73 results on '"Ranza, E."'
Search Results
2. Encephalopathy with Epilepsy and Movement Disorder Related to RNF13: Case Report
- Author
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Korff, C., additional, Ranza, E., additional, Blanc, X., additional, Santoni, F., additional, and Antonarakis, S., additional
- Published
- 2022
- Full Text
- View/download PDF
3. Hearing Loss Is Not an Obligatory Hallmark of SPATA5 Early-Onset Epileptic Encephalopathy with Microcephaly and Hypomyelination
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Fluss, J., additional, Kern, I., additional, Antonarakis, S., additional, Borel, C., additional, Rodrigues, M. T. C. A., additional, and Ranza, E., additional
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- 2022
- Full Text
- View/download PDF
4. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction
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Hoed, J. den, Boer, E. de, Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L.J.M. van de, Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C.F., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P, Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S, Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A.K., Pfundt, R.P., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Snijders Blok, L., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-Dos-Santos, J.H., Schrier Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., Vissers, L.E.L.M., Hoed, J. den, Boer, E. de, Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L.J.M. van de, Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C.F., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P, Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S, Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A.K., Pfundt, R.P., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Snijders Blok, L., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-Dos-Santos, J.H., Schrier Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., and Vissers, L.E.L.M.
- Abstract
Contains fulltext : 231687.pdf (Publisher’s version ) (Closed access), Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
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- 2021
5. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns
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Stamberger, H., Hammer, T.B., Gardella, E., Vlaskamp, D.R.M., Bertelsen, B., Mandelstam, S., Lange, I. de, Zhang, J., Myers, C.T., Fenger, C., Afawi, Z., Fuerte, E.P. Almanza, Andrade, D.M., Balcik, Y., Zeev, B. Ben, Bennett, M.F., Berkovic, S.F., Isidor, B., Bouman, A., Brilstra, E., Ø, L. Busk, Cairns, A., Caumes, R., Chatron, N., Dale, R.C., Geus, C. de, Edery, P., Gill, D., Granild-Jensen, J.B., Gunderson, L., Gunning, B., Heimer, G., Helle, J.R., Hildebrand, M.S., Hollingsworth, G., Kharytonov, V., Klee, E.W., Koeleman, B.P.C., Koolen, D.A., Korff, C., Küry, S., Lesca, G., Lev, D., Leventer, R.J., Mackay, M.T., Macke, E.L., McEntagart, M., Mohammad, S.S., Monin, P., Montomoli, M., Morava, E., Moutton, S., Muir, A.M., Parrini, E., Procopis, P., Ranza, E., Reed, L., Reif, P.S., Rosenow, F., Rossi, M., Sadleir, L.G., Sadoway, T., Schelhaas, H.J., Schneider, A.L., Shah, K., Shalev, R., Sisodiya, S.M., Smol, T., Stumpel, C., Stuurman, K., Symonds, J.D., Mau-Them, F.T., Verbeek, N., Verhoeven, J.S., Wallace, G., Yosovich, K., Zarate, Y.A., Zerem, A., Zuberi, S.M., Guerrini, R., Mefford, H.C., Patel, C., Zhang, Y.H., Møller, R.S., Scheffer, I.E., Stamberger, H., Hammer, T.B., Gardella, E., Vlaskamp, D.R.M., Bertelsen, B., Mandelstam, S., Lange, I. de, Zhang, J., Myers, C.T., Fenger, C., Afawi, Z., Fuerte, E.P. Almanza, Andrade, D.M., Balcik, Y., Zeev, B. Ben, Bennett, M.F., Berkovic, S.F., Isidor, B., Bouman, A., Brilstra, E., Ø, L. Busk, Cairns, A., Caumes, R., Chatron, N., Dale, R.C., Geus, C. de, Edery, P., Gill, D., Granild-Jensen, J.B., Gunderson, L., Gunning, B., Heimer, G., Helle, J.R., Hildebrand, M.S., Hollingsworth, G., Kharytonov, V., Klee, E.W., Koeleman, B.P.C., Koolen, D.A., Korff, C., Küry, S., Lesca, G., Lev, D., Leventer, R.J., Mackay, M.T., Macke, E.L., McEntagart, M., Mohammad, S.S., Monin, P., Montomoli, M., Morava, E., Moutton, S., Muir, A.M., Parrini, E., Procopis, P., Ranza, E., Reed, L., Reif, P.S., Rosenow, F., Rossi, M., Sadleir, L.G., Sadoway, T., Schelhaas, H.J., Schneider, A.L., Shah, K., Shalev, R., Sisodiya, S.M., Smol, T., Stumpel, C., Stuurman, K., Symonds, J.D., Mau-Them, F.T., Verbeek, N., Verhoeven, J.S., Wallace, G., Yosovich, K., Zarate, Y.A., Zerem, A., Zuberi, S.M., Guerrini, R., Mefford, H.C., Patel, C., Zhang, Y.H., Møller, R.S., and Scheffer, I.E.
- Abstract
Contains fulltext : 231688.pdf (Publisher’s version ) (Closed access), PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.
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- 2021
6. De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects
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Manole, A, Efthymiou, S, O'Connor, E, Mendes, MI, Jennings, M, Maroofian, R, Davagnanam, I, Mankad, K, Lopez, MR, Salpietro, V, Harripaul, R, Badalato, L, Walia, J, Francklyn, CS, Athanasiou-Fragkouli, A, Sullivan, R, Desai, S, Baranano, K, Zafar, F, Rana, N, Ilyas, M, Horga, A, Kara, M, Mattioli, F, Goldenberg, A, Griffin, H, Piton, A, Henderson, LB, Kara, B, Aslanger, AD, Raaphorst, J, Pfundt, R, Portier, R, Shinawi, M, Kirby, A, Christensen, KM, Wang, L, Rosti, RO, Paracha, SA, Sarwar, MT, Jenkins, D, SYNAPS Study Group, Ahmed, J, Santoni, FA, Ranza, E, Iwaszkiewicz, J, Cytrynbaum, C, Weksberg, R, Wentzensen, IM, Guillen Sacoto, MJ, Si, Y, Telegrafi, A, Andrews, MV, Baldridge, D, Gabriel, H, Mohr, J, Oehl-Jaschkowitz, B, Debard, S, Senger, B, Fischer, F, van Ravenwaaij, C, Fock, AJM, Stevens, SJC, Bähler, J, Nasar, A, Mantovani, JF, Manzur, A, Sarkozy, A, Smith, DEC, Salomons, GS, Ahmed, ZM, Riazuddin, S, Usmani, MA, Seibt, A, Ansar, M, Antonarakis, SE, Vincent, JB, Ayub, M, Grimmel, M, Jelsig, AM, Hjortshøj, TD, Karstensen, HG, Hummel, M, Haack, TB, Jamshidi, Y, Distelmaier, F, Horvath, R, Gleeson, JG, Becker, H, Mandel, J-L, Koolen, DA, and Houlden, H
- Abstract
Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.
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- 2020
7. Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder
- Author
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den Hoed, J., De Boer, E., Voisin, N., Guex, N., Blok, L. Snijders, Chrast, J., Manwaring, L., Willing, M., Waheeb, A., Osmond, M., McWalter, K., Vitobello, A., Demurger, F., Lavillaureix, A., Odent, S., Mazel, B., Faivre, L., Thiffault, I., Schwager, C., Amudhavalli, S. M., Rosenfeld, J. A., Radtke, K., Preiksaitiene, E., Ranza, E., Depienne, C., Kuechler, A., Mohammed, S., Abedi, Y. Hamzavi, Bonagura, V. R., Zuccarelli, B., Horist, B., Krishnamurthy, V., Kattentidt-Mouravieva, A. A., Granger, L., Petersen, A., Jones, K. L., Sinnema, M., Stegmann, A. P. A., Newbury-Ecob, R., Kini, U., Newbury, D. F., Gilissen, C., Brunner, H., Kleefstra, T., Reymond, A., Vissers, L. E. L. M., Fisher, S. E., Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Université de Lausanne (UNIL), Washington University in Saint Louis (WUSTL), GeneDx [Gaithersburg, MD, USA], Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Groupe Hospitalier Bretagne Sud (GHBS), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Ambry Genetics [Aliso Viejo, CA, USA], University of Kansas [Lawrence] (KU), Maastricht University [Maastricht], Radboud University [Nijmegen], Université de Lausanne = University of Lausanne (UNIL), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
- Subjects
[SDV]Life Sciences [q-bio] ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2020
8. Chondrodysplasia with multiple dislocations: comprehensive study of a series of 30 cases
- Author
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Ranza, E., Huber, C., Levin, N., Baujat, G., Bole-Feysot, C., Nitschke, P., Masson, C., Alanay, Y., Al-Gazali, L., Bitoun, P., Boute, O., Campeau, P., Coubes, C., McEntagart, M., Elcioglu, N., Faivre, Laurence, Gezdirici, A., Johnson, D., Mihci, E., Nur, B., Perrin, L., Quelin, C., Terhal, P., Tuysuz, B., Cormier-Daire, V., Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Hôpital Universitaire de Genève, Plateforme de génomique [Necker], Structure Fédérative de Recherche Necker ( SFR Necker - UMS 3633 / US24 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Plate Forme Paris Descartes de Bioinformatique ( BIP-D ), Université Paris Descartes - Paris 5 ( UPD5 ), Department of Pediatrics, Istanbul Faculty of Medicine, Department of Pediatrics, Faculty of Medicine and Health Sciences, UAE University, Service de Pédiatrie [Jean Verdier], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris 13 ( UP13 ) -Hôpital Jean Verdier, Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Département de Pédiatrie [CHU Sainte -Justine Montréal], Université de Montréal-CHU Sainte Justine [Montréal], Service de Génétique Clinique, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Head of the Department of Medical Genetics, Department of Pediatric Genetics, Marmara University Medical Faculty, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Service de génétique clinique [Debré], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, CHU Pontchaillou [Rennes], Wilhelmina Childrens Hosp, Pediatrics, Istanbul University Cerrahpasa, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Sainte Justine [Montréal], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Sheffield Children's NHS Foundation Trust, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré
- Subjects
Adult ,Male ,Spondyloepimetaphyseal Dysplasia ,Adolescent ,Joint Dislocations ,Osteochondrodysplasias ,Gene ,Catel-Manzke Syndrome ,Intellectual Disability ,Exome Sequencing ,Proteoglycan Synthesis ,Humans ,Child ,[ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics ,Genetic Association Studies ,Larsen-Syndrome ,Targeted Ngs ,Joint Laxity ,Infant, Newborn ,Infant ,Phenotypic Spectrum ,Musculoskeletal Abnormalities ,Radiography ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Child, Preschool ,Chondrodysplasia ,Genotype-Phenotype Correlation ,Deficiency ,Female ,Proteoglycans ,Desbuquois Dysplasia ,Mutations - Abstract
IF 3.326; International audience; The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.
- Published
- 2017
9. GRIN2B encephalopathy: Novel findings on phenotype, variant clustering, functional consequences and treatment aspects
- Author
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Platzer, K, Yuan, H, Schütz, H, Winschel, A, Chen, W, Hu, C, Kusumoto, H, Heyne, HO, Helbig, KL, Tang, S, Willing, MC, Tinkle, BT, Adams, DJ, Depienne, C, Keren, B, Mignot, C, Frengen, E, Strømme, P, Biskup, S, Döcker, D, Strom, TM, Mefford, HC, Myers, CT, Muir, AM, LaCroix, A, Sadleir, L, Scheffer, IE, Brilstra, E, van Haelst, MM, van der Smagt, JJ, Bok, LA, Møller, RS, Jensen, UB, Millichap, JJ, Berg, AT, Goldberg, EM, De Bie, I, Fox, S, Major, P, Jones, JR, Zackai, EH, Abou Jamra, R, Rolfs, A, Leventer, RJ, Lawson, JA, Roscioli, T, Jansen, FE, Ranza, E, Korff, CM, Lehesjoki, AE, Courage, C, Linnankivi, T, Smith, DR, Stanley, C, Mintz, M, McKnight, D, Decker, A, Tan, WH, Tarnopolsky, MA, Brady, LI, Wolff, M, Dondit, L, Pedro, HF, Parisotto, SE, Jones, KL, Patel, AD, Franz, DN, Vanzo, R, Marco, E, Ranells, JD, Di Donato, N, Dobyns, WB, Laube, B, Traynelis, SF, Lemke, JR, Platzer, K, Yuan, H, Schütz, H, Winschel, A, Chen, W, Hu, C, Kusumoto, H, Heyne, HO, Helbig, KL, Tang, S, Willing, MC, Tinkle, BT, Adams, DJ, Depienne, C, Keren, B, Mignot, C, Frengen, E, Strømme, P, Biskup, S, Döcker, D, Strom, TM, Mefford, HC, Myers, CT, Muir, AM, LaCroix, A, Sadleir, L, Scheffer, IE, Brilstra, E, van Haelst, MM, van der Smagt, JJ, Bok, LA, Møller, RS, Jensen, UB, Millichap, JJ, Berg, AT, Goldberg, EM, De Bie, I, Fox, S, Major, P, Jones, JR, Zackai, EH, Abou Jamra, R, Rolfs, A, Leventer, RJ, Lawson, JA, Roscioli, T, Jansen, FE, Ranza, E, Korff, CM, Lehesjoki, AE, Courage, C, Linnankivi, T, Smith, DR, Stanley, C, Mintz, M, McKnight, D, Decker, A, Tan, WH, Tarnopolsky, MA, Brady, LI, Wolff, M, Dondit, L, Pedro, HF, Parisotto, SE, Jones, KL, Patel, AD, Franz, DN, Vanzo, R, Marco, E, Ranells, JD, Di Donato, N, Dobyns, WB, Laube, B, Traynelis, SF, and Lemke, JR
- Abstract
Background: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. Methods: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. Results: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. Conclusions: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.
- Published
- 2017
10. P3987Targeted exome sequencing for mendelian cardiac disorders within the Genome Clinic in Geneva
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Fokstuen, S., primary, Guipponi, M., additional, Hammar, E.B., additional, Makrythanasis, P., additional, Meyer, P.H., additional, Beghetti, M., additional, Sekarski, N., additional, Ranza, E., additional, Lidgren, M., additional, Santoni, F.A., additional, Gehrig, C., additional, Nouspikel, T.H., additional, Antonarakis, S.E., additional, and Blouin, J.L., additional
- Published
- 2017
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11. Prescribing practice and off-label use of psychotropic medications in post-acute brain injury rehabilitation centres: A cross-sectional survey
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Pisa, Federica Edith, Cosano, Giorgia, Giangreco, Manuela, Giorgini, Tullio, Biasutti, Emanuele, Barbone, Fabio, Formisano, R., Buzzi, M. G., Pistarini, C., Aiachini, B., Basaglia, Nino, Montis, A., Lucca, L. F., Lombardi, F., Ranza, E., Vallasciani, M., Celentano, A., Naldi, A., Castellani, G., Lamberti, G., Lanzillo, B., Posteraro, F., Logi, F., Molteni, F., Lanfranchi, M., Gramigna, C., Bertagnoni, G., Dell'Oste, P., Tonin, P., Iaia, V., Sagliocco, L., Beatrici, M., Giunta, N., Dore, T., Galardi, G., Sant'Angelo, N., Piperno, R., Battistini, A., Zampolini, M., Scarponi, F., Sanna, V., Biella, A. M., Premoselli, S., Zaro, F., Bernasconi, K., Carnovali, M., Chierici, S., Antenucci, R., Salvi, G. P., Mazzini, N., Ventura, F., Lonati, M. C., Brianti, R., Mammi, P., Molinero, G., De Tanti, A., Bertolino, C., Boldrini, P., Bargellesi, S., and Tessari, A.
- Subjects
Adult ,Male ,medicine.medical_specialty ,Cross-sectional study ,medicine.medical_treatment ,Neuroscience (miscellaneous) ,Practice Patterns ,Logistic regression ,Off-label use ,Rehabilitation Centers ,NO ,Pharmacotherapy ,Arts and Humanities (miscellaneous) ,medicine ,Antiepileptic agents ,Prevalence ,Developmental and Educational Psychology ,Antipsychotics ,Humans ,Practice Patterns, Physicians' ,Psychiatry ,Survey ,Psychotropic Drugs ,Rehabilitation ,Physicians' ,Off-label ,business.industry ,Pharmacoepidemiology ,Acquired brain injuries ,Antidepressants ,Prescribing ,Psychotropic medications ,Brain Injuries ,Cross-Sectional Studies ,Female ,Italy ,Middle Aged ,Off-Label Use ,Neurology (clinical) ,Odds ratio ,Confidence interval ,Emergency medicine ,business - Abstract
Guidance on pharmacotherapy of neurobehavioural sequelae post-acquired brain injury (ABI) is limited. Clinicians face the choice of prescribing off-label. This survey assesses prescribing practice and off-label use of psychotropic medications in Italian brain injury rehabilitation centres and factors associated with atypical antipsychotics use.Centres were identified through the roster of the Italian Society for Rehabilitation Medicine. Information was collected through a structured questionnaire. This study calculated the prevalence of centres reporting to use off-label individual medications and unconditional logistic regression Odds Ratio (OR), with 95% confidence interval (95% CI) of atypical antipsychotics use.Psychotropic medications were commonly used. More than 50% of the 35 centres (participation ratio 87.5%) reported to use off-label selected antipsychotics, mostly for agitation (90.5%) and behavioural disturbances (19.0%), and antidepressants, mostly for insomnia (37.5%) and pain (25.0%). Atypical antipsychotic use was directly associated with age40 years (OR = 2.68; 95% CI = 1.25-5.76), recent ABI (1.74; 0.74-4.09), not with reported off-label use (0.98; 0.44-2.18).In clinical practice, the effectiveness and safety of medications, in particular off-label, should be systematically monitored. Studies are needed to improve the quality of evidence guiding pharmacotherapy and to evaluate effectiveness and safety of off-label prescribing.
- Published
- 2015
12. Experience of a multidisciplinary task force with exome sequencing for Mendelian disorders
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Fokstuen, S., primary, Makrythanasis, P., additional, Hammar, E., additional, Guipponi, M., additional, Ranza, E., additional, Varvagiannis, K., additional, Santoni, F. A., additional, Albarca-Aguilera, M., additional, Poleggi, M. E., additional, Couchepin, F., additional, Brockmann, C., additional, Mauron, A., additional, Hurst, S. A., additional, Moret, C., additional, Gehrig, C., additional, Vannier, A., additional, Bevillard, J., additional, Araud, T., additional, Gimelli, S., additional, Stathaki, E., additional, Paoloni-Giacobino, A., additional, Bottani, A., additional, Sloan-Béna, F., additional, Sizonenko, L. D’Amato, additional, Mostafavi, M., additional, Hamamy, H., additional, Nouspikel, T., additional, Blouin, J. L., additional, and Antonarakis, S. E., additional
- Published
- 2016
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13. Mutations in the NHEJ component XRCC4 cause primordial dwarfism
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Murray, J.E. (Jennie E.), Burg, M. (Mirjam) van der, IJspeert, H. (Hanna), Carroll, P. (Paula), Wu, Q. (Qian), Ochi, T. (Takashi), Leitch, A. (Andrea), Miller, E.S. (Edward S.), Kysela, B. (Boris), Jawad, A. (Alireza), Bottani, A. (Armand), Brancati, F. (Fred), Cappa, M. (Marco), Cormier-Daire, V. (Valerie), Deshpande, C. (Charu), Faqeih, E.A. (Eissa A.), Graham, G.E. (Gail E.), Ranza, E. (Emmanuelle), Blundell, T.L. (Tom L.), Jackson, A.P. (Andrew), Stewart, G.S. (Grant S.), Bicknell, L.S. (Louise), Murray, J.E. (Jennie E.), Burg, M. (Mirjam) van der, IJspeert, H. (Hanna), Carroll, P. (Paula), Wu, Q. (Qian), Ochi, T. (Takashi), Leitch, A. (Andrea), Miller, E.S. (Edward S.), Kysela, B. (Boris), Jawad, A. (Alireza), Bottani, A. (Armand), Brancati, F. (Fred), Cappa, M. (Marco), Cormier-Daire, V. (Valerie), Deshpande, C. (Charu), Faqeih, E.A. (Eissa A.), Graham, G.E. (Gail E.), Ranza, E. (Emmanuelle), Blundell, T.L. (Tom L.), Jackson, A.P. (Andrew), Stewart, G.S. (Grant S.), and Bicknell, L.S. (Louise)
- Abstract
Non-homologous end joining (NHEJ) is a key cellular process ensuring genome integrity. Mutations in several components of the NHEJ pathway have been identified, often associated with severe combined immunodeficiency (SCID), consistent with the requirement for NHEJ during V(D)J recombination to ensure diversity of the adaptive immune system. In contrast, we have recently found that biallelic mutations in LIG4 are a common cause of microcephalic primordial dwarfism (MPD), a phenotype characterized by prenatal-onset extreme global growth failure. Here we provide definitive molecular genetic evidence supported by biochemical, cellular, and immunological data for mutations in XRCC4, encoding the obligate binding partner of LIG4, causing MPD. We report the identification of biallelic mutations in XRCC4 in five families. Biochemical and cellular studies demonstrate that these alterations substantially decrease XRCC4 protein levels leading to reduced cellular ligase IV activity. Consequently, NHEJ-dependent repair of ionizing-radiation-induced DNA double-strand breaks is compromised in XRCC4 cells. Similarly, immunoglobulin junctional diversification is impaired in cells. However, immunoglobulin levels are normal, and individuals lack overt signs of immunodeficiency. Additionally, in contrast to individuals with LIG4 mutations, pancytopenia leading to bone marrow failure has not been
- Published
- 2015
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14. Biallelic variants in FBXL3 cause intellectual disability, delayed motor development and short stature
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Sayyed Fahim Shah, Emilie Falconnet, Roberto Colombo, Federico Santoni, André Mégarbané, Azhar Ali Qaisar, Alessandro Serretti, Vincent Zoete, Jawad Ahmed, Jamshed Khan, Sohail A. Paracha, Stylianos E. Antonarakis, Justyna Iwaszkiewicz, Muhammad T. Sarwar, Muhammad Ansar, Emmanuelle Ranza, Periklis Makrythanasis, Ansar M., Paracha S.A., Serretti A., Sarwar M.T., Khan J., Ranza E., Falconnet E., Iwaszkiewicz J., Shah S.F., Qaisar A.A., Santoni F.A., Zoete V., Megarbane A., Ahmed J., Colombo R., Makrythanasis P., and Antonarakis S.E.
- Subjects
Adult ,Male ,Models, Molecular ,Protein Conformation ,Developmental Disabilities ,DNA Mutational Analysis ,Dwarfism ,Consanguinity ,Biology ,Short stature ,Frameshift mutation ,no ,Structure-Activity Relationship ,Young Adult ,03 medical and health sciences ,Intellectual Disability ,Intellectual disability ,Genetics ,medicine ,Humans ,Allele ,Molecular Biology ,Alleles ,Genetics (clinical) ,Exome sequencing ,0303 health sciences ,F-Box Proteins ,Homozygote ,030305 genetics & heredity ,Facies ,Genetic Variation ,General Medicine ,Middle Aged ,Disease gene identification ,medicine.disease ,Pedigree ,Phenotype ,Ubiquitin ligase complex ,Female ,General Article ,medicine.symptom - Abstract
FBXL3 (F-Box and Leucine Rich Repeat Protein 3) encodes a protein that contains an F-box and several tandem leucine-rich repeats (LRR) domains. FBXL3 is part of the SCF (Skp1-Cullin-F box protein) ubiquitin ligase complex that binds and leads to phosphorylation-dependent degradation of the central clock protein cryptochromes (CRY1 and CRY2) by the proteasome and its absence causes circadian phenotypes in mice and behavioral problems. No FBXL3-related phenotypes have been described in humans. By a combination of exome sequencing and homozygosity mapping, we analyzed two consanguineous families with intellectual disability and identified homozygous loss-of-function (LoF) variants in FBXL3. In the first family, from Pakistan, an FBXL3 frameshift variant [NM-012158.2:c.885delT:p.(Leu295Phefs∗25)] was the onlysegregating variant in five affected individuals in two family loops (LOD score: 3.12). In the second family, from Lebanon, we identified a nonsense variant [NM-012158.2:c.445C>T:p.(Arg149∗)]. In a third patient from Italy, a likely deleterious non-synonymous variant [NM-012158.2:c.1072T>C:p.(Cys358Arg)] was identified in homozygosity. Protein 3D modeling predicted that the Cys358Arg change influences the binding with CRY2 by destabilizing the structure of the FBXL3, suggesting that this variant is also likely to be LoF. The eight affected individuals from the three families presented with a similar phenotype that included intellectual disability, developmental delay, short stature and mild facial dysmorphism, mainly large nose with a bulbous tip. The phenotypic similarity and the segregation analysis suggest that FBXL3 biallelic, LoF variants link this gene with syndromic autosomal recessive developmental delay/intellectual disability.
- Published
- 2019
15. Fleck Retina of Kandori Associated with a De Novo Mutation of a Heterozygous Variant in the CAMK2A Gene.
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Voide N, Macherel M, and Ranza E
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- Female, Humans, Heterozygote, Mutation, Retinal Diseases genetics, Child, Calcium-Calmodulin-Dependent Protein Kinase Type 2 genetics
- Abstract
Competing Interests: The authors declare that they have no conflict of interest.
- Published
- 2024
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16. FOXI3 pathogenic variants cause one form of craniofacial microsomia.
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Mao K, Borel C, Ansar M, Jolly A, Makrythanasis P, Froehlich C, Iwaszkiewicz J, Wang B, Xu X, Li Q, Blanc X, Zhu H, Chen Q, Jin F, Ankamreddy H, Singh S, Zhang H, Wang X, Chen P, Ranza E, Paracha SA, Shah SF, Guida V, Piceci-Sparascio F, Melis D, Dallapiccola B, Digilio MC, Novelli A, Magliozzi M, Fadda MT, Streff H, Machol K, Lewis RA, Zoete V, Squeo GM, Prontera P, Mancano G, Gori G, Mariani M, Selicorni A, Psoni S, Fryssira H, Douzgou S, Marlin S, Biskup S, De Luca A, Merla G, Zhao S, Cox TC, Groves AK, Lupski JR, Zhang Q, Zhang YB, and Antonarakis SE
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- Animals, Mice, Facial Asymmetry, Pedigree, Forkhead Transcription Factors, Goldenhar Syndrome pathology
- Abstract
Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in FOXI3. Biochemical experiments on transcriptional activity and subcellular localization of the likely pathogenic FOXI3 variants, and knock-in mouse studies strongly support the involvement of FOXI3 in CFM. Our findings indicate autosomal dominant inheritance with reduced penetrance, and/or autosomal recessive inheritance. The phenotypic expression of the FOXI3 variants is variable. The penetrance of the likely pathogenic variants in the seemingly dominant form is reduced, since a considerable number of such variants in affected individuals were inherited from non-affected parents. Here we provide suggestive evidence that common variation in the FOXI3 allele in trans with the pathogenic variant could modify the phenotypic severity and accounts for the incomplete penetrance., (© 2023. The Author(s).)
- Published
- 2023
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17. Hyper-IgE syndrome presenting with early life craniosynostosis in monozygotic twin sisters.
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Peirolo A, Verolet C, Ranza E, Rohr M, Laurent M, Ruchonnet-Metrailler I, Worth AJJ, and Blanchard-Rohner G
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- Humans, Female, Twins, Monozygotic, Immunoglobulin E, Job Syndrome diagnosis, Job Syndrome genetics, Craniosynostoses diagnosis, Craniosynostoses genetics
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- 2023
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18. Post-COVID-19 Ongoing Symptoms and Health-Related Quality of Life: Does Rehabilitation Matter?: Preliminary Evidence.
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Mammi P, Ranza E, Rampello A, Ravanetti D, Cavaldonati A, Moretti S, Gobbi E, Rodà F, and Brianti R
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- Humans, Pain, Dyspnea etiology, Fatigue etiology, Surveys and Questionnaires, Quality of Life, COVID-19
- Abstract
Objective: Individuals with persisting symptoms after coronavirus disease 2019 have reported a decrease in health-related quality of life. This study explores the outcome of 50 subjects with post-coronavirus disease 2019 ongoing symptoms including "long COVID"(symptoms lasting over 3 mos), after a rehabilitation program focused on three symptoms: fatigue, breathlessness, and pain. The aims were as follows: to assess the feasibility of the program, to observe a possible change in symptoms and quality of life (null hypothesis: no differences in variables before and after treatment), and to investigate a possible relationship between symptoms and quality of life., Design: This is a retrospective observational study., Results: Symptoms intensity measured with numeric rating scale decreased. Mean differences are as follows: breathlessness, -2.91; fatigue, -2.05; and pain, -2.41 ( P > 0.001). Quality of life measured with Euroqol-5D improved. Mean differences are as follows: Euroqol-5D index, 0.104, and Euroqol-5D visual analog scale, 19.21 ( P < 0.001). Effect size of these changings is classifiable as large (Cohen d > 0.8 and <1.3) except for Euroqol-5D index (Cohen d = -0.575), resulting medium (>0.5 and <0.8). Correlation (Pearson r ) between symptoms and Euroqol-5D resulted moderate for pain and fatigue (-0.609 and -0.531, P < 0.001) and low for breathlessness (-0.533, P < 0.001)., Conclusions: Rehabilitation can be feasible and may improve symptoms and quality of life. Further research is needed., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2023
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19. Retrospective evaluation of clinical and molecular data of 148 cases of esophageal atresia.
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Ranza E, Le Gouez M, Guimier A, Dunlop NK, Beaudoin S, Malan V, Michot C, Baujat G, Rio M, Cormier-Daire V, Abadie V, Sarnacki S, Delacourt C, Lyonnet S, Attié-Bitach T, Pingault V, Rousseau V, and Amiel J
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- Infant, Newborn, Pregnancy, Female, Humans, Retrospective Studies, Trachea abnormalities, Spine abnormalities, Kidney abnormalities, Peptide Elongation Factors, Ribonucleoprotein, U5 Small Nuclear, Esophageal Atresia diagnosis, Esophageal Atresia genetics, Tracheoesophageal Fistula genetics, Limb Deformities, Congenital diagnosis, Limb Deformities, Congenital genetics, Limb Deformities, Congenital complications, Heart Defects, Congenital diagnosis, Heart Defects, Congenital genetics, Heart Defects, Congenital complications
- Abstract
Developmental abnormalities provide a unique opportunity to seek for the molecular mechanisms underlying human organogenesis. Esophageal development remains incompletely understood and elucidating causes for esophageal atresia (EA) in humans would contribute to achieve a better comprehension. Prenatal detection, syndromic classification, molecular diagnosis, and prognostic factors in EA are challenging. Some syndromes have been described to frequently include EA, such as CHARGE, EFTUD2-mandibulofacial dysostosis, Feingold syndrome, trisomy 18, and Fanconi anemia. However, no molecular diagnosis is made in most cases, including frequent associations, such as Vertebral-Anal-Cardiac-Tracheo-Esophageal-Renal-Limb defects (VACTERL). This study evaluates the clinical and genetic test results of 139 neonates and 9 fetuses followed-up at the Necker-Enfants Malades Hospital over a 10-years period. Overall, 52 cases were isolated EA (35%), and 96 were associated with other anomalies (65%). The latter group is divided into three subgroups: EA with a known genomic cause (9/148, 6%); EA with Vertebral-Anal-Cardiac-Tracheo-Esophageal-Renal-Limb defects (VACTERL) or VACTERL/Oculo-Auriculo-Vertebral Dysplasia (VACTERL/OAV) (22/148, 14%); EA with associated malformations including congenital heart defects, duodenal atresia, and diaphragmatic hernia without known associations or syndromes yet described (65/148, 44%). Altogether, the molecular diagnostic rate remains very low and may underlie frequent non-Mendelian genetic models., (© 2022 Wiley Periodicals LLC.)
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- 2023
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20. GABBR1 monoallelic de novo variants linked to neurodevelopmental delay and epilepsy.
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Cediel ML, Stawarski M, Blanc X, Nosková L, Magner M, Platzer K, Gburek-Augustat J, Baldridge D, Constantino JN, Ranza E, Bettler B, and Antonarakis SE
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- Humans, gamma-Aminobutyric Acid metabolism, HEK293 Cells, Epilepsy genetics, Intellectual Disability genetics, Nervous System Malformations, Neurodevelopmental Disorders genetics, Receptors, GABA-B genetics
- Abstract
GABA
B receptors are obligatory heterodimers responsible for prolonged neuronal inhibition in the central nervous system. The two receptor subunits are encoded by GABBR1 and GABBR2. Variants in GABBR2 have been associated with a Rett-like phenotype (MIM: 617903), epileptic encephalopathy (MIM: 617904), and milder forms of developmental delay with absence epilepsy. To date, however, no phenotypes associated with pathogenic variants of GABBR1 have been established. Through GeneMatcher, we have ascertained four individuals who each have a monoallelic GABBR1 de novo non-synonymous variant; these individuals exhibit motor and/or language delay, ranging from mild to severe, and in one case, epilepsy. Further phenotypic features include varying degrees of intellectual disability, learning difficulties, autism, ADHD, ODD, sleep disorders, and muscular hypotonia. We functionally characterized the four de novo GABBR1 variants, p.Glu368Asp, p.Ala397Val, p.Ala535Thr, and p.Gly673Asp, in transfected HEK293 cells. GABA fails to efficiently activate the variant receptors, most likely leading to an increase in the excitation/inhibition balance in the central nervous system. Variant p.Gly673Asp in transmembrane domain 3 (TMD3) renders the receptor completely inactive, consistent with failure of the receptor to reach the cell surface. p.Glu368Asp is located near the orthosteric binding site and reduces GABA potency and efficacy at the receptor. GABA exhibits normal potency but decreased efficacy at the p.Ala397Val and p.Ala535Thr variants. Functional characterization of GABBR1-related variants provides a rationale for understanding the severity of disease phenotypes and points to possible therapeutic strategies., Competing Interests: Declaration of interests S.E.A. is a cofounder and CEO of Medigenome, Swiss Institute of Genomic Medicine; he is also a member of the Scientific Advisory Board of the “Imagine Institute”, Paris. E.R. is also a cofounder and medical director of Medigenome, Swiss Institute of Genomic Medicine. M.L.C. is an intern in the federally recognized clinical training program for Genetic Medicine of Medigenome. L.N. was supported by the grant NV19-07-00136 from the Ministry of Health of the Czech Republi, and The National Center for Medical Genomics (LM2018132) for support with the WES analyses., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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21. De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability.
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Schalk A, Cousin MA, Dsouza NR, Challman TD, Wain KE, Powis Z, Minks K, Trimouille A, Lasseaux E, Lacombe D, Angelini C, Michaud V, Van-Gils J, Spataro N, Ruiz A, Gabau E, Stolerman E, Washington C, Louie R, Lanpher BC, Kemppainen JL, Innes M, Kooy F, Meuwissen M, Goldenberg A, Lecoquierre F, Vera G, Diderich KEM, Sheidley B, El Achkar CM, Park M, Hamdan FF, Michaud JL, Lewis AJ, Zweier C, Reis A, Wagner M, Weigand H, Journel H, Keren B, Passemard S, Mignot C, van Gassen K, Brilstra EH, Itzikowitz G, O'Heir E, Allen J, Donald KA, Korf BR, Skelton T, Thompson M, Robin NH, Rudy NL, Dobyns WB, Foss K, Zarate YA, Bosanko KA, Alembik Y, Durand B, Tran Mau-Them F, Ranza E, Blanc X, Antonarakis SE, McWalter K, Torti E, Millan F, Dameron A, Tokita M, Zimmermann MT, Klee EW, Piton A, and Gerard B
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- Humans, Amino Acids genetics, Heterozygote, RNA, Messenger, Intellectual Disability genetics, Intellectual Disability pathology, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders pathology, Argonaute Proteins genetics
- Abstract
Background: High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD)., Methods: This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28)., Results: A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations., Conclusion: Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2 -related NDD., Competing Interests: Competing interests: KMW, ET, FM, AD and MJT are employees of GeneDx. ZP and KM are employees of Ambry Genetics., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
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22. Rare pathogenic variants in WNK3 cause X-linked intellectual disability.
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Küry S, Zhang J, Besnard T, Caro-Llopis A, Zeng X, Robert SM, Josiah SS, Kiziltug E, Denommé-Pichon AS, Cogné B, Kundishora AJ, Hao LT, Li H, Stevenson RE, Louie RJ, Deb W, Torti E, Vignard V, McWalter K, Raymond FL, Rajabi F, Ranza E, Grozeva D, Coury SA, Blanc X, Brischoux-Boucher E, Keren B, Õunap K, Reinson K, Ilves P, Wentzensen IM, Barr EE, Guihard SH, Charles P, Seaby EG, Monaghan KG, Rio M, van Bever Y, van Slegtenhorst M, Chung WK, Wilson A, Quinquis D, Bréhéret F, Retterer K, Lindenbaum P, Scalais E, Rhodes L, Stouffs K, Pereira EM, Berger SM, Milla SS, Jaykumar AB, Cobb MH, Panchagnula S, Duy PQ, Vincent M, Mercier S, Gilbert-Dussardier B, Le Guillou X, Audebert-Bellanger S, Odent S, Schmitt S, Boisseau P, Bonneau D, Toutain A, Colin E, Pasquier L, Redon R, Bouman A, Rosenfeld JA, Friez MJ, Pérez-Peña H, Akhtar Rizvi SR, Haider S, Antonarakis SE, Schwartz CE, Martínez F, Bézieau S, Kahle KT, and Isidor B
- Subjects
- Brain abnormalities, Catalytic Domain genetics, Hemizygote, Humans, Loss of Function Mutation, Male, Maternal Inheritance genetics, Mutation, Missense, Phosphorylation, Mental Retardation, X-Linked genetics, Protein Serine-Threonine Kinases chemistry, Protein Serine-Threonine Kinases genetics, Symporters metabolism
- Abstract
Purpose: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown., Method: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID)., Results: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had ID with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition., Conclusion: Pathogenic WNK3 variants cause a rare form of human X-linked ID with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism., Competing Interests: Conflict of Interest E.T., K.M., K.R., I.M.W., K.G.M., and L.R. are employees of GeneDx, LLC. K.R. is a shareholder of OPKO Health, Inc. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics Laboratories. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
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- 2022
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23. Heterozygous variants in CTR9, which encodes a major component of the PAF1 complex, are associated with a neurodevelopmental disorder.
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Meuwissen M, Verstraeten A, Ranza E, Iwaszkiewicz J, Bastiaansen M, Mateiu L, Nemegeer M, Meester JAN, Afenjar A, Amaral M, Ballhausen D, Barnett S, Barth M, Asselbergh B, Spaas K, Heeman B, Bassetti J, Blackburn P, Schaer M, Blanc X, Zoete V, Casas K, Courtin T, Doummar D, Guerry F, Keren B, Pappas J, Rabin R, Begtrup A, Shinawi M, Vulto-van Silfhout AT, Kleefstra T, Wagner M, Ziegler A, Schaefer E, Gerard B, De Bie CI, Holwerda SJB, Abbot MA, Antonarakis SE, and Loeys B
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- Gene Expression Regulation, Heterozygote, Humans, Autism Spectrum Disorder, Intellectual Disability genetics, Neurodevelopmental Disorders genetics, Phosphoproteins genetics, Transcription Factors genetics
- Abstract
Purpose: CTR9 is a subunit of the PAF1 complex (PAF1C) that plays a crucial role in transcription regulation by binding CTR9 to RNA polymerase II. It is involved in transcription-coupled histone modification through promoting H3K4 and H3K36 methylation. We describe the clinical and molecular studies in 13 probands, harboring likely pathogenic CTR9 missense variants, collected through GeneMatcher., Methods: Exome sequencing was performed in all individuals. CTR9 variants were assessed through 3-dimensional modeling of the activated human transcription complex Pol II-DSIF-PAF-SPT6 and the PAF1/CTR9 complex. H3K4/H3K36 methylation analysis, mitophagy assessment based on tetramethylrhodamine ethyl ester perchlorate immunofluorescence, and RNA-sequencing in skin fibroblasts from 4 patients was performed., Results: Common clinical findings were variable degrees of intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, and autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. For 11 CTR9 variants, de novo occurrence was shown. Three-dimensional modeling predicted a likely disruptive effect of the variants on local CTR9 structure and protein interaction. Additional studies in fibroblasts did not unveil the downstream functional consequences of the identified variants., Conclusion: We describe a neurodevelopmental disorder caused by (mainly) de novo variants in CTR9, likely affecting PAF1C function., Competing Interests: Conflict of Interest Amber Begtrup is an employee of GeneDx, Inc. Stylianos E. Antonarakis and Emmanuelle Ranza are cofounders of MediGenome. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
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- 2022
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24. CoverageMaster: comprehensive CNV detection and visualization from NGS short reads for genetic medicine applications.
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Rapti M, Zouaghi Y, Meylan J, Ranza E, Antonarakis SE, and Santoni FA
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- Comparative Genomic Hybridization methods, High-Throughput Nucleotide Sequencing methods, Exome Sequencing, Whole Genome Sequencing, DNA Copy Number Variations, Exome
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CoverageMaster (CoM) is a copy number variation (CNV) calling algorithm based on depth-of-coverage maps designed to detect CNVs of any size in exome [whole exome sequencing (WES)] and genome [whole genome sequencing (WGS)] data. The core of the algorithm is the compression of sequencing coverage data in a multiscale Wavelet space and the analysis through an iterative Hidden Markov Model. CoM processes WES and WGS data at nucleotide scale resolution and accurately detects and visualizes full size range CNVs, including single or partial exon deletions and duplications. The results obtained with this approach support the possibility for coverage-based CNV callers to replace probe-based methods such as array comparative genomic hybridization and multiplex ligation-dependent probe amplification in the near future., (© The Author(s) 2022. Published by Oxford University Press.)
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- 2022
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25. Childhood-Onset Movement Disorders Can Mask a Primary Immunodeficiency: 6 Cases of Classical Ataxia-Telangiectasia and Variant Forms.
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Blanchard-Rohner G, Peirolo A, Coulon L, Korff C, Horvath J, Burkhard PR, Gumy-Pause F, Ranza E, Jandus P, Dibra H, Taylor AMR, and Fluss J
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- Adolescent, Adult, Ataxia Telangiectasia immunology, Ataxia Telangiectasia metabolism, Ataxia Telangiectasia Mutated Proteins metabolism, Child, Child, Preschool, Cross-Sectional Studies, Delayed Diagnosis, Diagnosis, Differential, Female, Genetic Testing methods, Genotype, Humans, Male, Neurodegenerative Diseases immunology, Neurodegenerative Diseases metabolism, Phenotype, Retrospective Studies, Young Adult, Ataxia Telangiectasia diagnosis, Ataxia Telangiectasia genetics, Ataxia Telangiectasia Mutated Proteins genetics, Movement Disorders diagnosis, Mutation, Neurodegenerative Diseases diagnosis, Neurodegenerative Diseases genetics
- Abstract
Ataxia-telangiectasia (A-T) is a neurodegenerative and primary immunodeficiency disorder (PID) characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient's needs. Besides the classical ataxia-telangiectasia (classical A-T) phenotype, a variant phenotype (variant A-T) exists with partly overlapping but some distinctive disease characteristics. Here we present a case series of 6 patients with classical A-T and variant A-T, which illustrates the phenotypic variability of A-T that can present in childhood with prominent extrapyramidal features, with or without cerebellar ataxia. We report the clinical data, together with a detailed genotype description, immunological analyses, and related expression of the ATM protein. We show that the presence of some residual ATM kinase activity leads to the clinical phenotype variant A-T that differs from the classical A-T. Our data illustrate that the diagnosis of the variant form of A-T can be delayed and difficult, while early recognition of the variant form as well as the classical A-T is a prerequisite for providing a correct prognosis and appropriate rehabilitation and support, including the avoidance of diagnostic X-ray procedures, given the increased risk of malignancies and the higher risk for side effects of subsequent cancer treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Blanchard-Rohner, Peirolo, Coulon, Korff, Horvath, Burkhard, Gumy-Pause, Ranza, Jandus, Dibra, Taylor and Fluss.)
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- 2022
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26. Case Report: Persistent Hypogammaglobulinemia More Than 10 Years After Rituximab Given Post-HSCT.
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Luterbacher F, Bernard F, Baleydier F, Ranza E, Jandus P, and Blanchard-Rohner G
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- Adolescent, Agammaglobulinemia blood, Agammaglobulinemia chemically induced, Anemia, Aplastic immunology, Anemia, Aplastic therapy, Epstein-Barr Virus Infections immunology, Graft vs Host Disease immunology, Humans, Male, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma immunology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma therapy, Time Factors, Young Adult, Agammaglobulinemia diagnosis, Epstein-Barr Virus Infections drug therapy, Graft vs Host Disease drug therapy, Hematopoietic Stem Cell Transplantation adverse effects, Rituximab adverse effects
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Rituximab (RTX) is an anti-CD20 monoclonal antibody that targets B cells-from the immature pre-B-cell stage in the bone marrow to mature circulating B cells-while preserving stem cells and plasma cells. It is used to treat autoimmune diseases, hematological malignancies, or complications after hematopoietic stem cell transplantation (HSCT). Its safety profile is acceptable; however, a subset of patients can develop persistent hypogammaglobulinemia and associated severe complications, especially in pediatric populations. We report the unrelated cases of two young men aged 17 and 22, presenting with persistent hypogammaglobulinemia more than 7 and 10 years after treatment with RTX, respectively, and administered after HSCT for hemolytic anemia and Epstein-Barr virus reactivation, respectively. Both patients' immunological workups showed low levels of total immunoglobulin, vaccine antibodies, and class switched-memory B cells but an increase in naive B cells, which can also be observed in primary immunodeficiencies such as those making up common variable immunodeficiency. Whole exome sequencing for one of the patients failed to detect a pathogenic variant causing a Mendelian immunological disorder. Annual assessments involving interruption of immunoglobulin replacement therapy each summer failed to demonstrate the recovery of endogenous immunoglobulin production or normal numbers of class switched-memory B cells 7 and 10 years after the patients' respective treatments with RTX. Although the factors that may lead to prolonged hypogammaglobulinemia after rituximab treatment (if necessary) remain unclear, a comprehensive immunological workup before treatment and long-term follow-up are mandatory to assess long-term complications, especially in children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Luterbacher, Bernard, Baleydier, Ranza, Jandus and Blanchard-Rohner.)
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- 2021
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27. Botulinum toxin therapy during the COVID-19 outbreak: Experience of an Italian multidisciplinary team.
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Ranza E, Mammi P, Rampello A, Annamaria S, and Brianti R
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- Disease Outbreaks, Humans, Italy epidemiology, Patient Care Team, SARS-CoV-2, Botulinum Toxins, Type A, COVID-19
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- 2021
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28. Correction: Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.
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Rodan LH, Spillmann RC, Kurata HT, Lamothe SM, Maghera J, Jamra RA, Alkelai A, Antonarakis SE, Atallah I, Bar-Yosef O, Bilan F, Bjorgo K, Blanc X, Van Bogaert P, Bolkier Y, Burrage LC, Christ BU, Granadillo JL, Dickson P, Donald KA, Dubourg C, Eliyahu A, Emrick L, Engleman K, Gonfiantini MV, Good JM, Kalser J, Kloeckner C, Lachmeijer G, Macchiaiolo M, Nicita F, Odent S, O'Heir E, Ortiz-Gonzalez X, Pacio-Miguez M, Palomares-Bralo M, Pena L, Platzer K, Quinodoz M, Ranza E, Rosenfeld JA, Roulet-Perez E, Santani A, Santos-Simarro F, Pode-Shakked B, Skraban C, Slaugh R, Superti-Furga A, Thiffault I, van Jaabrsveld RH, Vincent M, Wang HG, Zacher P, Rush E, Pitt GS, Au PYB, and Shashi V
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- 2021
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29. Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.
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Rodan LH, Spillmann RC, Kurata HT, Lamothe SM, Maghera J, Jamra RA, Alkelai A, Antonarakis SE, Atallah I, Bar-Yosef O, Bilan F, Bjorgo K, Blanc X, Van Bogaert P, Bolkier Y, Burrage LC, Christ BU, Granadillo JL, Dickson P, Donald KA, Dubourg C, Eliyahu A, Emrick L, Engleman K, Gonfiantini MV, Good JM, Kalser J, Kloeckner C, Lachmeijer G, Macchiaiolo M, Nicita F, Odent S, O'Heir E, Ortiz-Gonzalez X, Pacio-Miguez M, Palomares-Bralo M, Pena L, Platzer K, Quinodoz M, Ranza E, Rosenfeld JA, Roulet-Perez E, Santani A, Santos-Simarro F, Pode-Shakked B, Skraban C, Slaugh R, Superti-Furga A, Thiffault I, van Jaabrsveld RH, Vincent M, Wang HG, Zacher P, Rush E, Pitt GS, Au PYB, and Shashi V
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- Humans, Phenotype, Autistic Disorder genetics, Calcium Channels, L-Type genetics, Long QT Syndrome, Syndactyly
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Purpose: CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype., Methods: We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations., Results: Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism., Conclusion: We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome., (© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)
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- 2021
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30. Benefits of Exome Sequencing in Children with Suspected Isolated Hearing Loss.
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Van Heurck R, Carminho-Rodrigues MT, Ranza E, Stafuzza C, Quteineh L, Gehrig C, Hammar E, Guipponi M, Abramowicz M, Senn P, Guinand N, Cao-Van H, and Paoloni-Giacobino A
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- Adult, Child, Child, Preschool, Deafness diagnosis, Deafness pathology, Exome genetics, Female, Hearing Loss, Sensorineural diagnosis, Hearing Loss, Sensorineural pathology, Humans, Male, Mutation genetics, Pathology, Molecular, Pedigree, Exome Sequencing standards, Actins genetics, Collagen Type XI genetics, Connexin 26 genetics, Deafness genetics, Hearing Loss, Sensorineural genetics, Intercellular Signaling Peptides and Proteins genetics
- Abstract
Purpose: Hearing loss is characterized by an extensive genetic heterogeneity and remains a common disorder in children. Molecular diagnosis is of particular benefit in children, and permits the early identification of clinically-unrecognized hearing loss syndromes, which permits effective clinical management and follow-up, including genetic counselling., Methods: We performed whole-exome sequencing with the analysis of a panel of 189 genes associated with hearing loss in a prospective cohort of 61 children and 9 adults presenting mainly with isolated hearing loss., Results: The overall diagnostic rate using exome sequencing was 47.2% (52.5% in children; 22% in adults). In children with confirmed molecular results, 17/32 (53.2%) showed autosomal recessive inheritance patterns, 14/32 (43.75%) showed an autosomal dominant condition, and one case had X-linked hearing loss. In adults, the two patients showed an autosomal dominant inheritance pattern. Among the 32 children, 17 (53.1%) had nonsyndromic hearing loss and 15 (46.7%) had syndromic hearing loss. One adult was diagnosed with syndromic hearing loss and one with nonsyndromic hearing loss. The most common causative genes were STRC (5 cases), GJB2 (3 cases), COL11A1 (3 cases), and ACTG1 (3 cases)., Conclusions: Exome sequencing has a high diagnostic yield in children with hearing loss and can reveal a syndromic hearing loss form before other organs/systems become involved, allowing the surveillance of unrecognized present and/or future complications associated with these syndromes.
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- 2021
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31. An Experience of Multiple Sclerosis Telerehabilitation During the COVID-19 Pandemic.
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Nora M, Giannarelli M, Zicchinella C, Mammi P, Ranza E, and Brianti R
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- Humans, Outpatients, Pandemics, Patient Satisfaction, SARS-CoV-2, Speech Therapy, COVID-19, Multiple Sclerosis, Telemedicine, Telerehabilitation
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- 2021
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32. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.
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den Hoed J, de Boer E, Voisin N, Dingemans AJM, Guex N, Wiel L, Nellaker C, Amudhavalli SM, Banka S, Bena FS, Ben-Zeev B, Bonagura VR, Bruel AL, Brunet T, Brunner HG, Chew HB, Chrast J, Cimbalistienė L, Coon H, Délot EC, Démurger F, Denommé-Pichon AS, Depienne C, Donnai D, Dyment DA, Elpeleg O, Faivre L, Gilissen C, Granger L, Haber B, Hachiya Y, Abedi YH, Hanebeck J, Hehir-Kwa JY, Horist B, Itai T, Jackson A, Jewell R, Jones KL, Joss S, Kashii H, Kato M, Kattentidt-Mouravieva AA, Kok F, Kotzaeridou U, Krishnamurthy V, Kučinskas V, Kuechler A, Lavillaureix A, Liu P, Manwaring L, Matsumoto N, Mazel B, McWalter K, Meiner V, Mikati MA, Miyatake S, Mizuguchi T, Moey LH, Mohammed S, Mor-Shaked H, Mountford H, Newbury-Ecob R, Odent S, Orec L, Osmond M, Palculict TB, Parker M, Petersen AK, Pfundt R, Preikšaitienė E, Radtke K, Ranza E, Rosenfeld JA, Santiago-Sim T, Schwager C, Sinnema M, Snijders Blok L, Spillmann RC, Stegmann APA, Thiffault I, Tran L, Vaknin-Dembinsky A, Vedovato-Dos-Santos JH, Schrier Vergano SA, Vilain E, Vitobello A, Wagner M, Waheeb A, Willing M, Zuccarelli B, Kini U, Newbury DF, Kleefstra T, Reymond A, Fisher SE, and Vissers LELM
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- Chromatin metabolism, Female, Genetic Association Studies, Haploinsufficiency, Humans, Male, Matrix Attachment Region Binding Proteins chemistry, Matrix Attachment Region Binding Proteins metabolism, Models, Molecular, Mutation, Missense, Protein Binding, Protein Domains, Transcription, Genetic, Matrix Attachment Region Binding Proteins genetics, Mutation, Neurodevelopmental Disorders genetics
- Abstract
Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
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- 2021
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33. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns.
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Stamberger H, Hammer TB, Gardella E, Vlaskamp DRM, Bertelsen B, Mandelstam S, de Lange I, Zhang J, Myers CT, Fenger C, Afawi Z, Almanza Fuerte EP, Andrade DM, Balcik Y, Ben Zeev B, Bennett MF, Berkovic SF, Isidor B, Bouman A, Brilstra E, Busk ØL, Cairns A, Caumes R, Chatron N, Dale RC, de Geus C, Edery P, Gill D, Granild-Jensen JB, Gunderson L, Gunning B, Heimer G, Helle JR, Hildebrand MS, Hollingsworth G, Kharytonov V, Klee EW, Koeleman BPC, Koolen DA, Korff C, Küry S, Lesca G, Lev D, Leventer RJ, Mackay MT, Macke EL, McEntagart M, Mohammad SS, Monin P, Montomoli M, Morava E, Moutton S, Muir AM, Parrini E, Procopis P, Ranza E, Reed L, Reif PS, Rosenow F, Rossi M, Sadleir LG, Sadoway T, Schelhaas HJ, Schneider AL, Shah K, Shalev R, Sisodiya SM, Smol T, Stumpel CTRM, Stuurman K, Symonds JD, Mau-Them FT, Verbeek N, Verhoeven JS, Wallace G, Yosovich K, Zarate YA, Zerem A, Zuberi SM, Guerrini R, Mefford HC, Patel C, Zhang YH, Møller RS, and Scheffer IE
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- Female, Genes, X-Linked genetics, Humans, Male, Nerve Tissue Proteins, Seizures genetics, Autism Spectrum Disorder genetics, Brain Diseases genetics, Epilepsy genetics
- Abstract
Purpose: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy., Methods: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy., Results: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism., Conclusion: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.
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- 2021
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34. Correction to: Hyperinsulinism associated with GLUD1 mutation: allosteric regulation and functional characterization of p.G446V glutamate dehydrogenase.
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Luczkowska K, Stekelenburg C, Sloan-Béna F, Ranza E, Gastaldi G, Schwitzgebel V, and Maechler P
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- 2021
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35. De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy.
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Itai T, Hamanaka K, Sasaki K, Wagner M, Kotzaeridou U, Brösse I, Ries M, Kobayashi Y, Tohyama J, Kato M, Ong WP, Chew HB, Rethanavelu K, Ranza E, Blanc X, Uchiyama Y, Tsuchida N, Fujita A, Azuma Y, Koshimizu E, Mizuguchi T, Takata A, Miyake N, Takahashi H, Miyagi E, Tsurusaki Y, Doi H, Taguri M, Antonarakis SE, Nakashima M, Saitsu H, Miyatake S, and Matsumoto N
- Subjects
- Female, Heterozygote, Humans, Nuclear Localization Signals genetics, RNA-Binding Proteins genetics, CELF Proteins genetics, Epilepsy genetics, Intellectual Disability genetics, Nerve Tissue Proteins genetics
- Abstract
We report heterozygous CELF2 (NM_006561.3) variants in five unrelated individuals: Individuals 1-4 exhibited developmental and epileptic encephalopathy (DEE) and Individual 5 had intellectual disability and autistic features. CELF2 encodes a nucleocytoplasmic shuttling RNA-binding protein that has multiple roles in RNA processing and is involved in the embryonic development of the central nervous system and heart. Whole-exome sequencing identified the following CELF2 variants: two missense variants [c.1558C>T:p.(Pro520Ser) in unrelated Individuals 1 and 2, and c.1516C>G:p.(Arg506Gly) in Individual 3], one frameshift variant in Individual 4 that removed the last amino acid of CELF2 c.1562dup:p.(Tyr521Ter), possibly resulting in escape from nonsense-mediated mRNA decay (NMD), and one canonical splice site variant, c.272-1G>C in Individual 5, also probably leading to NMD. The identified variants in Individuals 1, 2, 4, and 5 were de novo, while the variant in Individual 3 was inherited from her mosaic mother. Notably, all identified variants, except for c.272-1G>C, were clustered within 20 amino acid residues of the C-terminus, which might be a nuclear localization signal. We demonstrated the extranuclear mislocalization of mutant CELF2 protein in cells transfected with mutant CELF2 complementary DNA plasmids. Our findings indicate that CELF2 variants that disrupt its nuclear localization are associated with DEE., (© 2020 Wiley Periodicals LLC.)
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- 2021
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36. Rehabilitative treatment of patients with COVID-19 infection: the P.A.R.M.A. evidence based clinical practice protocol.
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Petraglia F, Chiavilli M, Zaccaria B, Nora M, Mammi P, Ranza E, Rampello A, Marcato A, Pessina F, Salghetti A, Costantino C, Frizziero A, Fanzaghi P, Faverzani S, Bergamini O, Allegri S, Rodà F, Brianti R, and Rehabilitation Group TC
- Subjects
- Clinical Protocols, Evidence-Based Medicine, Humans, Practice Guidelines as Topic, COVID-19 rehabilitation
- Abstract
Background: The impact of the SARS-CoV-2 on the National Health System (NHS) required a reorganization of the various levels of care, which also involved the rehabilitation reality., Aim of the Work: A clinical practice review of the literature was conducted to provide operational-rehabilitation guidelines adapted to the local reality and to the recent corporate reorganization in the context of the COVID-19 emergency., Methods: A practice review of the available scientific evidence was regularly conducted from the start of the COVID-19 pandemic to periodically update the clinical practice guidelines. Articles that met the following inclusion criteria were included: studies conducted on human adult subjects with COVID-19 infection, undergoing rehabilitation in any hospitalization setting., Results: The results of this clinical practice update were periodically discussed with colleagues and collaborators in a multi-professional team, in order to guarantee a good clinical practice protocol, named P.A.R.M.A., Conclusions: The P.A.R.M.A. protocol is the result of a periodic review literature update, which has allowed us to take charge of patients affected by COVID-19 according to the most up-to-date clinical evidences, guaranteeing a shared and uniform treatment within a local reality in an era of health emergency.
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- 2020
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37. De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.
- Author
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Manole A, Efthymiou S, O'Connor E, Mendes MI, Jennings M, Maroofian R, Davagnanam I, Mankad K, Lopez MR, Salpietro V, Harripaul R, Badalato L, Walia J, Francklyn CS, Athanasiou-Fragkouli A, Sullivan R, Desai S, Baranano K, Zafar F, Rana N, Ilyas M, Horga A, Kara M, Mattioli F, Goldenberg A, Griffin H, Piton A, Henderson LB, Kara B, Aslanger AD, Raaphorst J, Pfundt R, Portier R, Shinawi M, Kirby A, Christensen KM, Wang L, Rosti RO, Paracha SA, Sarwar MT, Jenkins D, Ahmed J, Santoni FA, Ranza E, Iwaszkiewicz J, Cytrynbaum C, Weksberg R, Wentzensen IM, Guillen Sacoto MJ, Si Y, Telegrafi A, Andrews MV, Baldridge D, Gabriel H, Mohr J, Oehl-Jaschkowitz B, Debard S, Senger B, Fischer F, van Ravenwaaij C, Fock AJM, Stevens SJC, Bähler J, Nasar A, Mantovani JF, Manzur A, Sarkozy A, Smith DEC, Salomons GS, Ahmed ZM, Riazuddin S, Riazuddin S, Usmani MA, Seibt A, Ansar M, Antonarakis SE, Vincent JB, Ayub M, Grimmel M, Jelsig AM, Hjortshøj TD, Karstensen HG, Hummel M, Haack TB, Jamshidi Y, Distelmaier F, Horvath R, Gleeson JG, Becker H, Mandel JL, Koolen DA, and Houlden H
- Subjects
- Alleles, Amino Acyl-tRNA Synthetases genetics, Cell Line, Female, Genetic Predisposition to Disease genetics, Humans, Male, Pedigree, RNA, Transfer genetics, Stem Cells physiology, Aspartate-tRNA Ligase genetics, Gain of Function Mutation genetics, Loss of Function Mutation genetics, Neurodevelopmental Disorders genetics, RNA, Transfer, Amino Acyl genetics
- Abstract
Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function., (Copyright © 2020. Published by Elsevier Inc.)
- Published
- 2020
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38. In Response to: Simpson and Robinson: Rehabilitation After Critical Illness in People With COVID-19 Infection.
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Mammi P, Ranza E, Petraglia F, Rampello A, Pessina F, Zaccaria B, Marcato A, Nora M, and Brianti R
- Subjects
- COVID-19, Critical Illness, Humans, SARS-CoV-2, Betacoronavirus, Coronavirus Infections, Pandemics, Pneumonia, Viral
- Published
- 2020
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39. Kirrel3-Mediated Synapse Formation Is Attenuated by Disease-Associated Missense Variants.
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Taylor MR, Martin EA, Sinnen B, Trilokekar R, Ranza E, Antonarakis SE, and Williams ME
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- Animals, Autistic Disorder genetics, Autistic Disorder metabolism, Cell Adhesion physiology, Cells, Cultured, Female, Hippocampus cytology, Intellectual Disability genetics, Intellectual Disability metabolism, Male, Membrane Proteins metabolism, Mice, Rats, Hippocampus metabolism, Membrane Proteins genetics, Mutation, Missense, Neurons metabolism, Synapses metabolism
- Abstract
Missense variants in Kirrel3 are repeatedly identified as risk factors for autism spectrum disorder and intellectual disability, but it has not been reported if or how these variants disrupt Kirrel3 function. Previously, we studied Kirrel3 loss of function using KO mice and showed that Kirrel3 is a synaptic adhesion molecule necessary to form one specific type of hippocampal synapse in vivo Here, we developed an in vitro , gain-of-function assay for Kirrel3 using neuron cultures prepared from male and female mice and rats. We find that WT Kirrel3 induces synapse formation selectively between Kirrel3-expressing neurons via homophilic, transcellular binding. We tested six disease-associated Kirrel3 missense variants and found that five attenuate this synaptogenic function. All variants tested traffic to the cell surface and localize to synapses similar to WT Kirrel3. Two tested variants lack homophilic transcellular binding, which likely accounts for their reduced synaptogenic function. Interestingly, we also identified variants that bind in trans but cannot induce synapses, indicating that Kirrel3 transcellular binding is necessary but not sufficient for its synaptogenic function. Collectively, these results suggest Kirrel3 functions as a synaptogenic, cell-recognition molecule, and this function is attenuated by missense variants associated with autism spectrum disorder and intellectual disability. Thus, we provide critical insight to the mechanism of Kirrel3 function and the consequences of missense variants associated with autism and intellectual disability. SIGNIFICANCE STATEMENT Here, we advance our understanding of mechanisms mediating target-specific synapse formation by providing evidence that Kirrel3 transcellular interactions mediate target recognition and signaling to promote synapse development. Moreover, this study tests the effects of disease-associated Kirrel3 missense variants on synapse formation, and thereby, increases understanding of the complex etiology of neurodevelopmental disorders arising from rare missense variants in synaptic genes., (Copyright © 2020 the authors.)
- Published
- 2020
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40. Overlapping phenotypes between SHORT and Noonan syndromes in patients with PTPN11 pathogenic variants.
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Ranza E, Guimier A, Verloes A, Capri Y, Marques C, Auclair M, Mathieu-Dramard M, Morin G, Thevenon J, Faivre L, Thauvin-Robinet C, Innes AM, Dyment DA, Vigouroux C, and Amiel J
- Subjects
- Female, Humans, MAP Kinase Signaling System genetics, Male, Mitogen-Activated Protein Kinases genetics, Phenotype, Phosphatidylinositol 3-Kinases genetics, Signal Transduction genetics, Genetic Variation genetics, Growth Disorders genetics, Hypercalcemia genetics, Metabolic Diseases genetics, Nephrocalcinosis genetics, Noonan Syndrome genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics
- Abstract
Overlapping syndromes such as Noonan, Cardio-Facio-Cutaneous, Noonan syndrome (NS) with multiple lentigines and Costello syndromes are genetically heterogeneous conditions sharing a dysregulation of the RAS/mitogen-activated protein kinase (MAPK) pathway and are known collectively as the RASopathies. PTPN11 was the first disease-causing gene identified in NS and remains the more prevalent. We report seven patients from three families presenting heterozygous missense variants in PTPN11 probably responsible for a disease phenotype distinct from the classical Noonan syndrome. The clinical presentation and common features of these seven cases overlap with the SHORT syndrome. The latter is the consequence of PI3K/AKT signaling deregulation with the predominant disease-causing gene being PIK3R1. Our data suggest that the phenotypic spectrum associated with pathogenic variants of PTPN11 could be wider than previously described, and this could be due to the dual activity of SHP2 (ie, PTPN11 gene product) on the RAS/MAPK and PI3K/AKT signaling., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2020
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41. Biallelic variants in PSMB1 encoding the proteasome subunit β6 cause impairment of proteasome function, microcephaly, intellectual disability, developmental delay and short stature.
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Ansar M, Ebstein F, Özkoç H, Paracha SA, Iwaszkiewicz J, Gesemann M, Zoete V, Ranza E, Santoni FA, Sarwar MT, Ahmed J, Krüger E, Bachmann-Gagescu R, and Antonarakis SE
- Subjects
- Alleles, Animals, Child, Consanguinity, Developmental Disabilities complications, Developmental Disabilities genetics, Developmental Disabilities pathology, Dwarfism complications, Female, Homozygote, Humans, Intellectual Disability complications, Intellectual Disability genetics, Intellectual Disability pathology, Male, Microcephaly complications, Microcephaly pathology, Models, Molecular, Pedigree, Phenotype, Zebrafish genetics, Dwarfism genetics, Microcephaly genetics, Proteasome Endopeptidase Complex genetics
- Abstract
The molecular cause of the majority of rare autosomal recessive disorders remains unknown. Consanguinity due to extensive homozygosity unravels many recessive phenotypes and facilitates the detection of novel gene-disease links. Here, we report two siblings with phenotypic signs, including intellectual disability (ID), developmental delay and microcephaly from a Pakistani consanguineous family in which we have identified homozygosity for p(Tyr103His) in the PSMB1 gene (Genbank NM_002793) that segregated with the disease phenotype. PSMB1 encodes a β-type proteasome subunit (i.e. β6). Modeling of the p(Tyr103His) variant indicates that this variant weakens the interactions between PSMB1/β6 and PSMA5/α5 proteasome subunits and thus destabilizes the 20S proteasome complex. Biochemical experiments in human SHSY5Y cells revealed that the p(Tyr103His) variant affects both the processing of PSMB1/β6 and its incorporation into proteasome, thus impairing proteasome activity. CRISPR/Cas9 mutagenesis or morpholino knock-down of the single psmb1 zebrafish orthologue resulted in microcephaly, microphthalmia and reduced brain size. Genetic evidence in the family and functional experiments in human cells and zebrafish indicates that PSMB1/β6 pathogenic variants are the cause of a recessive disease with ID, microcephaly and developmental delay due to abnormal proteasome assembly., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
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42. SCN8A heterozygous variants are associated with anoxic-epileptic seizures.
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Ranza E, Z'Graggen W, Lidgren M, Beghetti M, Guipponi M, Antonarakis SE, Absoud M, Goyal S, Pal DK, and Korff CM
- Subjects
- Child, Child, Preschool, Electroencephalography, Female, Heterozygote, Humans, Infant, Male, Mutation, Phenotype, Seizures diagnostic imaging, Seizures epidemiology, Seizures pathology, Genetic Predisposition to Disease, NAV1.6 Voltage-Gated Sodium Channel genetics, Seizures genetics
- Abstract
Anoxic-epileptic seizures (AES) are rare outcomes of common childhood reflex anoxic syncope that trigger a true epileptic seizure. The term AES was coined by Stephenson in 1983, to differentiate these events from convulsive syncopes and the more common reflex anoxic syncopes. A genetic susceptibility for AES has been postulated; but, its molecular basis has up to now been elusive. We report here two illustrative cases and show the association of de novo SCN8A variants and AES. One of them had focal or generalized seizures and autonomic symptoms triggered by orthostatism; the second had breath-holding spells triggered by pain or exercise leading to tonic-clonic seizures; both had repeatedly normal EEGs and a family history of reflex syncope. The data of three additional AES patients further suggest, for the first time, a link between SCN8A pathogenic variants and AES. The neurodevelopment of four patients was abnormal. Four of the five SCN8A mutations observed here were previously described in patients with seizure disorders. Seizures responded particularly well to sodium channel blockers. Our observation enriches the spectrum of seizures linked with SCN8A pathogenic variants., (© 2020 Wiley Periodicals, Inc.)
- Published
- 2020
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43. Taurine treatment of retinal degeneration and cardiomyopathy in a consanguineous family with SLC6A6 taurine transporter deficiency.
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Ansar M, Ranza E, Shetty M, Paracha SA, Azam M, Kern I, Iwaszkiewicz J, Farooq O, Pournaras CJ, Malcles A, Kecik M, Rivolta C, Muzaffar W, Qurban A, Ali L, Aggoun Y, Santoni FA, Makrythanasis P, Ahmed J, Qamar R, Sarwar MT, Henry LK, and Antonarakis SE
- Subjects
- Adolescent, Biological Transport, Cardiomyopathies metabolism, Cardiomyopathies pathology, Child, Female, Humans, Male, Pedigree, Retinal Degeneration metabolism, Retinal Degeneration pathology, Cardiomyopathies drug therapy, Membrane Glycoproteins deficiency, Membrane Transport Proteins deficiency, Retinal Degeneration drug therapy, Taurine therapeutic use
- Abstract
In a consanguineous Pakistani family with two affected individuals, a homozygous variant Gly399Val in the eighth transmembrane domain of the taurine transporter SLC6A6 was identified resulting in a hypomorph transporting capacity of ~15% compared with normal. Three-dimensional modeling of this variant has indicated that it likely causes displacement of the Tyr138 (TM3) side chain, important for transport of taurine. The affected individuals presented with rapidly progressive childhood retinal degeneration, cardiomyopathy and almost undetectable plasma taurine levels. Oral taurine supplementation of 100 mg/kg/day resulted in maintenance of normal blood taurine levels. Following approval by the ethics committee, a long-term supplementation treatment was introduced. Remarkably, after 24-months, the cardiomyopathy was corrected in both affected siblings, and in the 6-years-old, the retinal degeneration was arrested, and the vision was clinically improved. Similar therapeutic approaches could be employed in Mendelian phenotypes caused by the dysfunction of the hundreds of other molecular transporters., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
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44. Hyperinsulinism associated with GLUD1 mutation: allosteric regulation and functional characterization of p.G446V glutamate dehydrogenase.
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Luczkowska K, Stekelenburg C, Sloan-Béna F, Ranza E, Gastaldi G, Schwitzgebel V, and Maechler P
- Subjects
- Adult, Allosteric Regulation, Case-Control Studies, Female, Glutamate Dehydrogenase chemistry, Humans, Hyperinsulinism genetics, Infant, Newborn, Lymphocytes metabolism, Male, Middle Aged, Protein Conformation, Glutamate Dehydrogenase genetics, Glutamate Dehydrogenase metabolism, Guanosine Triphosphate metabolism, Hyperinsulinism pathology, Lymphocytes pathology, Mutation
- Abstract
Background: Gain-of-function mutations in the GLUD1 gene, encoding for glutamate dehydrogenase (GDH), result in the hyperinsulinism/hyperammonemia HI/HA syndrome. HI/HA patients present with harmful hypoglycemia secondary to protein-induced HI and elevated plasma ammonia levels. These symptoms may be accompanied by seizures and mental retardation. GDH is a mitochondrial enzyme that catalyzes the oxidative deamination of glutamate to α-ketoglutarate, under allosteric regulations mediated by its inhibitor GTP and its activator ADP. The present study investigated the functional properties of the GDH-G446V variant (alias c.1496G > T, p.(Gly499Val) (NM_005271.4)) in patient-derived lymphoblastoid cells., Results: The calculated energy barrier between the opened and closed state of the enzyme was 41% lower in GDH-G446V compared to wild-type GDH, pointing to altered allosteric regulation. Computational analysis indicated conformational changes of GDH-G446V in the antenna region that is crucial for allosteric regulators. Enzymatic activity measured in patient-derived lymphoblastoid cells showed impaired allosteric responses of GDH-G446V to both regulators GTP and ADP. In particular, as opposed to control lymphoblastoid cells, GDH-G446V cells were not responsive to GTP in the lower range of ADP concentrations. Assessment of the metabolic rate revealed higher mitochondrial respiration in response to GDH-dependent substrates in the GDH-G446V lymphoblastoid cells compared to control cells. This indicates a shift toward glutaminolysis for energy provision in cells carrying the GDH-G446V variant., Conclusions: Substitution of the small amino acid glycine for the hydrophobic branched-chain valine altered the allosteric sensitivity to both inhibitory action of GTP and activation by ADP, rendering cells metabolically responsive to glutamine.
- Published
- 2020
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45. Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature.
- Author
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Ansar M, Chung HL, Al-Otaibi A, Elagabani MN, Ravenscroft TA, Paracha SA, Scholz R, Abdel Magid T, Sarwar MT, Shah SF, Qaisar AA, Makrythanasis P, Marcogliese PC, Kamsteeg EJ, Falconnet E, Ranza E, Santoni FA, Aldhalaan H, Al-Asmari A, Faqeih EA, Ahmed J, Kornau HC, Bellen HJ, and Antonarakis SE
- Subjects
- Adult, Alleles, Animals, Child, Dendritic Spines genetics, Drosophila genetics, Female, Humans, Male, Mice, Saudi Arabia, Synapses genetics, Young Adult, Developmental Disabilities genetics, Dwarfism genetics, Guanine Nucleotide Exchange Factors genetics, Intellectual Disability genetics, Mutation genetics
- Abstract
We report two consanguineous families with probands that exhibit intellectual disability, developmental delay, short stature, aphasia, and hypotonia in which homozygous non-synonymous variants were identified in IQSEC1 (GenBank: NM_001134382.3). In a Pakistani family, the IQSEC1 segregating variant is c.1028C>T (p.Thr343Met), while in a Saudi Arabian family the variant is c.962G>A (p.Arg321Gln). IQSEC1-3 encode guanine nucleotide exchange factors for the small GTPase ARF6 and their loss affects a variety of actin-dependent cellular processes, including AMPA receptor trafficking at synapses. The ortholog of IQSECs in the fly is schizo and its loss affects growth cone guidance at the midline in the CNS, also an actin-dependent process. Overexpression of the reference IQSEC1 cDNA in wild-type flies is lethal, but overexpression of the two variant IQSEC1 cDNAs did not affect viability. Loss of schizo caused embryonic lethality that could be rescued to 2
nd instar larvae by moderate expression of the human reference cDNA. However, the p.Arg321Gln and p.Thr343Met variants failed to rescue embryonic lethality. These data indicate that the variants behave as loss-of-function mutations. We also show that schizo in photoreceptors is required for phototransduction. Finally, mice with a conditional Iqsec1 deletion in cortical neurons exhibited an increased density of dendritic spines with an immature morphology. The phenotypic similarity of the affecteds and the functional experiments in flies and mice indicate that IQSEC1 variants are the cause of a recessive disease with intellectual disability, developmental delay, and short stature, and that axonal guidance and dendritic projection defects as well as dendritic spine dysgenesis may underlie disease pathogenesis., (Copyright © 2019. Published by Elsevier Inc.)- Published
- 2019
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46. Activated Phosphoinositide 3 Kinase Delta Syndrome (APDS): A Primary Immunodeficiency Mimicking Lymphoma.
- Author
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Baleydier F, Ranza E, Schäppi M, Rougemont AL, Merlini L, Ansari M, and Blanchard-Rohner G
- Subjects
- Child, Class I Phosphatidylinositol 3-Kinases, Diagnosis, Differential, Humans, Lymphoma pathology, Male, Primary Immunodeficiency Diseases pathology, Lymphoma diagnosis, Primary Immunodeficiency Diseases diagnosis
- Abstract
Malignant or nonmalignant lymphoproliferative disorders together with repeated ear, nose, and throat infections should strongly motivate immunologic investigations. Indeed, we report a 7-year-old patient with a history of persistent abdominal symptoms along with recurrent ear, nose, and throat infections, who presented with intra-abdominal masses highly suggestive of a diagnostic of lymphoma, and who was diagnosed with activated-PI3K-delta syndrome, a recently described primary immunodeficiency prone to lymphoproliferation.
- Published
- 2019
- Full Text
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47. [Genetics of hearing disorders in children].
- Author
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Paoloni-Giacobino A, Ranza E, Abramowicz M, Senn P, and Cao Van H
- Subjects
- Child, Deafness diagnosis, Deafness genetics, Deafness therapy, Early Diagnosis, Genetic Counseling, Hearing Loss diagnosis, Hearing Loss therapy, Humans, Molecular Targeted Therapy, Syndrome, Hearing Loss genetics
- Abstract
The majority of early hearing disorders are of genetic origin. In view of the genetic heterogeneity, high-throughput sequencing analysis of a panel of genes involved in hearing loss is the most effective and economical approach, providing a diagnostic yield of around 40 % today. The determination of a molecular diagnosis makes it possible to: i) adapt the audiological care; ii) to search for possible somatic problems associated with so-called syndromic hearing loss; (iii) to avoid unnecessary additional examinations in isolated hearing loss; (iv) to establish accurate genetic counseling for relatives, or even to provide early diagnosis; and (v) to lay the foundation for potential future molecular hearing loss therapies in selected cases., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.
- Published
- 2019
48. A 19-month-old Boy With Refractory Cervical Adenitis.
- Author
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Schneider A, Ranza E, Diana A, Laurent M, Rougemont AL, Hauri M, Reichenbach J, and Blanchard-Rohner G
- Subjects
- Cervix Uteri diagnostic imaging, Cervix Uteri pathology, Female, Humans, Infant, Liver diagnostic imaging, Liver pathology, Male, Mutant Proteins genetics, NADPH Oxidase 2 genetics, Point Mutation, Tomography, X-Ray Computed, Ultrasonography, Granulomatous Disease, Chronic diagnosis, Granulomatous Disease, Chronic pathology, Liver Abscess etiology, Liver Abscess pathology, Lymphadenitis etiology, Lymphadenitis pathology
- Published
- 2019
- Full Text
- View/download PDF
49. Infantile-Onset Paroxysmal Movement Disorder and Episodic Ataxia Associated with a TBC1D24 Mutation.
- Author
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Zimmern V, Riant F, Roze E, Ranza E, Lehmann-Horn F, de Bellescize J, Ville D, Lesca G, and Korff CM
- Subjects
- Age of Onset, Ataxia complications, Brain diagnostic imaging, Brain pathology, Humans, Infant, Male, Movement Disorders complications, Mutation, Ataxia diagnosis, Ataxia genetics, GTPase-Activating Proteins genetics, Movement Disorders diagnosis, Movement Disorders genetics
- Abstract
Mutations that disrupt the TBC1D24 presynaptic protein have been implicated in various neurological disorders including epilepsy, chronic encephalopathy, DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures) syndrome, nonsyndromic hearing loss, and myoclonus. We present the case of a 22-month-old male with infantile-onset paroxysmal episodes of facial and limb myoclonus. The episodes were linked to biallelic variants in exon 2 of the TBC1D24 gene that lead to amino acid changes (c.304C >T/p.Pro102Ser and c.410T > C/p.Val137Ala), each variant being inherited from a parent. Follow-up imaging in adolescence revealed widened right cerebellar sulci. We discuss the evolving landscape of TBC1D24 associated phenotypes; this case adds to a growing body of evidence linking this gene to movement disorders in children., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)
- Published
- 2019
- Full Text
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50. Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features.
- Author
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Ansar M, Ullah F, Paracha SA, Adams DJ, Lai A, Pais L, Iwaszkiewicz J, Millan F, Sarwar MT, Agha Z, Shah SF, Qaisar AA, Falconnet E, Zoete V, Ranza E, Makrythanasis P, Santoni FA, Ahmed J, Katsanis N, Walsh C, Davis EE, and Antonarakis SE
- Subjects
- Adult, Alleles, Amino Acid Sequence, Animals, Child, Preschool, Craniofacial Abnormalities pathology, Dyneins chemistry, Dyneins metabolism, Exome, Female, Homozygote, Humans, Infant, Intellectual Disability pathology, Intracranial Arteriovenous Malformations pathology, Male, Microcephaly pathology, Pedigree, Phenotype, Protein Conformation, Sequence Homology, Exome Sequencing, Young Adult, Zebrafish genetics, Zebrafish metabolism, Craniofacial Abnormalities etiology, Dyneins genetics, Intellectual Disability etiology, Intracranial Arteriovenous Malformations etiology, Microcephaly etiology, Mutation, Zebrafish growth & development
- Abstract
Cargo transport along the cytoplasmic microtubular network is essential for neuronal function, and cytoplasmic dynein-1 is an established molecular motor that is critical for neurogenesis and homeostasis. We performed whole-exome sequencing, homozygosity mapping, and chromosomal microarray studies in five individuals from three independent pedigrees and identified likely-pathogenic variants in DYNC1I2 (Dynein Cytoplasmic 1 Intermediate Chain 2), encoding a component of the cytoplasmic dynein 1 complex. In a consanguineous Pakistani family with three affected individuals presenting with microcephaly, severe intellectual disability, simplification of cerebral gyration, corpus callosum hypoplasia, and dysmorphic facial features, we identified a homozygous splice donor site variant (GenBank: NM_001378.2:c.607+1G>A). We report two additional individuals who have similar neurodevelopmental deficits and craniofacial features and harbor deleterious variants; one individual bears a c.740A>G (p.Tyr247Cys) change in trans with a 374 kb deletion encompassing DYNC1I2, and an unrelated individual harbors the compound-heterozygous variants c.868C>T (p.Gln290
∗ ) and c.740A>G (p.Tyr247Cys). Zebrafish larvae subjected to CRISPR-Cas9 gene disruption or transient suppression of dync1i2a displayed significantly altered craniofacial patterning with concomitant reduction in head size. We monitored cell death and cell cycle progression in dync1i2a zebrafish models and observed significantly increased apoptosis, likely due to prolonged mitosis caused by abnormal spindle morphology, and this finding offers initial insights into the cellular basis of microcephaly. Additionally, complementation studies in zebrafish demonstrate that p.Tyr247Cys attenuates gene function, consistent with protein structural analysis. Our genetic and functional data indicate that DYNC1I2 dysfunction probably causes an autosomal-recessive microcephaly syndrome and highlight further the critical roles of the dynein-1 complex in neurodevelopment., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
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