., Oettinger, M., Levy, R., Caspi, A., Faraggi, D., Knobler, H., Mats, I., Solodky, A., Ben-Gal, T., Battler, A., Zafrir, N., Varani, E., Balducelli, M., Severi, S., Patroncini, A., Vecchi, G., Gatti, C., Corbelli, C., Casanova, R., Maresta, A., Cittanti, C., Valgimigli, M., Giganti, M., Malagutti, P., Percoco, G., Bagatin, E., Panareo, S., Avigni, N., Ferrari, R., Feggi, L., Filardi, P., Cuocolo, A., Storto, G., Brevetti, G., Dellegrottaglie, S., Corrado, L., Cafiero, M., Polimeno, M., Zarrilli, A., Chiariello, M., Marcassa, C., Campini, R., Calza, P., Giannuzzi, P., Galassi, A., Grasso, C., Azzarelli, S., Leotta, E., Moshiri, S., Tamburino, C., Acampa, W., Ferro, A., Petretta, M., Salvatore, M., Pieri, P., Berta, R., Moscatelli, G., Buccoliero, F., Inglese, E., Medolago, G., Imperiale, A., Rimini, M., Bertagna, F., Sullo, P., Lupo, M., Cappagli, M., Fukuda, H., Kunimasa, T., Furuhashi, T., Moroi, M., Yasuhi, W., Akihiro, S., Akio, Y., Ryou, K., Kimio, T., Yasunori, W., Yasuhiko, T., Nariaki, E., Watabe, H., Teramoto, N., Ohta, Y., Kou, Y., Hayashi, T., Iida, H., Bom, H., Song, H., Min, J., Heo, Y., Seo, J., Lee, J., Bae, J., Jeong, S., Ahn, B., Chae, S., Lee, K., Popiel, M., Grajek, S., Czepczynski, R., Breborowicz, P., Lesiak, M., Czyz, A., Sawinski, K., Komarnicki, M., Cieslinski, A., Sowinski, J., Ferreira, A., Ventosa, A., Gil, V., Calqueiro, J., Lima, S., Aguiar, C., Couto, R., Raposo, L., Seabra-Gomes, R., Vasconcelos, M., Martins, E., Faria, T., Oliveira, A., Garcia, M., Rocha-Gonçalves, F., Lourenço, C., Roque, C., Ferrer-Antunes, A., Ferreira, M., Providência, L., Lima, J., Medrea, C., Bogdan, R., Lazar, A., Mot, S., Capilneanu, R., Kozulin, V., Berkovich, O., Ivashchenko, T., Larionova, V., Esipovich, I., Gordeev, M., Panov, A., Shlyakhto, E., Burova, N., Baranov, D., Timoshin, V., Chuprova, S., Shkolnikova, M., Zaklyazminskaya, E., Poliakov, A., Sazonova, S., Romero-Farina, G., Arenillas, J., Candell-Riera, J., Aguadè-Bruix, S., Leon, G., Molina, C., Chacon, P., Montaner, J., Rovira, A., Alvarez-Sabin, J., Namdar, M., Siegrist, P., Grathwohl, R., Delaloye, R., Koepfli, P., Wyss, C., Kaufmann, P., Bartenstein, N., Hellermann, J., Pollack, C., Schurr, U., Zellweger, M., Burger, P., Mueller-Brand, J., Pfisterer, M., Gordon, L., Epps, A., Chiarameda, S., Navare, S., Ahlberg, A., Cyr, G., Katten, D., Ausef, A., Heller, G., Darrow, B., Thomas, G., Ip, T., Thompson, R., Kramer, D., Rice, D., Thomas, J., Miyamoto, M., Druz, R., Nichols, K., Akinboboye, O., Reichek, N., Podrasky, E., Tuttle, R., Shaw, L., Hanson, M., Borges-Neto, S., Lundbye, J., Werden, S., Kazi, F., Whalen, A., Noble, G., O'Sullivan, D., Boden, W., Danias, P., Papaioannou, G., Leka, I., Beretta, M., Viňas, S., Gonzalez, A., Vidal, I., and Rener, A.

Published
2018

32. Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections

Author

Meester, J.A., Vandeweyer, G., Pintelon, I., Lammens, M., Hoorick, L. Van, Belder, S. De, Waitzman, K., Young, L., Markham, L.W., Vogt, J., Richer, J., Beauchesne, L.M., Unger, S., Superti-Furga, A., Prsa, M., Dhillon, R., Reyniers, E., Dietz, H.C., Wuyts, W., Mortier, G., Verstraeten, A., Laer, L. Van, Loeys, B.L., Meester, J.A., Vandeweyer, G., Pintelon, I., Lammens, M., Hoorick, L. Van, Belder, S. De, Waitzman, K., Young, L., Markham, L.W., Vogt, J., Richer, J., Beauchesne, L.M., Unger, S., Superti-Furga, A., Prsa, M., Dhillon, R., Reyniers, E., Dietz, H.C., Wuyts, W., Mortier, G., Verstraeten, A., Laer, L. Van, and Loeys, B.L.

Abstract

Contains fulltext : 175552.pdf (Publisher’s version ) (Open Access), PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families. METHODS: We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed. RESULTS: We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-beta signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture. CONCLUSION: In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-beta signaling.Genet Med 19 4, 386-395.

Published
2017

33. Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections

Author

Meester, J.A., Vandeweyer, G., Pintelon, I., Lammens, M., Hoorick, L. Van, Belder, S. De, Waitzman, K., Young, L., Markham, L.W., Vogt, J., Richer, J., Beauchesne, L.M., Unger, S., Superti-Furga, A., Prsa, M., Dhillon, R., Reyniers, E., Dietz, H.C., Wuyts, W., Mortier, G., Verstraeten, A., Laer, L. Van, Loeys, B.L., Meester, J.A., Vandeweyer, G., Pintelon, I., Lammens, M., Hoorick, L. Van, Belder, S. De, Waitzman, K., Young, L., Markham, L.W., Vogt, J., Richer, J., Beauchesne, L.M., Unger, S., Superti-Furga, A., Prsa, M., Dhillon, R., Reyniers, E., Dietz, H.C., Wuyts, W., Mortier, G., Verstraeten, A., Laer, L. Van, and Loeys, B.L.

Abstract

Contains fulltext : 175552.pdf (Publisher’s version ) (Open Access), PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families. METHODS: We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed. RESULTS: We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-beta signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture. CONCLUSION: In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-beta signaling.Genet Med 19 4, 386-395.

Published
2017

34. Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections

Author

Meester, J.A., Vandeweyer, G., Pintelon, I., Lammens, M., Hoorick, L. Van, Belder, S. De, Waitzman, K., Young, L., Markham, L.W., Vogt, J., Richer, J., Beauchesne, L.M., Unger, S., Superti-Furga, A., Prsa, M., Dhillon, R., Reyniers, E., Dietz, H.C., Wuyts, W., Mortier, G., Verstraeten, A., Laer, L. Van, Loeys, B.L., Meester, J.A., Vandeweyer, G., Pintelon, I., Lammens, M., Hoorick, L. Van, Belder, S. De, Waitzman, K., Young, L., Markham, L.W., Vogt, J., Richer, J., Beauchesne, L.M., Unger, S., Superti-Furga, A., Prsa, M., Dhillon, R., Reyniers, E., Dietz, H.C., Wuyts, W., Mortier, G., Verstraeten, A., Laer, L. Van, and Loeys, B.L.

Abstract

Contains fulltext : 175552.pdf (Publisher’s version ) (Open Access), PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families. METHODS: We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed. RESULTS: We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-beta signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture. CONCLUSION: In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-beta signaling.Genet Med 19 4, 386-395.

Published
2017

35. Density-dependent shift from facilitation to competition in a dwarf Avicennia germinans forest

Author

Pranchai, A., Jenke, M., Vogt, J., Grueters, U., Lin, Yue, Machado de Menezes, M., Wagner, S., Berger, U., Pranchai, A., Jenke, M., Vogt, J., Grueters, U., Lin, Yue, Machado de Menezes, M., Wagner, S., and Berger, U.

Abstract

The global effort to rehabilitate and restore destroyed mangrove forests is unable to keep up with the high mangrove deforestation rates, which exceed the average pace of global deforestation. Although facilitation theory presents new possibilities for the restoration of heavily degraded mangrove sites, knowledge of tree–tree interactions in stressed mangrove forest ecosystems is too limited to utilize facilitation appropriately. The aim was to determine the mode of local interaction among stressed mangrove trees by investigating the effect of clustering on tree size and crown morphology under contrasting stand densities. The study was conducted in a dwarf Avicennia germinans forest in Northern Brazil, in which tree growth is limited by infrequent inundation and high pore-water salinity. Autoregressive regression, Voronoi tessellation and spatial point pattern statistics were used to address the spatial processes underlying tree interaction. Under low stand density (1.2 trees m−2) dwarf trees which grew in clustered cohorts of A. germinans had a less stunted crown morphology revealing the dominance of a positive neighborhood influence among plants. In contrast, dwarf trees in the denser forest stand (2.7 trees m−2) were interacting competitively as indicated by the more negative effect of neighbors on crown morphology and size. The shift from facilitative to competitive interactions is an important feature of mangrove forest regeneration under harsh environmental conditions. If mangrove trees are unable to regenerate naturally on severely degraded sites, intraspecific facilitation could be used to assist regeneration by planting seedlings in clusters and not evenly spaced.

Published
2017

36. Implementing the 'Sustainable Development Goals': towards addressing three key governance challenges—collective action, trade-offs, and accountability

Author

Bowen, K.J., Cradock-Henry, N.A., Koch, Florian, Patterson, J., Häyhä, T., Vogt, J., Barbi, F., Bowen, K.J., Cradock-Henry, N.A., Koch, Florian, Patterson, J., Häyhä, T., Vogt, J., and Barbi, F.

Abstract

Realising the aspirations of the “Sustainable Development Goals” (SDGs) to reduce inequality, limit ecological damage, and secure resilient livelihoods is a grand challenge for sustainability science, civil society and government. We identify three key governance challenges that are central for implementing the SDGs: (i) cultivating collective action by creating inclusive decision spaces for stakeholder interaction across multiple sectors and scales; (ii) making difficult trade-offs, focusing on equity, justice and fairness; and (iii) ensuring mechanisms exist to hold societal actors to account regarding decision-making, investment, action, and outcomes. The paper explains each of these three governance challenges, identifying possible avenues for addressing them, and highlights the importance of interlinkages between the three challenges.

Published
2017

37. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

Author

Kim, J.H., Shinde, D.N., Reijnders, M.R.F., Hauser, N.S., Belmonte, R.L., Wilson, G.R., Bosch, D.G.M., Bubulya, P.A., Shashi, V., Petrovski, S., Stone, J.K., Park, E.Y., Veltman, J.A., Sinnema, M., Stumpel, C.T., Draaisma, J.M., Nicolai, J., Yntema, H.G., Lindstrom, K., Vries, B.B. de, Jewett, T., Santoro, S.L., Vogt, J., Bachman, K.K., Seeley, A.H., Krokosky, A., Turner, C., Rohena, L., Hempel, M., Kortum, F., Lessel, D., Neu, A., Strom, T.M., Wieczorek, D., Bramswig, N., Laccone, F.A., Behunova, J., Rehder, H., Gordon, C.T., Rio, M. del, Romana, S., Tang, S., El-Khechen, D., Cho, M.T., McWalter, K., Douglas, G., Baskin, B., Begtrup, A., Funari, T., Schoch, K., Stegmann, A.P., Stevens, S.J., Zhang, D.E., Traver, D., Yao, X., MacArthur, D.G., Brunner, H.G., Mancini, G.M., Myers, R.M., Owen, L.B., Lim, S.T., Stachura, D.L., Vissers, L.E.L.M., Ahn, E.Y., Kim, J.H., Shinde, D.N., Reijnders, M.R.F., Hauser, N.S., Belmonte, R.L., Wilson, G.R., Bosch, D.G.M., Bubulya, P.A., Shashi, V., Petrovski, S., Stone, J.K., Park, E.Y., Veltman, J.A., Sinnema, M., Stumpel, C.T., Draaisma, J.M., Nicolai, J., Yntema, H.G., Lindstrom, K., Vries, B.B. de, Jewett, T., Santoro, S.L., Vogt, J., Bachman, K.K., Seeley, A.H., Krokosky, A., Turner, C., Rohena, L., Hempel, M., Kortum, F., Lessel, D., Neu, A., Strom, T.M., Wieczorek, D., Bramswig, N., Laccone, F.A., Behunova, J., Rehder, H., Gordon, C.T., Rio, M. del, Romana, S., Tang, S., El-Khechen, D., Cho, M.T., McWalter, K., Douglas, G., Baskin, B., Begtrup, A., Funari, T., Schoch, K., Stegmann, A.P., Stevens, S.J., Zhang, D.E., Traver, D., Yao, X., MacArthur, D.G., Brunner, H.G., Mancini, G.M., Myers, R.M., Owen, L.B., Lim, S.T., Stachura, D.L., Vissers, L.E.L.M., and Ahn, E.Y.

Abstract

Item does not contain fulltext, The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.

Published
2016

38. De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

Author

Reijnders, M.R.F., Zachariadis, V., Latour, B.L., Jolly, L., Mancini, G.M., Pfundt, R.P., Wu, K.M., Ravenswaaij-Arts, C.M.A. van, Veenstra-Knol, H.E., Anderlid, B.M., Wood, S.A., Cheung, S.W., Barnicoat, A., Probst, F., Magoulas, P., Brooks, A.S., Malmgren, H., Harila-Saari, A., Marcelis, C.M., Vreeburg, M., Hobson, E., Sutton, V.R., Stark, Z., Vogt, J., Cooper, N., Lim, J.Y., Price, S., Lai, A.H., Domingo, D., Reversade, B., Gecz, J., Gilissen, C., Brunner, H.G., Kini, U., Roepman, R., Nordgren, A., Kleefstra, T., Reijnders, M.R.F., Zachariadis, V., Latour, B.L., Jolly, L., Mancini, G.M., Pfundt, R.P., Wu, K.M., Ravenswaaij-Arts, C.M.A. van, Veenstra-Knol, H.E., Anderlid, B.M., Wood, S.A., Cheung, S.W., Barnicoat, A., Probst, F., Magoulas, P., Brooks, A.S., Malmgren, H., Harila-Saari, A., Marcelis, C.M., Vreeburg, M., Hobson, E., Sutton, V.R., Stark, Z., Vogt, J., Cooper, N., Lim, J.Y., Price, S., Lai, A.H., Domingo, D., Reversade, B., Gecz, J., Gilissen, C., Brunner, H.G., Kini, U., Roepman, R., Nordgren, A., and Kleefstra, T.

Abstract

Item does not contain fulltext, Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.

Published
2016

39. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

Author

Kim, J.-H. (Jung-Hyun), Shinde, D.N. (Deepali N.), Reijnders, M.R.F. (Margot R.F.), Hauser, N.S. (Natalie S.), Belmonte, R.L. (Rebecca L.), Wilson, G.R. (Gregory R.), Bosch, D.G.M. (Daniëlle G.M.), Bubulya, P.A. (Paula A.), Shashi, V. (Vandana), Petrovski, S. (Slavé), Stone, J.K. (Joshua K.), Park, E.Y. (Eun Young), Veltman, J.A. (Joris), Sinnema, M. (Margje), Stumpel, C. (Connie), Draaisma, J. (Jos), Nicolai, J. (Joost), Yntema, H.G., Lindstrom, K. (Kristin), Vries, B. (Boukje) de, Jewett, T. (Tamison), Santoro, S.L. (Stephanie L.), Vogt, J. (Julie), Bachman, K.K. (Kristine K.), Seeley, A.H. (Andrea ), Krokosky, A. (Alyson), Turner, C. (Clesson), Rohena, L. (Luis), Hempel, M. (Maja), Kortüm, F. (Fanny), Lessel, D. (Davor), Neu, A. (Axel), Strom, T.M. (Tim), Wieczorek, D. (Dagmar), Bramswig, N. (Nuria), Laccone, F.A. (Franco A.), Behunova, J. (Jana), Rehder, H. (Helga), Gordon, C.T. (Christopher T.), Rio, M. (Marlène), Romana, S. (Serge), Tang, S. (Sha), El-Khechen, D. (Dima), Cho, M.T. (Megan T.), McWalter, K. (Kirsty), Douglas, G. (Ganka), Baskin, B. (Berivan), Begtrup, A. (Amber), Funari, T. (Tara), Schoch, K. (Kelly), Stegmann, A.P.A. (Alexander P.A.), Stevens, S.J., Zhang, D.-E. (Dong-Er), Traver, D. (David), Yao, X. (Xu), MacArthur, D.G. (Daniel G.), Brunner, H.G., Mancini, G.M.S. (Grazia), Myers, R.H. (Richard), Owen, L.B. (Laurie B.), Lim, S.-T. (Ssang-Taek), Stachura, D.L. (David L.), Vissers, L.E.L.M., Ahn, E.-Y.E. (Eun-Young Erin), Kim, J.-H. (Jung-Hyun), Shinde, D.N. (Deepali N.), Reijnders, M.R.F. (Margot R.F.), Hauser, N.S. (Natalie S.), Belmonte, R.L. (Rebecca L.), Wilson, G.R. (Gregory R.), Bosch, D.G.M. (Daniëlle G.M.), Bubulya, P.A. (Paula A.), Shashi, V. (Vandana), Petrovski, S. (Slavé), Stone, J.K. (Joshua K.), Park, E.Y. (Eun Young), Veltman, J.A. (Joris), Sinnema, M. (Margje), Stumpel, C. (Connie), Draaisma, J. (Jos), Nicolai, J. (Joost), Yntema, H.G., Lindstrom, K. (Kristin), Vries, B. (Boukje) de, Jewett, T. (Tamison), Santoro, S.L. (Stephanie L.), Vogt, J. (Julie), Bachman, K.K. (Kristine K.), Seeley, A.H. (Andrea ), Krokosky, A. (Alyson), Turner, C. (Clesson), Rohena, L. (Luis), Hempel, M. (Maja), Kortüm, F. (Fanny), Lessel, D. (Davor), Neu, A. (Axel), Strom, T.M. (Tim), Wieczorek, D. (Dagmar), Bramswig, N. (Nuria), Laccone, F.A. (Franco A.), Behunova, J. (Jana), Rehder, H. (Helga), Gordon, C.T. (Christopher T.), Rio, M. (Marlène), Romana, S. (Serge), Tang, S. (Sha), El-Khechen, D. (Dima), Cho, M.T. (Megan T.), McWalter, K. (Kirsty), Douglas, G. (Ganka), Baskin, B. (Berivan), Begtrup, A. (Amber), Funari, T. (Tara), Schoch, K. (Kelly), Stegmann, A.P.A. (Alexander P.A.), Stevens, S.J., Zhang, D.-E. (Dong-Er), Traver, D. (David), Yao, X. (Xu), MacArthur, D.G. (Daniel G.), Brunner, H.G., Mancini, G.M.S. (Grazia), Myers, R.H. (Richard), Owen, L.B. (Laurie B.), Lim, S.-T. (Ssang-Taek), Stachura, D.L. (David L.), Vissers, L.E.L.M., and Ahn, E.-Y.E. (Eun-Young Erin)

Abstract

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses c

Published
2016
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40. De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

Author

Reijnders, M.R.F. (Margot R.F.), Zachariadis, V. (Vasilios), Latour, B. (Brooke), Jolly, L. (Lachlan), Mancini, G.M.S. (Grazia), Pfundt, R. (Rolph), Wu, K.M. (Ka Man), Ravenswaaij-Arts, C.M.A. (Conny) van, Veenstra-Knol, H.E. (Hermine), Anderlid, B.-M.M. (Britt-Marie M.), Wood, S.A. (Stephen A.), Cheung, S.W. (Sau Wai), Barnicoat, A. (Angela), Probst, F. (Frank), Magoulas, P. (Pilar), Brooks, A.S. (Alice), Malmgren, H. (Helena), Harila-Saari, A. (Arja), Marcelis, C.M. (Carlo M.), Vreeburg, J.T.M. (Jan), Hobson, E. (Emma), Sutton, V.R. (V. Reid), Stark, Z. (Zornitza), Vogt, J. (Julie), Cooper, N. (Nicola), Lim, J.Y. (Jiin Ying), Price, S. (Susan), Lai, A.H.M. (Angeline Hwei Meeng), Domingo, D. (Deepti), Reversade, B. (Bruno), Gecz, J. (Jozef), Gilissen, C. (Christian), Brunner, H.G. (Han G.), Kini, U. (Usha), Roepman, R. (Ronald), Nordgren, A. (Ann), Kleefstra, T. (Tjitske), Reijnders, M.R.F. (Margot R.F.), Zachariadis, V. (Vasilios), Latour, B. (Brooke), Jolly, L. (Lachlan), Mancini, G.M.S. (Grazia), Pfundt, R. (Rolph), Wu, K.M. (Ka Man), Ravenswaaij-Arts, C.M.A. (Conny) van, Veenstra-Knol, H.E. (Hermine), Anderlid, B.-M.M. (Britt-Marie M.), Wood, S.A. (Stephen A.), Cheung, S.W. (Sau Wai), Barnicoat, A. (Angela), Probst, F. (Frank), Magoulas, P. (Pilar), Brooks, A.S. (Alice), Malmgren, H. (Helena), Harila-Saari, A. (Arja), Marcelis, C.M. (Carlo M.), Vreeburg, J.T.M. (Jan), Hobson, E. (Emma), Sutton, V.R. (V. Reid), Stark, Z. (Zornitza), Vogt, J. (Julie), Cooper, N. (Nicola), Lim, J.Y. (Jiin Ying), Price, S. (Susan), Lai, A.H.M. (Angeline Hwei Meeng), Domingo, D. (Deepti), Reversade, B. (Bruno), Gecz, J. (Jozef), Gilissen, C. (Christian), Brunner, H.G. (Han G.), Kini, U. (Usha), Roepman, R. (Ronald), Nordgren, A. (Ann), and Kleefstra, T. (Tjitske)

Abstract

Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected

Published
2016
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41. Breath pacing system and method for pacing the respiratory activity of a subject

Author

Krans, J.M., van de Sluis, B., Vogt, J., Aarts, R.M., Tijs, T., Brada, Y., van den Boogaard, M., Bennik, J., Raymann, R.J.E.M., Zwartkruis-Pelgrim, P.H., Du, J., Krans, J.M., van de Sluis, B., Vogt, J., Aarts, R.M., Tijs, T., Brada, Y., van den Boogaard, M., Bennik, J., Raymann, R.J.E.M., Zwartkruis-Pelgrim, P.H., and Du, J.

Abstract

To provide a breath pacing system and a corresponding method for pacing the respiratory activity of a subject that provide the possibility to adapt the output signal to the respiration characteristics of the subject automatically and effectively a breath pacing system (10) for pacing the respiratory activity of a subject and a respective method is proposed, comprising: an input unit (14) for generating or determining an input signal related to a respiration characteristic of a subject, a signal analyzing unit (16) provided to recognize a signal pattern within the input signal, and an output unit (12) for outputting output signals corresponding to a desired breathing sequence, wherein said output unit (12) is provided to be activated, upon a starting signal, to output a sequence of output signals comprising a signal pattern related to a previously recognized signal pattern.

Published
2016

42. Extracellular electrical recording of pH-triggered bursts in C6 glioma cell populations

Author

Rocha, P.R.F. (author), Medeiros, C.R. (author), Kintzel, U. (author), Vogt, J. (author), Araújo, I.M. (author), Mestre, A.L.G. (author), Mailänder, V. (author), Schlett, P. (author), Dröge, M. (author), Schneider, L (author), Biscarini,, F. (author), de Leeuw, D.M. (author), Gomes, H.L. (author), Rocha, P.R.F. (author), Medeiros, C.R. (author), Kintzel, U. (author), Vogt, J. (author), Araújo, I.M. (author), Mestre, A.L.G. (author), Mailänder, V. (author), Schlett, P. (author), Dröge, M. (author), Schneider, L (author), Biscarini,, F. (author), de Leeuw, D.M. (author), and Gomes, H.L. (author)

Abstract

Glioma patients often suffer from epileptic seizures because of the tumor’s impact on the brain physiology. Using the rat glioma cell line C6 as a model system, we performed long-term live recordings of the electrical activity of glioma populations in an ultrasensitive detection method. The transducer exploits large-area electrodes that maximize double-layer capacitance, thus increasing the sensitivity. This strategy allowed us to record glioma electrical activity. We show that although glioma cells are nonelectrogenic, they display a remarkable electrical burst activity in time. The low-frequency current noise after cell adhesion is dominated by the flow of Na+ ions through voltage-gated ion channels. However, after an incubation period of many hours, the current noise markedly increased. This electric bursting phenomenon was not associated with apoptosis because the cells were viable and proliferative during the period of increased electric activity. We detected a rapid cell culture medium acidification accompanying this event. By using specific inhibitors, we showed that the electrical bursting activity was prompted by extracellular pH changes, which enhanced Na+ ion flux through the psalmotoxin 1–sensitive acidsensing ion channels. Our model of pH-triggered bursting was unambiguously supported by deliberate, external acidification of the cell culture medium. This unexpected, acidosis-driven electrical activity is likely to directly perturb, in vivo, the functionality of the healthy neuronal network in the vicinity of the tumor bulk and may contribute to seizures in glioma patients., Novel Aerospace Materials

Published
2016

44. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

Author

Kim, J.H., Shinde, D.N., Reijnders, M.R.F., Hauser, N.S., Belmonte, R.L., Wilson, G.R., Bosch, D.G.M., Bubulya, P.A., Shashi, V., Petrovski, S., Stone, J.K., Park, E.Y., Veltman, J.A., Sinnema, M., Stumpel, C.T., Draaisma, J.M., Nicolai, J., Yntema, H.G., Lindstrom, K., Vries, B.B. de, Jewett, T., Santoro, S.L., Vogt, J., Bachman, K.K., Seeley, A.H., Krokosky, A., Turner, C., Rohena, L., Hempel, M., Kortum, F., Lessel, D., Neu, A., Strom, T.M., Wieczorek, D., Bramswig, N., Laccone, F.A., Behunova, J., Rehder, H., Gordon, C.T., Rio, M. del, Romana, S., Tang, S., El-Khechen, D., Cho, M.T., McWalter, K., Douglas, G., Baskin, B., Begtrup, A., Funari, T., Schoch, K., Stegmann, A.P., Stevens, S.J., Zhang, D.E., Traver, D., Yao, X., MacArthur, D.G., Brunner, H.G., Mancini, G.M., Myers, R.M., Owen, L.B., Lim, S.T., Stachura, D.L., Vissers, L.E.L.M., Ahn, E.Y., Kim, J.H., Shinde, D.N., Reijnders, M.R.F., Hauser, N.S., Belmonte, R.L., Wilson, G.R., Bosch, D.G.M., Bubulya, P.A., Shashi, V., Petrovski, S., Stone, J.K., Park, E.Y., Veltman, J.A., Sinnema, M., Stumpel, C.T., Draaisma, J.M., Nicolai, J., Yntema, H.G., Lindstrom, K., Vries, B.B. de, Jewett, T., Santoro, S.L., Vogt, J., Bachman, K.K., Seeley, A.H., Krokosky, A., Turner, C., Rohena, L., Hempel, M., Kortum, F., Lessel, D., Neu, A., Strom, T.M., Wieczorek, D., Bramswig, N., Laccone, F.A., Behunova, J., Rehder, H., Gordon, C.T., Rio, M. del, Romana, S., Tang, S., El-Khechen, D., Cho, M.T., McWalter, K., Douglas, G., Baskin, B., Begtrup, A., Funari, T., Schoch, K., Stegmann, A.P., Stevens, S.J., Zhang, D.E., Traver, D., Yao, X., MacArthur, D.G., Brunner, H.G., Mancini, G.M., Myers, R.M., Owen, L.B., Lim, S.T., Stachura, D.L., Vissers, L.E.L.M., and Ahn, E.Y.

Abstract

Contains fulltext : 167701.pdf (Publisher’s version ) (Closed access), The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.

Published
2016

45. De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

Author

Reijnders, M.R.F., Zachariadis, V., Latour, B.L., Jolly, L., Mancini, G.M., Pfundt, R.P., Wu, K.M., Ravenswaaij-Arts, C.M.A. van, Veenstra-Knol, H.E., Anderlid, B.M., Wood, S.A., Cheung, S.W., Barnicoat, A., Probst, F., Magoulas, P., Brooks, A.S., Malmgren, H., Harila-Saari, A., Marcelis, C.M., Vreeburg, M., Hobson, E., Sutton, V.R., Stark, Z., Vogt, J., Cooper, N., Lim, J.Y., Price, S., Lai, A.H., Domingo, D., Reversade, B., Gecz, J., Gilissen, C., Brunner, H.G., Kini, U., Roepman, R., Nordgren, A., Kleefstra, T., Reijnders, M.R.F., Zachariadis, V., Latour, B.L., Jolly, L., Mancini, G.M., Pfundt, R.P., Wu, K.M., Ravenswaaij-Arts, C.M.A. van, Veenstra-Knol, H.E., Anderlid, B.M., Wood, S.A., Cheung, S.W., Barnicoat, A., Probst, F., Magoulas, P., Brooks, A.S., Malmgren, H., Harila-Saari, A., Marcelis, C.M., Vreeburg, M., Hobson, E., Sutton, V.R., Stark, Z., Vogt, J., Cooper, N., Lim, J.Y., Price, S., Lai, A.H., Domingo, D., Reversade, B., Gecz, J., Gilissen, C., Brunner, H.G., Kini, U., Roepman, R., Nordgren, A., and Kleefstra, T.

Abstract

Item does not contain fulltext, Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.

Published
2016

46. De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

Author

Reijnders, M.R.F., Zachariadis, V., Latour, B.L., Jolly, L., Mancini, G.M., Pfundt, R.P., Wu, K.M., Ravenswaaij-Arts, C.M.A. van, Veenstra-Knol, H.E., Anderlid, B.M., Wood, S.A., Cheung, S.W., Barnicoat, A., Probst, F., Magoulas, P., Brooks, A.S., Malmgren, H., Harila-Saari, A., Marcelis, C.M., Vreeburg, M., Hobson, E., Sutton, V.R., Stark, Z., Vogt, J., Cooper, N., Lim, J.Y., Price, S., Lai, A.H., Domingo, D., Reversade, B., Gecz, J., Gilissen, C., Brunner, H.G., Kini, U., Roepman, R., Nordgren, A., Kleefstra, T., Reijnders, M.R.F., Zachariadis, V., Latour, B.L., Jolly, L., Mancini, G.M., Pfundt, R.P., Wu, K.M., Ravenswaaij-Arts, C.M.A. van, Veenstra-Knol, H.E., Anderlid, B.M., Wood, S.A., Cheung, S.W., Barnicoat, A., Probst, F., Magoulas, P., Brooks, A.S., Malmgren, H., Harila-Saari, A., Marcelis, C.M., Vreeburg, M., Hobson, E., Sutton, V.R., Stark, Z., Vogt, J., Cooper, N., Lim, J.Y., Price, S., Lai, A.H., Domingo, D., Reversade, B., Gecz, J., Gilissen, C., Brunner, H.G., Kini, U., Roepman, R., Nordgren, A., and Kleefstra, T.

Abstract

Contains fulltext : 167699.pdf (Publisher’s version ) (Open Access), Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.

Published
2016

48. The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease

Author

Ng, Y, Aston, C, Diodato, D, Morris, A, Ulrick, N, Kmoch, S, Houšt?k, J, Martinelli, D, Haghighi, A, Atiq, M, Anton Gamero, M, Garcia-Martinez, E, Kratochvilova, H, Santra, S, Brown, R, Brown, G, Ragge, N, Monaravi, A, Pysden, K, Ravn, K, Cassey, J, Khan, A, Chakrapani, A, Vassallo, G, Simons, C, McKeever, K, O'Sullivan, S, Childs, A, Østergaard, E, Vanderver, A, Goldstein, A, Vogt, J, Taylor, R, McFarland, R, Ng, Y, Aston, C, Diodato, D, Morris, A, Ulrick, N, Kmoch, S, Houšt?k, J, Martinelli, D, Haghighi, A, Atiq, M, Anton Gamero, M, Garcia-Martinez, E, Kratochvilova, H, Santra, S, Brown, R, Brown, G, Ragge, N, Monaravi, A, Pysden, K, Ravn, K, Cassey, J, Khan, A, Chakrapani, A, Vassallo, G, Simons, C, McKeever, K, O'Sullivan, S, Childs, A, Østergaard, E, Vanderver, A, Goldstein, A, Vogt, J, Taylor, R, and McFarland, R

Abstract

Background Mutations in the RMND1 (Required for Meiotic Nuclear Division protein 1) gene have recently been linked to infantile onset mitochondrial disease characterised by multiple mitochondrial respiratory chain defects. Methods We summarised the clinical, biochemical and molecular genetic investigation of an international cohort of affected individuals with RMND1 mutations. In addition, we reviewed all the previously published cases to determine the genotype–phenotype correlates and performed survival analysis to identify prognostic factors. Results We identified 14 new cases from 11 pedigrees that harbour recessive RMND1 mutations, including 6 novel variants: c.533C>A, p.(Thr178Lys); c.565C>T, p.(Gln189*); c.631G>A, p.(Val211Met); c.1303C>T, p.(Leu435Phe); c.830+1G>A and c.1317+1G>T. Together with all previously published cases (n=32), we show that congenital sensorineural deafness, hypotonia, developmental delay and lactic acidaemia are common clinical manifestations with disease onset under 2 years. Renal involvement is more prevalent than seizures (66% vs 44%). In addition, median survival time was longer in patients with renal involvement compared with those without renal disease (6 years vs 8 months, p=0.009). The neurological phenotype also appears milder in patients with renal involvement. Conclusions The clinical phenotypes and prognosis associated with RMND1 mutations are more heterogeneous than that were initially described. Regular monitoring of kidney function is imperative in the clinical practice in light of nephropathy being present in over 60% of cases. Furthermore, renal replacement therapy should be considered particularly in those patients with mild neurological manifestation as shown in our study that four recipients of kidney transplant demonstrate good clinical outcome to date.

Published
2016

49. Compound heterozygous RMND1 gene variants associated with chronic kidney disease, dilated cardiomyopathy and neurological involvement: a case report

Author

Gupta, A, Colmenero, I, Ragge, N, Blakely, E, He, L, McFarland, R, Taylor, R, Vogt, J, Milford, D, Gupta, A, Colmenero, I, Ragge, N, Blakely, E, He, L, McFarland, R, Taylor, R, Vogt, J, and Milford, D

Abstract

Background Nuclear gene mutations are being increasingly recognised as causes of mitochondrial disease. The nuclear gene RMND1 has recently been implicated in mitochondrial disease, but the spectrum of pathogenic variants and associated phenotype for this gene, has not been fully elucidated. Case presentation An 11-month-old boy presented with renal impairment associated with a truncal ataxia, bilateral sensorineural hearing loss, hypotonia, delayed visual maturation and global developmental delay. Over a 9-year period, he progressed to chronic kidney disease stage V and developed a dilated cardiomyopathy. Abnormalities in renal and muscle biopsy as well as cytochrome c oxidase activity prompted genetic testing. After exclusion of mitochondrial DNA defects, nuclear genetic studies identified compound heterozygous RMND1 (c.713A>G, p. Asn238Ser and c.565C>T, p.Gln189*) variants. Conclusion We report RMND1 gene variants associated with end stage renal failure, dilated cardiomyopathy, deafness and neurological involvement due to mitochondrial disease. This case expands current knowledge of mitochondrial disease secondary to mutation of the RMND1 gene by further delineating renal manifestations including histopathology. To our knowledge dilated cardiomyopathy has not been reported with renal failure in mitochondrial disease due to mutations of RMND1. The presence of this complication was important in this case as it precluded renal transplantation.

Published
2016

50. Breath pacing system and method for pacing the respiratory activity of a subject

Author

Krans, J.M., van de Sluis, B., Vogt, J., Aarts, R.M., Tijs, T., Brada, Y., van den Boogaard, M., Bennik, J., Raymann, R.J.E.M., Zwartkruis-Pelgrim, P.H., Du, J., Krans, J.M., van de Sluis, B., Vogt, J., Aarts, R.M., Tijs, T., Brada, Y., van den Boogaard, M., Bennik, J., Raymann, R.J.E.M., Zwartkruis-Pelgrim, P.H., and Du, J.

Abstract

To provide a breath pacing system and a corresponding method for pacing the respiratory activity of a subject that provide the possibility to adapt the output signal to the respiration characteristics of the subject automatically and effectively a breath pacing system (10) for pacing the respiratory activity of a subject and a respective method is proposed, comprising: an input unit (14) for generating or determining an input signal related to a respiration characteristic of a subject, a signal analyzing unit (16) provided to recognize a signal pattern within the input signal, and an output unit (12) for outputting output signals corresponding to a desired breathing sequence, wherein said output unit (12) is provided to be activated, upon a starting signal, to output a sequence of output signals comprising a signal pattern related to a previously recognized signal pattern.

Published
2016

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