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1. Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1‐dependent TFEB/TFE3 regulation

Author

Reini E N van der Welle, Rebekah Jobling, Christian Burns, Paolo Sanza, Jan A van der Beek, Alfonso Fasano, Lan Chen, Fried J Zwartkruis, Susan Zwakenberg, Edward F Griffin, Corlinda ten Brink, Tineke Veenendaal, Nalan Liv, Conny M A van Ravenswaaij‐Arts, Henny H Lemmink, Rolph Pfundt, Susan Blaser, Carolina Sepulveda, Andres M Lozano, Grace Yoon, Teresa Santiago‐Sim, Cedric S Asensio, Guy A Caldwell, Kim A Caldwell, David Chitayat, and Judith Klumperman

Subjects
Autophagy, HOPS complex, lysosome‐associated disorder, mTORC1, TFEB/TFE3, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Vacuolar protein sorting 41 (VPS41) is as part of the Homotypic fusion and Protein Sorting (HOPS) complex required for lysosomal fusion events and, independent of HOPS, for regulated secretion. Here, we report three patients with compound heterozygous mutations in VPS41 (VPS41S285P and VPS41R662*;VPS41c.1423‐2A>G and VPS41R662*) displaying neurodegeneration with ataxia and dystonia. Cellular consequences were investigated in patient fibroblasts and VPS41‐depleted HeLa cells. All mutants prevented formation of a functional HOPS complex, causing delayed lysosomal delivery of endocytic and autophagic cargo. By contrast, VPS41S285P enabled regulated secretion. Strikingly, loss of VPS41 function caused a cytosolic redistribution of mTORC1, continuous nuclear localization of Transcription Factor E3 (TFE3), enhanced levels of LC3II, and a reduced autophagic response to nutrient starvation. Phosphorylation of mTORC1 substrates S6K1 and 4EBP1 was not affected. In a C. elegans model of Parkinson’s disease, co‐expression of VPS41S285P/VPS41R662* abolished the neuroprotective function of VPS41 against α‐synuclein aggregates. We conclude that the VPS41 variants specifically abrogate HOPS function, which interferes with the TFEB/TFE3 axis of mTORC1 signaling, and cause a neurodegenerative disease.

Published
2021
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2. A recurrent, de novo pathogenic variant in ARPC4 disrupts actin filament formation and causes microcephaly and speech delay

Author

Dianne Laboy Cintron, Alison M. Muir, Abbey Scott, Marie McDonald, Kristin G. Monaghan, Teresa Santiago-Sim, Ingrid M. Wentzensen, Chiara De Luca, Francesco Brancati, David J. Harris, Cecilia Goueli, Rolf Stottmann, Carlos E. Prada, Marta Biderman Waberski, and Heather C. Mefford

Subjects
actin, microcephaly, ARPC4, developmental delay, de novo, genetic, Genetics, QH426-470
Abstract

Summary: We report seven affected individuals from six families with a recurrent, de novo variant in the ARPC4 gene (c.472C>T [p.Arg158Cys (GenBank: NM_005718.4)]). Core features in affected individuals include microcephaly, mild motor delays, and significant speech impairment. ARPC4 is a core subunit of the actin-related protein (ARP2/3) complex, which catalyzes the formation of F-actin networks. We show that the recurrent ARPC4 missense change is associated with a decreased amount of F-actin in cells from two affected individuals. Taken together, our results implicate heterozygous ARPC4 missense variants as a cause of neurodevelopmental disorders and microcephaly.

Published
2022
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3. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Vincenzo Salpietro, Christine L. Dixon, Hui Guo, Oscar D. Bello, Jana Vandrovcova, Stephanie Efthymiou, Reza Maroofian, Gali Heimer, Lydie Burglen, Stephanie Valence, Erin Torti, Moritz Hacke, Julia Rankin, Huma Tariq, Estelle Colin, Vincent Procaccio, Pasquale Striano, Kshitij Mankad, Andreas Lieb, Sharon Chen, Laura Pisani, Conceicao Bettencourt, Roope Männikkö, Andreea Manole, Alfredo Brusco, Enrico Grosso, Giovanni Battista Ferrero, Judith Armstrong-Moron, Sophie Gueden, Omer Bar-Yosef, Michal Tzadok, Kristin G. Monaghan, Teresa Santiago-Sim, Richard E. Person, Megan T. Cho, Rebecca Willaert, Yongjin Yoo, Jong-Hee Chae, Yingting Quan, Huidan Wu, Tianyun Wang, Raphael A. Bernier, Kun Xia, Alyssa Blesson, Mahim Jain, Mohammad M. Motazacker, Bregje Jaeger, Amy L. Schneider, Katja Boysen, Alison M. Muir, Candace T. Myers, Ralitza H. Gavrilova, Lauren Gunderson, Laura Schultz-Rogers, Eric W. Klee, David Dyment, Matthew Osmond, Mara Parellada, Cloe Llorente, Javier Gonzalez-Peñas, Angel Carracedo, Arie Van Haeringen, Claudia Ruivenkamp, Caroline Nava, Delphine Heron, Rosaria Nardello, Michele Iacomino, Carlo Minetti, Aldo Skabar, Antonella Fabretto, SYNAPS Study Group, Miquel Raspall-Chaure, Michael Chez, Anne Tsai, Emily Fassi, Marwan Shinawi, John N. Constantino, Rita De Zorzi, Sara Fortuna, Fernando Kok, Boris Keren, Dominique Bonneau, Murim Choi, Bruria Benzeev, Federico Zara, Heather C. Mefford, Ingrid E. Scheffer, Jill Clayton-Smith, Alfons Macaya, James E. Rothman, Evan E. Eichler, Dimitri M. Kullmann, and Henry Houlden

Subjects
Science
Abstract

Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca2+ transport and AMPAR currents.”

Published
2019
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4. Heterozygous variants in PRPF8 are associated with neurodevelopmental disorders

Author

Lauren O'Grady, Samantha A. Schrier Vergano, Trevor L. Hoffman, Dean Sarco, Sara Cherny, Emily Bryant, Laura Schultz‐Rogers, Wendy K. Chung, Stephanie Sacharow, Ladonna L. Immken, Susan Holder, Rebecca R. Blackwell, Catherine Buchanan, Roman Yusupov, François Lecoquierre, Anne‐Marie Guerrot, Lance Rodan, Bert B. A. de Vries, Erik Jan Kamsteeg, Fernando Santos Simarro, Maria Palomares‐Bralo, Natasha Brown, Lynn Pais, Alejandro Ferrer, Eric W. Klee, Dusica Babovic‐Vuksanovic, Lindsay Rhodes, Richard Person, Amber Begtrup, Jennifer Keller‐Ramey, Teresa Santiago‐Sim, Rhonda E. Schnur, David A. Sweetser, and Nina B. Gold

Subjects
Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genetics, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Genetics (clinical)
Abstract

Contains fulltext : 282684.pdf (Publisher’s version ) (Closed access) The pre-mRNA-processing factor 8, encoded by PRPF8, is a scaffolding component of a spliceosome complex involved in the removal of introns from mRNA precursors. Previously, heterozygous pathogenic variants in PRPF8 have been associated with autosomal dominant retinitis pigmentosa. More recently, PRPF8 was suggested as a candidate gene for autism spectrum disorder due to the enrichment of sequence variants in this gene in individuals with neurodevelopmental disorders. We report 14 individuals with various forms of neurodevelopmental conditions, found to have heterozygous, predominantly de novo, missense, and loss-of-function variants in PRPF8. These individuals have clinical features that may represent a new neurodevelopmental syndrome.

Published
2022
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5. De novo variants in CNOT9 cause a neurodevelopmental disorder with or without epilepsy

Author

Lydia von Wintzingerode, Bruria Ben-Zeev, Claudia Cesario, Katie M. Chan, Christel Depienne, Orly Elpeleg, Maria Iascone, Whitley V. Kelley, Marie-Cécile Nassogne, Marcello Niceta, Lidia Pezzani, Nils Rahner, Nicole Revencu, Mir Reza Bekheirnia, Teresa Santiago-Sim, Marco Tartaglia, Michelle L. Thompson, Marina Trivisano, Julia Hentschel, Heinrich Sticht, Rami Abou Jamra, and Henry Oppermann

Subjects
Medizin, Genetics (clinical)
Published
2023

6. Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation

Author

David Chitayat, Carolina Sepulveda, Tineke Veenendaal, Grace Yoon, Cedric S. Asensio, Henny H. Lemmink, Nalan Liv, Susan Zwakenberg, Andres M. Lozano, Guy A. Caldwell, Edward F Griffin, Fried J. T. Zwartkruis, Rolph Pfundt, Reini E.N. van der Welle, Judith Klumperman, Corlinda ten Brink, Christian H. Burns, Lan Chen, Rebekah Jobling, Paolo Sanza, Susan Blaser, Teresa Santiago-Sim, Alfonso Fasano, Kim A. Caldwell, Jan van der Beek, Conny M. A. van Ravenswaaij-Arts, and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
0301 basic medicine, Medicine (General), Endocytic cycle, Vesicular Transport Proteins, P70-S6 Kinase 1, mTORC1, Mechanistic Target of Rapamycin Complex 1, QH426-470, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, R5-920, Protein targeting, medicine, Genetics, Autophagy, associated disorder, Animals, Humans, Caenorhabditis elegans, lysosome‐associated disorder, Vacuolar protein sorting, TFEB, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], lysosome&#8208, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Chemistry, Neurodegeneration, Neurodegenerative Diseases, Articles, medicine.disease, Cell biology, HOPS complex, TFE3, Protein Transport, 030104 developmental biology, TFEB/TFE3, Molecular Medicine, Phosphorylation, Genetics, Gene Therapy & Genetic Disease, Lysosomes, 030217 neurology & neurosurgery, Neuroscience, HeLa Cells
Abstract

Vacuolar protein sorting 41 (VPS41) is as part of the Homotypic fusion and Protein Sorting (HOPS) complex required for lysosomal fusion events and, independent of HOPS, for regulated secretion. Here, we report three patients with compound heterozygous mutations in VPS41 (VPS41S285P and VPS41R662 * ; VPS41 c.1423‐2A>G and VPS41R662 *) displaying neurodegeneration with ataxia and dystonia. Cellular consequences were investigated in patient fibroblasts and VPS41‐depleted HeLa cells. All mutants prevented formation of a functional HOPS complex, causing delayed lysosomal delivery of endocytic and autophagic cargo. By contrast, VPS41S285P enabled regulated secretion. Strikingly, loss of VPS41 function caused a cytosolic redistribution of mTORC1, continuous nuclear localization of Transcription Factor E3 (TFE3), enhanced levels of LC3II, and a reduced autophagic response to nutrient starvation. Phosphorylation of mTORC1 substrates S6K1 and 4EBP1 was not affected. In a C. elegans model of Parkinson’s disease, co‐expression of VPS41S285P/VPS41R662 * abolished the neuroprotective function of VPS41 against α‐synuclein aggregates. We conclude that the VPS41 variants specifically abrogate HOPS function, which interferes with the TFEB/TFE3 axis of mTORC1 signaling, and cause a neurodegenerative disease., Compound heterozygous mutations in VPS41 were identified in patients with a neurodegenerative phenotype with dystonia and cerebellar atrophy. VPS41 variants obstruct the HOPS complex, leading to decreased endocytic and autophagy cargo transfer to lysosomes and inhibition of mTORC1 signaling.

Published
2021
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7. Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects

Author

Cyril Goizet, Arthur Sorlin, Antonio Novelli, Christophe Philippe, Mathilde Nizon, Joan M. Stoler, Maria J. Guillen Sacoto, Marielle Alders, Grace Yoon, Binnaz Yalcin, Aurélien Trimouille, Anna R. Duncan, Valerie E. Vancollie, Emanuele Agolini, Lance H. Rodan, Monica H. Wojcik, Christopher J. Lelliott, Saskia M. Maas, Antonio Vitobello, Pankaj B. Agrawal, Ange Line Bruel, Laurence Faivre, Paolo Prontera, Stephan C. Collins, Teresa Santiago-Sim, Casie A. Genetti, Ann Seman, Jiahai Shi, Marieke F. van Dooren, Patricia Ellen Grant, Clinical Genetics, Boston Children's Hospital, Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), FHU TRANSLAD (CHU de Dijon), The Wellcome Trust Sanger Institute [Cambridge], City University of Hong Kong [Hong Kong] (CUHK), Bambino Gesù Children’s Hospital [Rome, Italy], Università degli Studi di Perugia = University of Perugia (UNIPG), GeneDx [Gaithersburg, MD, USA], Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre hospitalier universitaire de Nantes (CHU Nantes), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Amsterdam UMC - Amsterdam University Medical Center, Centre de référence des maladies rares des déficiences intellectuelles de causes rares (CHU Dijon) (CRMR des déficiences intellectuelles de causes rares), The Hospital for sick children [Toronto] (SickKids), Dupuis, Christine, Human Genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, ACS - Pulmonary hypertension & thrombosis, Amsterdam Reproduction & Development (AR&D), Lelliott, Christopher [0000-0001-8087-4530], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Jumonji Domain-Containing Histone Demethylases, [SDV]Life Sciences [q-bio], Developmental Disabilities, Corpus callosum, Hippocampus, Epigenesis, Genetic, Histones, Mice, 0302 clinical medicine, Neurodevelopmental disorder, Polymicrogyria, Global developmental delay, Agenesis of the corpus callosum, Genetics (clinical), Brain, Magnetic Resonance Imaging, [SDV] Life Sciences [q-bio], intellectual disability, Brain size, Female, dysmorphic hippocampi, Signal Transduction, Heterozygote, heterozygous variant, global developmental delay, Biology, Nervous System Malformations, Methylation, 03 medical and health sciences, Seizures, Report, KDM4B, Genetics, medicine, Animals, Humans, neurodevelopmental disorder, Dentate gyrus, Genetic Variation, JMJD2B, medicine.disease, 030104 developmental biology, agenesis of the corpus callosum, Neuroscience, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, Ventriculomegaly
Abstract

International audience; KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b þ/À), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery.

Published
2020
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8. Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Author

Marcello Scala, Saskia B. Wortmann, Namik Kaya, Menno D. Stellingwerff, Angela Pistorio, Emma Glamuzina, Clara D. Karnebeek, Cristina Skrypnyk, Katarzyna Iwanicka‐Pronicka, Dorota Piekutowska‐Abramczuk, Elżbieta Ciara, Frederic Tort, Beth Sheidley, Annapurna Poduri, Parul Jayakar, Anuj Jayakar, Jariya Upadia, Nicolette Walano, Tobias B. Haack, Holger Prokisch, Hesham Aldhalaan, Ehsan G. Karimiani, Yilmaz Yildiz, Ahmet C. Ceylan, Teresa Santiago‐Sim, Amy Dameron, Hui Yang, Mehran B. Toosi, Farah Ashrafzadeh, Javad Akhondian, Shima Imannezhad, Hanieh S. Mirzadeh, Shazia Maqbool, Aisha Farid, Mohamed A. Al‐Muhaizea, Meznah O. Alshwameen, Lama Aldowsari, Maysoon Alsagob, Ashwaq Alyousef, Rawan AlMass, Aljouhra AlHargan, Ali H. Alwadei, Maha M. AlRasheed, Dilek Colak, Hanan Alqudairy, Sameena Khan, Matthew A. Lines, M. Ángeles García Cazorla, Antonia Ribes, Eva Morava, Farah Bibi, Shahzad Haider, Matteo P. Ferla, Jenny C. Taylor, Hessa S. Alsaif, Abdulwahab Firdous, Mais Hashem, Chingiz Shashkin, Kairgali Koneev, Rauan Kaiyrzhanov, Stephanie Efthymiou, Queen Square Genomics, Thomas Schmitt‐Mechelke, Andreas Ziegler, Mahmoud Y. Issa, Hasnaa M. Elbendary, Pasquale Striano, Fowzan S. Alkuraya, Maha S. Zaki, Joseph G. Gleeson, Tahsin Stefan Barakat, Jorgen Bierau, Marjo S. Knaap, Reza Maroofian, Henry Houlden, Pediatric surgery, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Integrative Neurophysiology, Clinical Genetics, ANS - Cellular & Molecular Mechanisms, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, MUMC+: DA KG Lab Centraal Lab (9), and RS: FHML non-thematic output

Subjects
MUTATIONS, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], ASSOCIATION, heart disease, white matter abnormalities, Prognosis, Inosine, Itpa, Itpase, Congenital Microcephaly, Developmental And Epileptic Encephalopathy 35, Heart Disease, White Matter Abnormalities, ITPA, SDG 3 - Good Health and Well-being, Mutation, Genetics, Microcephaly, GROWTH, Humans, Inosine Triphosphate, Epilepsy, Generalized, ITPase, NUCLEOTIDE POOLS, Pyrophosphatases, congenital microcephaly, RETARDATION, developmental and epileptic encephalopathy 35, Genetics (clinical)
Abstract

Contains fulltext : 283128.pdf (Publisher’s version ) (Open Access) Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.

Published
2022
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9. A recurrent, de novo pathogenic variant in ARPC4 disrupts actin filament formation and causes microcephaly and speech delay

Author

David J. Harris, Teresa Santiago Sim, Heather C Mefford, Chiara De Luca, Cecilia Goueli, Alison M. Muir, Kristin G. Monaghan, Carlos E. Prada, Francesco Brancati, Marie T. McDonald, Dianne Laboy Citron, Rolf Stottman, Marta Biderman Waberski, Abbey A. Scott, and Ingrid M. Wentzensen

Subjects
Genetics, Microcephaly, de novo, Protein subunit, QH426-470, Biology, medicine.disease, ARPC4, Protein filament, developmental delay, Neurodevelopmental disorder, Report, Speech delay, medicine, Molecular Medicine, Missense mutation, microcephaly, medicine.symptom, genetic, actin, Gene, Genetics (clinical), Actin
Abstract

Summary We report seven affected individuals from six families with a recurrent, de novo variant in the ARPC4 gene (c.472C>T [p.Arg158Cys (GenBank: NM_005718.4)]). Core features in affected individuals include microcephaly, mild motor delays, and significant speech impairment. ARPC4 is a core subunit of the actin-related protein (ARP2/3) complex, which catalyzes the formation of F-actin networks. We show that the recurrent ARPC4 missense change is associated with a decreased amount of F-actin in cells from two affected individuals. Taken together, our results implicate heterozygous ARPC4 missense variants as a cause of neurodevelopmental disorders and microcephaly., We report a neurodevelopmental disorder with microcephaly in seven affected individuals with the same de novo variant in the ARPC4 gene. The recurrent variant in ARPC4, a subunit of the complex that catalyzes F-actin network formation, is associated with decreased F-actin in cells from affected individuals.

Published
2021

10. Gain-of-function variants in GABRD reveal a novel pathway for neurodevelopmental disorders and epilepsy

Author

Konrad Platzer, Christina Fenger, Ilona Krey, Elena Gardella, Kaja Kristine Selmer, Johannes R. Lemke, Vivian Wan Yu Liao, Holger Lerche, Astrid Bertsche, Mary Chebib, Steffen Syrbe, Philip K. Ahring, Barbro Stadheim, Rohini Coorg, Teresa Santiago-Sim, Mahmoud Koko, Rikke S. Møller, Evan E. Eichler, Katrine M Johannesen, Hannah Davis, Tue Diemer, and Charlotte Peinhardt

Subjects
GABA Plasma Membrane Transport Proteins, SLC6A1, GABRD, Autism Spectrum Disorder, autism, Bioinformatics, Epilepsy, GABA receptor, Seizures, Intellectual disability, medicine, Missense mutation, Humans, Generalized epilepsy, gamma-Aminobutyric Acid, biology, GABAA receptor, business.industry, medicine.disease, Receptors, GABA-A, Autism spectrum disorder, Neurodevelopmental Disorders, Gain of Function Mutation, biology.protein, Autism, epilepsy, Original Article, Epilepsy, Generalized, Neurology (clinical), business
Abstract

A potential link between GABRD encoding the δ subunit of extrasynaptic GABAA receptors and neurodevelopmental disorders has largely been disregarded due to conflicting conclusions from early studies. However, we identified seven heterozygous missense GABRD variants in 10 patients with neurodevelopmental disorders and generalized epilepsy. One variant occurred in two sibs of healthy parents with presumed somatic mosaicism, another segregated with the disease in three affected family members, and the remaining five occurred de novo in sporadic patients. Electrophysiological measurements were used to determine the functional consequence of the seven missense δ subunit variants in receptor combinations of α1β3δ and α4β2δ GABAA receptors. This was accompanied by analysis of electro-clinical phenotypes of the affected individuals. We determined that five of the seven variants caused altered function of the resulting α1β3δ and α4β2δ GABAA receptors. Surprisingly, four of the five variants led to gain-of-function effects whereas one led to a loss-of-function effect. The stark differences between the gain-of-function and loss-of function effects were mirrored by the clinical phenotypes. Six patients with gain-of-function variants shared common phenotypes: neurodevelopmental disorders with generalized epilepsy, behavioral issues, and various degrees of intellectual disability. Six patients with gain-of-function variants shared common phenotypes: neurodevelopmental disorders with behavioral issues, various degrees of intellectual disability, generalized epilepsy with atypical absences and generalized myoclonic and/or bilateral tonic-clonic seizures. The EEG showed qualitative analogies among the different gain-of-function variant carriers consisting of focal slowing in the occipital regions often preceding irregular generalized epileptiform discharges, with frontal predominance. In contrast, the one patient carrying a loss-of-function variant had normal intelligence, no seizure history but has a diagnosis of autism spectrum disorder and suffering from elevated internalizing psychiatric symptoms. We hypothesize that increase in tonic GABA-evoked current levels mediated by δ-containing extrasynaptic GABAA receptors lead to abnormal neurotransmission, which represent a novel mechanism for severe neurodevelopmental disorders. In support of this, the electro-clinical findings for the gain-of-function GABRD variants resemble the phenotypic spectrum reported in patients with missense SLC6A1 (GABA uptake transporter) variants. This also indicates that the phenomenon of extrasynaptic receptor over-activity is observed in a broader range of patients with neurodevelopmental disorders, since SLC6A1 loss-of-function variants also lead to overactive extrasynaptic δ-containing GABAA receptors. These findings have implications when selecting potential treatment options, since a substantial portion of available anti-seizure medication act by enhancing GABAergic function either directly or indirectly, which could exacerbate symptoms in patients with gain-of-function GABRD variants.

Published
2021
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11. Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies

Author

Leah Slattery, Emma L. Baple, Hilde Van Esch, Eyby Leon, Farida Abid, Margaret P. Adam, Bo Yuan, Cecilie F. Rustad, Amy M. Breman, Juanita Neira, Weimin Bi, Weihong Jin, Olivia Wenger, Yaping Yang, Jill A. Rosenfeld, John Dean, Laura Jenkins, Jennifer E. Posey, Chin-To Fong, Christian P. Schaaf, Asbjørg Stray-Pedersen, Lettie E. Rawlins, Teresa Santiago-Sim, Marguerite Pietryga, Linda A. Ramsdell, Sau Wai Cheung, Jullianne Diaz, Davut Pehlivan, Laura Martin, Andrew H. Crosby, Chad A. Shaw, Christine M. Eng, Louanne Hudgins, Pengfei Liu, Dorothy K. Grange, Suneeta Madan-Khetarpal, James R. Lupski, LaDonna Immken, Alison A. Bertuch, Marianne McGuire, Kristian Tveten, Xiaofei Song, Scott E. Hickey, Rui Xiao, Vipulkumar Patel, and Janice L. Smith

Subjects
Male, 0301 basic medicine, Cornelia de Lange Syndrome, Adolescent, Chromosomal Proteins, Non-Histone, STAG2, STAG1, Cell Cycle Proteins, 030105 genetics & heredity, Biology, Polymorphism, Single Nucleotide, Article, Cohort Studies, Genetic Heterogeneity, 03 medical and health sciences, Gene Frequency, INDEL Mutation, Locus heterogeneity, De Lange Syndrome, Proto-Oncogene Proteins, Exome Sequencing, medicine, Humans, Exome, clinical exome sequencing (CES), Allele, Child, Alleles, Genetics (clinical), Exome sequencing, Retrospective Studies, Genetics, Genetic heterogeneity, Nuclear Proteins, Antigens, Nuclear, Atypical cohesinopathies, NIPBL, medicine.disease, Human genetics, 3. Good health, Phenotype, cohesin pathway, 030104 developmental biology, Biological Variation, Population, Child, Preschool, Mutation, Female, Carrier Proteins
Abstract

Purpose: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange Syndrome (CdLS). We aim to delineate mutations in known and candidate cohesinopathy genes from a clinical exome perspective. Methods: We retrospectively studied patients referred for clinical exome sequencing (CES, N=10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization. Results: Pathogenic or likely pathogenic single nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N=5), SMC1A (N=14), SMC3 (N=4), RAD21 (N=2) and HDAC8 (N=8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared to phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N=3), STAG2 (N=5), PDS5A (N=1) and WAPL (N=1), and one inherited SNV in PDS5A. We also identified copy number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS. Conclusion: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

Published
2019
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12. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Vincenzo, Salpietro, Christine L, Dixon, Hui, Guo, Oscar D, Bello, Jana, Vandrovcova, Stephanie, Efthymiou, Reza, Maroofian, Gali, Heimer, Lydie, Burglen, Stephanie, Valence, Erin, Torti, Moritz, Hacke, Julia, Rankin, Huma, Tariq, Estelle, Colin, Vincent, Procaccio, Pasquale, Striano, Kshitij, Mankad, Andreas, Lieb, Sharon, Chen, Laura, Pisani, Conceicao, Bettencourt, Roope, Männikkö, Andreea, Manole, Alfredo, Brusco, Enrico, Grosso, Giovanni Battista, Ferrero, Judith, Armstrong-Moron, Sophie, Gueden, Omer, Bar-Yosef, Michal, Tzadok, Kristin G, Monaghan, Teresa, Santiago-Sim, Richard E, Person, Megan T, Cho, Rebecca, Willaert, Yongjin, Yoo, Jong-Hee, Chae, Yingting, Quan, Huidan, Wu, Tianyun, Wang, Raphael A, Bernier, Kun, Xia, Alyssa, Blesson, Mahim, Jain, Mohammad M, Motazacker, Bregje, Jaeger, Amy L, Schneider, Katja, Boysen, Alison M, Muir, Candace T, Myer, Ralitza H, Gavrilova, Lauren, Gunderson, Laura, Schultz-Roger, Eric W, Klee, David, Dyment, Matthew, Osmond, Mara, Parellada, Cloe, Llorente, Javier, Gonzalez-Peña, Angel, Carracedo, Arie, Van Haeringen, Claudia, Ruivenkamp, Caroline, Nava, Delphine, Heron, Rosaria, Nardello, Michele, Iacomino, Carlo, Minetti, Aldo, Skabar, Antonella, Fabretto, Hanna, Michael G., Bugiardini, Enrico, Hostettler, Isabel, O’Callaghan, Benjamin, Khan, Alaa, Cortese, Andrea, O’Connor, Emer, Yau, Wai Y., Bourinaris, Thoma, Kaiyrzhanov, Rauan, Chelban, Viorica, Madej, Monika, Diana, Maria C., Vari, Maria S., Pedemonte, Marina, Bruno, Claudio, Balagura, Ganna, Scala, Marcello, Fiorillo, Chiara, Nobili, Lino, Malintan, Nancy T., Zanetti, Maria N., Krishnakumar, Shyam S., Lignani, Gabriele, Jepson, James E. C., Broda, Paolo, Baldassari, Simona, Rossi, Pia, Fruscione, Floriana, Madia, Francesca, Traverso, Monica, De-Marco, Patrizia, Pérez-Dueñas, Belen, Munell, Francina, Kriouile, Yamna, El-Khorassani, Mohamed, Karashova, Blagovesta, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Van-Maldergem, Lionel, Nachbauer, Wolfgang, Boesch, Sylvia, Gagliano, Antonella, Amadori, Elisabetta, Goraya, Jatinder S., Sultan, Tipu, Kirmani, Salman, Ibrahim, Shahnaz, Jan, Farida, Mine, Jun, Banu, Selina, Veggiotti, Pierangelo, Zuccotti, Gian V., Ferrari, Michel D., Van Den Maagdenberg, Arn M. J., Verrotti, Alberto, Marseglia, Gian L., Savasta, Salvatore, Soler, Miguel A., Scuderi, Carmela, Borgione, Eugenia, Chimenz, Roberto, Gitto, Eloisa, Dipasquale, Valeria, Sallemi, Alessia, Fusco, Monica, Cuppari, Caterina, Cutrupi, Maria C., Ruggieri, Martino, Cama, Armando, Capra, Valeria, Mencacci, Niccolò E., Boles, Richard, Gupta, Neerja, Kabra, Madhulika, Papacostas, Savva, Zamba-Papanicolaou, Eleni, Dardiotis, Efthymio, Maqbool, Shazia, Rana, Nuzhat, Atawneh, Osama, Lim, Shen Y., Shaikh, Farooq, Koutsis, George, Breza, Marianthi, Coviello, Domenico A., Dauvilliers, Yves A., Alkhawaja, Issam, Alkhawaja, Mariam, Al-Mutairi, Fuad, Stojkovic, Tanya, Ferrucci, Veronica, Zollo, Massimo, Alkuraya, Fowzan S., Kinali, Maria, Sherifa, Hamed, Benrhouma, Hanene, Turki, Ilhem B. Y., Tazir, Meriem, Obeid, Makram, Bakhtadze, Sophia, Saadi, Nebal W., Zaki, Maha S., Triki, Chahnez C., Benfenati, Fabio, Gustincich, Stefano, Kara, Majdi, Belcastro, Vincenzo, Specchio, Nicola, Capovilla, Giuseppe, Karimiani, Ehsan G., Salih, Ahmed M., Okubadejo, Njideka U., Ojo, Oluwadamilola O., Oshinaike, Olajumoke O., Oguntunde, Olapeju, Wahab, Kolawole, Bello, Abiodun H., Abubakar, Sanni, Obiabo, Yahaya, Nwazor, Ernest, Ekenze, Oluchi, Williams, Uduak, Iyagba, Alagoma, Taiwo, Lolade, Komolafe, Morenikeji, Senkevich, Konstantin, Shashkin, Chingiz, Zharkynbekova, Nazira, Koneyev, Kairgali, Manizha, Ganieva, Isrofilov, Maksud, Guliyeva, Ulviyya, Salayev, Kamran, Khachatryan, Samson, Rossi, Salvatore, Silvestri, Gabriella, Haridy, Nourelhoda, Ramenghi, Luca A., Xiromerisiou, Georgia, David, Emanuele, Aguennouz, Mhammed, Fidani, Liana, Spanaki &amp, Cleanthe, Tucci, Arianna, Miquel, Raspall-Chaure, Michael, Chez, Anne, Tsai, Emily, Fassi, Marwan, Shinawi, John N, Constantino, Rita, De Zorzi, Sara, Fortuna, Fernando, Kok, Boris, Keren, Dominique, Bonneau, Murim, Choi, Bruria, Benzeev, Federico, Zara, Heather C, Mefford, Ingrid E, Scheffer, Jill, Clayton-Smith, Alfons, Macaya, James E, Rothman, Evan E, Eichler, Dimitri M, Kullmann, Henry, Houlden, Salvatore Rossi, Gabriella Silvestri (ORCID:0000-0002-1950-1468), Vincenzo, Salpietro, Christine L, Dixon, Hui, Guo, Oscar D, Bello, Jana, Vandrovcova, Stephanie, Efthymiou, Reza, Maroofian, Gali, Heimer, Lydie, Burglen, Stephanie, Valence, Erin, Torti, Moritz, Hacke, Julia, Rankin, Huma, Tariq, Estelle, Colin, Vincent, Procaccio, Pasquale, Striano, Kshitij, Mankad, Andreas, Lieb, Sharon, Chen, Laura, Pisani, Conceicao, Bettencourt, Roope, Männikkö, Andreea, Manole, Alfredo, Brusco, Enrico, Grosso, Giovanni Battista, Ferrero, Judith, Armstrong-Moron, Sophie, Gueden, Omer, Bar-Yosef, Michal, Tzadok, Kristin G, Monaghan, Teresa, Santiago-Sim, Richard E, Person, Megan T, Cho, Rebecca, Willaert, Yongjin, Yoo, Jong-Hee, Chae, Yingting, Quan, Huidan, Wu, Tianyun, Wang, Raphael A, Bernier, Kun, Xia, Alyssa, Blesson, Mahim, Jain, Mohammad M, Motazacker, Bregje, Jaeger, Amy L, Schneider, Katja, Boysen, Alison M, Muir, Candace T, Myer, Ralitza H, Gavrilova, Lauren, Gunderson, Laura, Schultz-Roger, Eric W, Klee, David, Dyment, Matthew, Osmond, Mara, Parellada, Cloe, Llorente, Javier, Gonzalez-Peña, Angel, Carracedo, Arie, Van Haeringen, Claudia, Ruivenkamp, Caroline, Nava, Delphine, Heron, Rosaria, Nardello, Michele, Iacomino, Carlo, Minetti, Aldo, Skabar, Antonella, Fabretto, Hanna, Michael G., Bugiardini, Enrico, Hostettler, Isabel, O’Callaghan, Benjamin, Khan, Alaa, Cortese, Andrea, O’Connor, Emer, Yau, Wai Y., Bourinaris, Thoma, Kaiyrzhanov, Rauan, Chelban, Viorica, Madej, Monika, Diana, Maria C., Vari, Maria S., Pedemonte, Marina, Bruno, Claudio, Balagura, Ganna, Scala, Marcello, Fiorillo, Chiara, Nobili, Lino, Malintan, Nancy T., Zanetti, Maria N., Krishnakumar, Shyam S., Lignani, Gabriele, Jepson, James E. C., Broda, Paolo, Baldassari, Simona, Rossi, Pia, Fruscione, Floriana, Madia, Francesca, Traverso, Monica, De-Marco, Patrizia, Pérez-Dueñas, Belen, Munell, Francina, Kriouile, Yamna, El-Khorassani, Mohamed, Karashova, Blagovesta, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Van-Maldergem, Lionel, Nachbauer, Wolfgang, Boesch, Sylvia, Gagliano, Antonella, Amadori, Elisabetta, Goraya, Jatinder S., Sultan, Tipu, Kirmani, Salman, Ibrahim, Shahnaz, Jan, Farida, Mine, Jun, Banu, Selina, Veggiotti, Pierangelo, Zuccotti, Gian V., Ferrari, Michel D., Van Den Maagdenberg, Arn M. J., Verrotti, Alberto, Marseglia, Gian L., Savasta, Salvatore, Soler, Miguel A., Scuderi, Carmela, Borgione, Eugenia, Chimenz, Roberto, Gitto, Eloisa, Dipasquale, Valeria, Sallemi, Alessia, Fusco, Monica, Cuppari, Caterina, Cutrupi, Maria C., Ruggieri, Martino, Cama, Armando, Capra, Valeria, Mencacci, Niccolò E., Boles, Richard, Gupta, Neerja, Kabra, Madhulika, Papacostas, Savva, Zamba-Papanicolaou, Eleni, Dardiotis, Efthymio, Maqbool, Shazia, Rana, Nuzhat, Atawneh, Osama, Lim, Shen Y., Shaikh, Farooq, Koutsis, George, Breza, Marianthi, Coviello, Domenico A., Dauvilliers, Yves A., Alkhawaja, Issam, Alkhawaja, Mariam, Al-Mutairi, Fuad, Stojkovic, Tanya, Ferrucci, Veronica, Zollo, Massimo, Alkuraya, Fowzan S., Kinali, Maria, Sherifa, Hamed, Benrhouma, Hanene, Turki, Ilhem B. Y., Tazir, Meriem, Obeid, Makram, Bakhtadze, Sophia, Saadi, Nebal W., Zaki, Maha S., Triki, Chahnez C., Benfenati, Fabio, Gustincich, Stefano, Kara, Majdi, Belcastro, Vincenzo, Specchio, Nicola, Capovilla, Giuseppe, Karimiani, Ehsan G., Salih, Ahmed M., Okubadejo, Njideka U., Ojo, Oluwadamilola O., Oshinaike, Olajumoke O., Oguntunde, Olapeju, Wahab, Kolawole, Bello, Abiodun H., Abubakar, Sanni, Obiabo, Yahaya, Nwazor, Ernest, Ekenze, Oluchi, Williams, Uduak, Iyagba, Alagoma, Taiwo, Lolade, Komolafe, Morenikeji, Senkevich, Konstantin, Shashkin, Chingiz, Zharkynbekova, Nazira, Koneyev, Kairgali, Manizha, Ganieva, Isrofilov, Maksud, Guliyeva, Ulviyya, Salayev, Kamran, Khachatryan, Samson, Rossi, Salvatore, Silvestri, Gabriella, Haridy, Nourelhoda, Ramenghi, Luca A., Xiromerisiou, Georgia, David, Emanuele, Aguennouz, Mhammed, Fidani, Liana, Spanaki &amp, Cleanthe, Tucci, Arianna, Miquel, Raspall-Chaure, Michael, Chez, Anne, Tsai, Emily, Fassi, Marwan, Shinawi, John N, Constantino, Rita, De Zorzi, Sara, Fortuna, Fernando, Kok, Boris, Keren, Dominique, Bonneau, Murim, Choi, Bruria, Benzeev, Federico, Zara, Heather C, Mefford, Ingrid E, Scheffer, Jill, Clayton-Smith, Alfons, Macaya, James E, Rothman, Evan E, Eichler, Dimitri M, Kullmann, Henry, Houlden, Salvatore Rossi, and Gabriella Silvestri (ORCID:0000-0002-1950-1468)

Abstract

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.

Published
2019

13. THSD1 (Thrombospondin Type 1 Domain Containing Protein 1) Mutation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage

Author

Ming-Sum Lee, Morgan L. Hennessy, Barbara McDonough, Calum A. MacRae, Christine E. Seidman, Georgene W. Hergenroeder, Xiaoqian Fang, Sarah M. Colosimo, Susan M. Dymecki, Steven R. DePalma, Dong H. Kim, John P. Hagan, Stephen V. Nalbach, Krista J. Qualmann, Kyla J. Patek, Teresa Santiago-Sim, Jonathan G. Seidman, Steven C. Greenway, and Dianna M. Milewicz

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Subarachnoid hemorrhage, Aneurysm, Ruptured, Pathogenesis, Mice, 03 medical and health sciences, Aneurysm, Animal Disease Models, medicine, Animals, Humans, Exome, Genetic Predisposition to Disease, Thrombospondins, Zebrafish, Advanced and Specialized Nursing, Thrombospondin, business.industry, Intracranial Aneurysm, Subarachnoid Hemorrhage, Zebrafish Proteins, medicine.disease, Pedigree, Disease Models, Animal, 030104 developmental biology, Codon, Nonsense, Mutation (genetic algorithm), Neurology (clinical), Cardiology and Cardiovascular Medicine, business
Abstract

Background and Purpose— A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage. This study seeks to define a specific gene whose mutation leads to disease. Methods— More than 500 IA probands and 100 affected families were enrolled and clinically characterized. Whole exome sequencing was performed on a large family, revealing a segregating THSD1 (thrombospondin type 1 domain containing protein 1) mutation. THSD1 was sequenced in other probands and controls. Thsd1 loss-of-function studies in zebrafish and mice were used for in vivo analyses and functional studies performed using an in vitro endothelial cell model. Results— A nonsense mutation in THSD1 was identified that segregated with the 9 affected (3 suffered subarachnoid hemorrhage and 6 had unruptured IA) and was absent in 13 unaffected family members (LOD score 4.69). Targeted THSD1 sequencing identified mutations in 8 of 507 unrelated IA probands, including 3 who had suffered subarachnoid hemorrhage (1.6% [95% confidence interval, 0.8%–3.1%]). These THSD1 mutations/rare variants were highly enriched in our IA patient cohort relative to 89 040 chromosomes in Exome Aggregation Consortium (ExAC) database ( P THSD1 loss impaired endothelial cell focal adhesion to the basement membrane. These adhesion defects could be rescued by expression of wild-type THSD1 but not THSD1 mutants identified in IA patients. Conclusions— This report identifies THSD1 mutations in familial and sporadic IA patients and shows that THSD1 loss results in cerebral bleeding in 2 animal models. This finding provides new insight into IA and subarachnoid hemorrhage pathogenesis and provides new understanding of THSD1 function, which includes endothelial cell to extracellular matrix adhesion.

Published
2016
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14. Exome Sequencing in the Clinical Setting

Author

Magalie S. Leduc, Teresa Santiago-Sim, Mari Tokita, Theodore Chiang, and Yaping Yang

Subjects
Disease gene, Clinical report, medicine.diagnostic_test, Microarray, Genetic heterogeneity, business.industry, Critically ill, Test quality, medicine, Computational biology, business, Exome sequencing, Genetic testing
Abstract

Exome sequencing has become a powerful tool in disease gene discoveries as well as diagnostic evaluations of genetic disorders. Clinical exome sequencing can identify contributing single nucleotide variants (SNVs) and some classes of copy-number variants (CNVs) in approximately 30% of unselected cases. For clinical laboratories that offer exome sequencing, it is important to establish reliable and robust NGS analysis, interpretation and reporting pipelines and procedures in order to ensure test quality, reliability and meet required turn-around-time (TAT). The clinical report for exome sequencing usually includes primary molecular findings related to the patient’s clinical phenotype, as well as opted in medically actionable secondary findings and carrier status for autosomal recessive disorders. Clinical exome sequencing, which was initially regarded as mainly the “last resort” for patients who had previously tested negative for specific genes, karyotype, and/or microarray studies, can now be utilized as an effective first tier test, usually for patients with nonspecific phenotypes or phenotypes suggesting substantial genetic heterogeneity. Additionally, the improvement of the methodologies, analysis tools, and TAT has brought new applications of exome sequencing into the genetic testing of patients, esp. prenatal patients or patients who are at high risk for potentially life-threatening conditions and are therefore considered critically ill.

Published
2017
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15. Biallelic variants in OTUD6B cause an intellectual disability syndrome associated with seizures and dysmorphic features

Author

Christine M. Eng, Thomas Besnard, Ingo Helbig, Holger Lerche, Bülent Kara, H. Hjalgrim, Peter-Michael Kloetzel, Mahmoud Y. Issa, Frédéric Ebstein, Isabelle Hazart, M. Cecilia Ljungberg, Eric LeGuern, Yaping Yang, Jill A. Rosenfeld, Rikke S. Møller, Alicia Braxton, Lindsay C. Burrage, Sarah Weckhuysen, Felix Rosenow, Peter De Jonghe, Johannes R. Lemke, Hiltrud Muhle, Elizabeth Roeder, Mary E. Dickinson, Nina Barišić, Bassam Abu-Libdeh, Federico Zara, Sara Wells, Carla Marini, Jennifer L. Silhavy, Marcus J. Miller, Maha S. Zaki, Bertrand Isidor, Teresa Santiago-Sim, LaDonna Immken, Andrea Lehmann, Joseph G. Gleeson, Karl Martin Klein, Mari Tokita, A Suls, Honey Nagakura, Rudi Balling, Rosa Guerrero-López, Katalin Sterbova, Benjamin Cogné, John R. Seavitt, Pasquale Striano, Maher Shahrour, Stéphanie Baulac, Renzo Guerrini, Sara Johnson, Lydia Teboul, Stéphane Bézieau, Kiely N. James, Katia Hardies, Orly Elpeleg, Dana Craiu, Jason D. Heaney, Sébastien Küry, Yvonne G. Weber, Zaid Afawi, Weimin Bi, Rebecca O. Littlejohn, Patrick May, Jose Serratosa, Magdalena Walkiewicz, Johanna A. Jähn, and EuroEPINOMICS RES Consortium Autos

Subjects
0301 basic medicine, Male, Microcephaly, Proteasome Endopeptidase Complex, Adolescent, Protein degradation, Deubiquitinating enzyme, 03 medical and health sciences, Mice, Ubiquitin, Seizures, Report, Intellectual Disability, Intellectual disability, Endopeptidases, Genetics, medicine, Journal Article, Animals, Humans, Abnormalities, Multiple, Global developmental delay, Child, Genetics (clinical), biology, Syndrome, medicine.disease, Hypotonia, Musculoskeletal Abnormalities, Pedigree, Disease Models, Animal, 030104 developmental biology, Proteasome, Child, Preschool, biology.protein, Female, Human medicine, medicine.symptom, Gene Deletion
Abstract

Ubiquitination is a posttranslational modification that regulates many cellular processes including protein degradation, intracellular trafficking, cell signaling, and protein-protein interactions. Deubiquitinating enzymes (DUBs), which reverse the process of ubiquitination, are important regulators of the ubiquitin system. OTUD6B encodes a member of the ovarian tumor domain(OTU)-containing subfamily of deubiquitinating enzymes. Herein, we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6 independent families with an intellectual disability syndrome associated with seizures and dysmorphic features. In subjects with predicted loss-of-function alleles, additional features include global developmental delay, microcephaly, absent speech, hypotonia, growth retardation with prenatal onset, feeding difficulties, structural brain abnormalities, congenital malformations including congenital heart disease, and musculoskeletal features. Homozygous Otud6b knockout mice were subviable, smaller in size, and had congenital heart defects, consistent with the severity of loss-of-function variants in humans. Analysis of peripheral blood mononuclear cells from an affected subject showed reduced incorporation of 19S subunits into 26S proteasomes, decreased chymotrypsin-like activity, and accumulation of ubiquitin-protein conjugates. Our findings suggest a role for OTUD6B in proteasome function, establish that defective OTUD6B function underlies a multisystemic human disorder, and provide additional evidence for the emerging relationship between the ubiquitin system and human disease.

Published
2017
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16. Introduction to Genetic Processes in Transplantation

Author

Sarah Colosimo, Teresa Santiago-Sim, and David J. Powner

Subjects
Graft Rejection, Genetic Processes, Transplantation, Genotype, Graft rejection, business.industry, Graft Survival, Structure and function, Mutation, Immunology, Humans, Medicine, Genetic Predisposition to Disease, Dosing, Genetic dna, Genetic Phenomena, business, Gene, Immunosuppressive Agents
Abstract

Recent investigations have explored how analyses of genetic DNA from organ donors and recipients may be helpful during organ allocation so as to reduce graft rejection or improve dosing of immunosuppressive medications. This discussion reviews those data and the processes by which genetic coding controls the production of protein that is important in cellular structure and function during donor and recipient care. Changes in gene structure (polymorphisms or mutations) may occur spontaneously or as a result of cell interactions with environmental factors, and may be associated with recognized diseases or, potentially, could reduce or worsen graft rejection.

Published
2012
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17. Regulated internalization of NMDA receptors drives PKD1-mediated suppression of the activity of residual cell-surface NMDA receptors

Author

Xing Hong Jiang, Florian Duclot, Wenkuan Xin, Teresa Santiago-Sim, Mohamed Kabbaj, Shuang Feng, Bradley R. Groveman, Xin Sheng Ding, Michael W. Salter, Wei Wang, Melissa Pflueger, Mohammad K. Ali, Jindong Xu, Xian Min Yu, Haifa Qiao, Xiao Qian Fang, and Shuang Xiu Lin

Subjects
N-Methylaspartate, media_common.quotation_subject, education, Glycine, Down-Regulation, Biology, Models, Biological, Receptors, N-Methyl-D-Aspartate, NMDA receptor internalization, Methoxyhydroxyphenylglycol, Mice, Phosphoserine, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, mental disorders, Animals, Humans, Phosphorylation, Rats, Wistar, Internalization, Receptor, Molecular Biology, Protein Kinase C, Protein kinase C, Ion channel, 030304 developmental biology, media_common, 0303 health sciences, Ligand-gated ion channels, Research, musculoskeletal, neural, and ocular physiology, Cell Membrane, Protein kinase D1, Endocytosis, Cell biology, Enzyme Activation, HEK293 Cells, nervous system, chemistry, Gene Knockdown Techniques, NMDA receptor, Ligand-gated ion channel, The function of remaining (non-internalized) surface receptors, psychological phenomena and processes, 030217 neurology & neurosurgery
Abstract

Background Constitutive and regulated internalization of cell surface proteins has been extensively investigated. The regulated internalization has been characterized as a principal mechanism for removing cell-surface receptors from the plasma membrane, and signaling to downstream targets of receptors. However, so far it is still not known whether the functional properties of remaining (non-internalized) receptor/channels may be regulated by internalization of the same class of receptor/channels. The N-methyl-D-aspartate receptor (NMDAR) is a principal subtype of glutamate-gated ion channel and plays key roles in neuronal plasticity and memory functions. NMDARs are well-known to undergo two types of regulated internalization – homologous and heterologous, which can be induced by high NMDA/glycine and DHPG, respectively. In the present work, we investigated effects of regulated NMDAR internalization on the activity of residual cell-surface NMDARs and neuronal functions. Results In electrophysiological experiments we discovered that the regulated internalization of NMDARs not only reduced the number of cell surface NMDARs but also caused an inhibition of the activity of remaining (non-internalized) surface NMDARs. In biochemical experiments we identified that this functional inhibition of remaining surface NMDARs was mediated by increased serine phosphorylation of surface NMDARs, resulting from the activation of protein kinase D1 (PKD1). Knockdown of PKD1 did not affect NMDAR internalization but prevented the phosphorylation and inhibition of remaining surface NMDARs and NMDAR-mediated synaptic functions. Conclusion These data demonstrate a novel concept that regulated internalization of cell surface NMDARs not only reduces the number of NMDARs on the cell surface but also causes an inhibition of the activity of remaining surface NMDARs through intracellular signaling pathway(s). Furthermore, modulating the activity of remaining surface receptors may be an effective approach for treating receptor internalization-induced changes in neuronal functions of the CNS. Electronic supplementary material The online version of this article (doi:10.1186/s13041-015-0167-1) contains supplementary material, which is available to authorized users.

Published
2015
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18. Abstract 110: Thrombospondin Type-1 Domain-Containing Protein 1 (THSD1), an Intracranial Aneurysm Susceptibility Gene, Mediates Cell Adhesion in Human Umbilical Vein Endothelial Cells

Author

Xiaoqian Fang, Dong H Kim, and Teresa Santiago-Sim

Subjects
Advanced and Specialized Nursing, Neurology (clinical), Cardiology and Cardiovascular Medicine
Abstract

Introduction: An intracranial aneurysm (IA) is a weak spot in cerebral blood vessel wall that can lead to its abnormal bulging. Previously, we reported that mutations in THSD1 , encoding thrombospondin type-1 domain-containing protein 1, are associated with IA in a subset of patients. THSD1 is a transmembrane molecule with a thrombospondin type-1 repeat (TSR). Proteins with TSR domain have been implicated in a variety of processes including regulation of matrix organization, cell adhesion and migration. We have shown that in mouse brain Thsd1 is expressed in endothelial cells. Hypothesis: THSD1 plays an important role in maintaining the integrity of the endothelium by promoting adhesion of endothelial cells to the underlying basement membrane. Methods: Human umbilical vein endothelial cells are used to investigate the role of THSD1 in vitro . THSD1 expression was knocked-down by RNA interference. Cell adhesion assay was done on collagen I-coated plates and focal adhesion formation was visualized using immunofluorescence by paxillin and phosphorylated focal adhesion kinase (pFAK) staining. THSD1 re-expression is accomplished by transfection with a pCR3.1-THSD1-encoding plasmid. Results: Knockdown of THSD1 caused striking change in cell morphology and size. Compared to control siRNA-treated cells that exhibited typical cobblestone morphology, THSD1 knockdown cells were narrow and elongated, and were significantly smaller ( p p p p Conclusions: Our studies provide evidence for a role of THSD1 and THSD1 mutations in endothelial cell adhesion and suggest a possible mechanism underlying THSD1 -mediated aneurysm disease.

Published
2015
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19. Use of Exome Sequencing for Infants in Intensive Care Units

Author

Weimin He, Christian P. Schaaf, Mari Tokita, James R. Lupski, Anirudh Saronwala, Jing Zhang, Carlos A. Bacino, Yaping Yang, Vernon R. Sutton, Magalie S. Leduc, Seema R. Lalani, Swetha Narayanan, Hadley Stevens Smith, Chad A. Shaw, Brendan Lee, Linyan Meng, Christine M. Eng, Rui Xiao, Lorraine Potocki, Hongzheng Dai, Teresa Santiago-Sim, Alicia Braxton, Donna M. Muzny, Richard A. Gibbs, Chester W. Brown, Marcus J. Miller, Laurie Robak, Fan Xia, Xiaoyan Ge, Daryl A. Scott, Theodore Chiang, Mohan Pammi, Jianhong Hu, Sharon E. Plon, Fernando Scaglia, Patricia A. Ward, Michael F. Wangler, Weimin Bi, Chunjing Qu, Arthur L. Beaudet, Avinash V. Dharmadhikari, Andrew R. Ghazi, Mahshid S. Azamian, Pilar L. Magoulas, Xia Wang, Magdalena Walkiewicz, Francesco Vetrini, Pengfei Liu, Neil A. Hanchard, Brett H. Graham, John W. Belmont, Lindsay C. Burrage, William J. Craigen, and Bret L. Bostwick

Subjects
Adult, 0301 basic medicine, Proband, Pediatrics, medicine.medical_specialty, Pathology, Critical Care, Genetic counseling, Genetic Counseling, Intensive Care Units, Pediatric, Article, law.invention, 03 medical and health sciences, law, Intensive care, Exome Sequencing, Reaction Time, medicine, Humans, Exome, Exome sequencing, Retrospective Studies, Pediatric intensive care unit, business.industry, Genetic Diseases, Inborn, Infant, Newborn, Disease Management, Infant, Retrospective cohort study, Length of Stay, Texas, Intensive care unit, Intensive Care Units, 030104 developmental biology, Infant Care, Pediatrics, Perinatology and Child Health, business
Abstract

Importance While congenital malformations and genetic diseases are a leading cause of early infant death, to our knowledge, the contribution of single-gene disorders in this group is undetermined. Objective To determine the diagnostic yield and use of clinical exome sequencing in critically ill infants. Design, Setting, and Participants Clinical exome sequencing was performed for 278 unrelated infants within the first 100 days of life who were admitted to Texas Children’s Hospital in Houston, Texas, during a 5-year period between December 2011 and January 2017. Exome sequencing types included proband exome, trio exome, and critical trio exome, a rapid genomic assay for seriously ill infants. Main Outcomes and Measures Indications for testing, diagnostic yield of clinical exome sequencing, turnaround time, molecular findings, patient age at diagnosis, and effect on medical management among a group of critically ill infants who were suspected to have genetic disorders. Results The mean (SEM) age for infants participating in the study was 28.5 (1.7) days; of these, the mean (SEM) age was 29.0 (2.2) days for infants undergoing proband exome sequencing, 31.5 (3.9) days for trio exome, and 22.7 (3.9) days for critical trio exome. Clinical indications for exome sequencing included a range of medical concerns. Overall, a molecular diagnosis was achieved in 102 infants (36.7%) by clinical exome sequencing, with relatively low yield for cardiovascular abnormalities. The diagnosis affected medical management for 53 infants (52.0%) and had a substantial effect on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome sequencing revealed a molecular diagnosis in 32 of 63 infants (50.8%) at a mean (SEM) of 33.1 (5.6) days of life with a mean (SEM) turnaround time of 13.0 (0.4) days. Clinical care was altered by the diagnosis in 23 of 32 patients (71.9%). The diagnostic yield, patient age at diagnosis, and medical effect in the group that underwent critical trio exome sequencing were significantly different compared with the group who underwent regular exome testing. For deceased infants (n = 81), genetic disorders were molecularly diagnosed in 39 (48.1%) by exome sequencing, with implications for recurrence risk counseling. Conclusions and Relevance Exome sequencing is a powerful tool for the diagnostic evaluation of critically ill infants with suspected monogenic disorders in the neonatal and pediatric intensive care units and its use has a notable effect on clinical decision making.

Published
2017
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21. Contributors

Author

Bizhan Aarabi, Rick Abbott, Saleem I. Abdulrauf, Frank L. Acosta, John R. Adler, Nzhde Agazaryan, Manish Aghi, Edward S. Ahn, Ali Alaraj, Gregory W. Albert, Leland Albright, Felipe C. Albuquerque, Tord D. Alden, Michael J. Alexander, Andrei V. Alexandrov, Ossama Al-Mefty, Ron L. Alterman, Lázaro Álvarez, Nduka M. Amankulor, Peter S. Amenta, Christopher P. Ames, Sepideh Amin-Hanjani, Mario Ammirati, Carryn Anderson, Richard C.E. Anderson, William S. Anderson, Peter D. Angevine, Hiba Arif, Jeffrey E. Arle, Rocco Armonda, Paul M. Arnold, Kaveh Asadi-Moghaddam, Ferhan A. Asghar, William W. Ashley, Sabri Aydin, Nafi Aygun, Joachim M. Baehring, Jacob H. Bagley, Diaa Bahgat, Julian E. Bailes, Jonathon R. Ball, Gordon H. Baltuch, Nicholas C. Bambakidis, Scott C. Baraban, Igor J. Barani, Nicholas M. Barbaro, Frederick G. Barker, Gene H. Barnett, Stanley L. Barnwell, Constance M. Barone, Daniel L. Barrow, Fabrice Bartolomei, Juan Bartolomei, Tracy T. Batchelor, H. Hunt Batjer, Andrew M. Bauer, Joel A. Bauman, Thomas K. Baumann, James E. Baumgartner, John Bayouth, Andrew Beaumont, Joshua B. Bederson, Rudolf Beisse, Randy S. Bell, Allan Belzberg, Alim Louis Benabid, Eduardo E. Benarroch, Abdelhamid Benazzouz, Bernard R. Bendok, Edward C. Benzel, Alejandro Berenstein, Mitchel S. Berger, Marvin Bergsneider, Helmut Bertalanffy, Tarun Bhalla, Dani S. Bidros, José Biller, Mark H. Bilsky, Devin K. Binder, William Bingaman, Rolfe Birch, Allen T. Bishop, Peter M. Black, Jeffrey P. Blount, Peter C. Blumbergs, Leif-Erik Bohman, Zackary E. Boomsaad, Frederick A. Boop, Pascal Bou-Haidar, Daniel R. Boué, Blaise F.D. Bourgeois, Robin M. Bowman, Oliver Bozinov, Helen M. Bramlett, Henry Brem, Steven Brem, Gavin W. Britz, Douglas L. Brockmeyer, David J. Brooks, Samuel R. Browd, Paul D. Brown, Robert D. Brown, Jeffrey N. Bruce, Janice E. Brunstrom-Hernandez, John Buatti, M. Ross Bullock, Kim J. Burchiel, Peter C. Burger, Marc R. Bussière, Mohamad Bydon, Richard W. Byrne, Maria Elisa Calcagnotto, Victoria A. Campbell, William Campbell, George M. Cannon, Louis P. Caragine, Benjamin S. Carson, Gregory D. Cascino, Ethan Cascio, Frédéric Castinetti, C. Michael Cawley, Justin S. Cetas, Stéphan Chabardès, Edward F. Chang, Eric C. Chang, Eric L. Chang, Steven D. Chang, Steven W. Chang, Susan M. Chang, Kevin Chao, Paul H. Chapman, Fady T. Charbel, Patrick Chauvel, Grace Chen, Boyle C. Cheng, Joseph S. Cheng, Joshua J. Chern, E. Antonio Chiocca, Ondrej Choutka, Shakeel A. Chowdhry, Cindy W. Christian, Kathy Chuang, Jan Claassen, Richard E. Clatterbuck, Elizabeth B. Claus, Daniel R. Cleary, Robert J. Coffey, Alan R. Cohen, Andrew J. Cole, E. Sander Connolly, Patrick J. Connolly, Anne G. Copay, Jeroen R. Coppens, James J. Corbett, Daniel M. Corcos, Domagoj Coric, Garth Rees Cosgrove, William T. Couldwell, Stirling Craig, Neil R. Crawford, Peter B. Crino, R. Webster Crowley, Bradford A. Curt, Marek Czosnyka, Zofia Czosnyka, Vladimir Y. Dadashev, Andrew T. Dailey, Deepa Danan, Shabbar F. Danish, Shervin R. Dashti, Carlos A. David, David J. David, Arthur L. Day, Antonio A.F. De Salles, Amir R. Dehdashti, Oscar H. Del Brutto, Johnny B. Delashaw, Bradley Delman, Mahlon R. DeLong, Franco DeMonte, Sanjay S. Dhall, Mark S. Dias, Curtis A. Dickman, W. Dalton Dietrich, Michael L. DiLuna, Francesco Di Meco, Peter Dirks, C. Edward Dixon, Jacob A. Donoghue, Ian G. Dorward, Amish H. Doshi, James Drake, Dan Drzymalski, Rose Du, Andrew Ducruet, Ann-Christine Duhaime, Aaron S. Dumont, Christopher D. Duntsch, Joshua R. Dusick, Suzan Dyve, James Eberwine, Paula Eboli, Robert D. Ecker, Richard J. Edwards, Marc E. Eichler, Doortje C. Engel, Nancy E. Epstein, Matthew G. Ewend, Hamad Farhat, Christopher J. Farrell, Michael G. Fehlings, Iman Feiz-Erfan, Neil A. Feldstein, Richard G. Fessler, Juan J. Figueroa, Aaron G. Filler, J. Max Findlay, Michael A. Finn, David J. Fiorella, James L. Fisher, Robert S. Fisher, Eugene S. Flamm, James D. Fleck, Kelly D. Flemming, John C. Flickinger, Laura Flores-Sarnat, Kenneth A. Follett, Kelly D. Foote, Daryl R. Fourney, Valerie Fraix, James L. Frazier, Itzhak Fried, Allan H. Friedman, William A. Friedman, Gerhard M. Friehs, Donald E. Fry, Gregory N. Fuller, Hector H. Garcia, Paul A. Gardner, Mark Garrett, Hugh Garton, Cormac G. Gavin, Alisa D. Gean, Thomas A. Gennarelli, Venelin Gerganov, Anand V. Germanwala, Massimo Gerosa, Elizabeth R. Gerstner, Peter C. Gerszten, Saadi Ghatan, Samer Ghostine, Steven Giannotta, Paul R. Gigante, Frank Gilliam, Holly Gilmer-Hill, Albert Gjedde, Roberta P. Glick, Ziya L. Gokaslan, Yakov Gologorsky, Kiarash Golshani, Nestor R. Gonzalez, James Tait Goodrich, Tessa Gordon, Alessandra A. Gorgulho, Liliana C. Goumnerova, M. Sean Grady, Jordan Grafman, Sylvie Grand, Gerald A. Grant, Gregory P. Graziano, Benjamin Greenberg, James Guest, Abhijit Guha, Murat Günel, Gaurav Gupta, Nalin Gupta, Jorge Guridi, Barton L. Guthrie, Georges F. Haddad, Michael M. Haglund, Regis W. Haid, Stephen J. Haines, Clement Hamani, Bronwyn E. Hamilton, D. Kojo Hamilton, Todd C. Hankinson, Leo T. Happel, Ihtsham Ul Haq, Raqeeb Haque, Robert E. Harbaugh, Ciara D. Harraher, Leo Harris, James S. Harrop, Wael Hassaneen, Cynthia Hawkins, Gregory W.J. Hawryluk, Neal G. Haynes, Robert F. Heary, Amy B. Heimberger, Mary M. Heinricher, Thomas M. Hemmen, Jaimie M. Henderson, Roberto C. Heros, Karl Herrup, Shawn L. Hervey-Jumper, Gregory G. Heuer, Lawrence J. Hirsch, Robert Hirschl, Brian L. Hoh, Daniel J. Hoh, Eric C. Holland, Paul E. Holtzheimer, L. Nelson Hopkins, Philip J. Horner, David A. Hovda, Matthew A. Howard, Patrick Hsieh, Yin C. Hu, Sherwin E. Hua, Jason H. Huang, Judy Huang, Samuel A. Hughes, Thierry A.G.M. Huisman, Matthew A. Hunt, R. John Hurlbert, Robert W. Hurst, Anita Huttner, Steven W. Hwang, Ioannis U. Isaias, Bermans J. Iskandar, Arun Jacob, Kurt A. Jaeckle, Jay Jagannathan, Regina I. Jakacki, George I. Jallo, John A. Jane, Ryan Janicki, Damir Janigro, N u Owase Jeelani, Kurt A. Jellinger, Arthur L. Jenkins, Sarah Jernigan, David F. Jimenez, Conrad E. Johanson, J. Patrick Johnson, Matthew D. Johnson, G. Alexander Jones, Rajni K. Jutla, Koijan Singh Kainth, Michael G. Kaiser, U. Kumar Kakarla, Iain H. Kalfas, Aleksandrs Uldis Kalnins, Hideyuki Kano, Yucel Kanpolat, Adam S. Kanter, Reza J. Karimi, Amin B. Kassam, Bruce A. Kaufman, Christian B. Kaufman, Hiroto Kawasaki, Brian C. Kelley, Christopher P. Kellner, Nicole C. Keong, John R.W. Kestle, Alexander A. Khalessi, Nadia Khan, Vini G. Khurana, Daniel H. Kim, Dong Gyu Kim, Dong H. Kim, Jong Hyun Kim, Louis J. Kim, Paul K. Kim, Thomas Aquinas Kim, Won Kim, James A.J. King, Ryan S. Kitagawa, Neil D. Kitchen, Paul Klimo, David G. Kline, Kazutaka Kobayashi, Patrick M. Kochanek, Douglas Kondziolka, Paul N. Kongkham, Tyler R. Koski, Thomas Kosztowski, Paul Krack, Joachim K. Krauss, Michael A. Kraut, Niklaus Krayenbühl, Thomas Kretschmer, Ajit Krishnaney, Charles Kuntz, Jeffrey V. Kuo, Brian K. Kwon, Nadia N. Issa Laack, Shivanand P. Lad, Alim M. Ladha, Amos K. Ladouceur, Arthur M. Lam, Frederick F. Lang, Giuseppe Lanzino, Sean D. Lavine, Edward R. Laws, Michael T. Lawton, Adrian W. Laxton, Tuong H. Le, Jean François LeBas, Brett D. Lebed, Richard L. Lebow, Amy Lee, Ian Lee, Seon-Kyu Lee, Emily Lehmann, James W. Leiphart, Gregory P. Lekovic, Frederick A. Lenz, Jeffrey R. Leonard, Peter D. LeRoux, Marc Lévêque, Allan D. Levi, Elad I. Levy, Linda M. Liau, Jason Liauw, Roger Lichtenbaum, Terry Lichtor, David D. Limbrick, Hester Lingsma, Michael J. Link, Mark E. Linskey, Brian Litt, Zachary N. Litvack, James K.C. Liu, Kenneth C. Liu, Jay S. Loeffler, Christopher M. Loftus, Russell R. Lonser, Angeliki Louvi, Andres M. Lozano, Daniel C. Lu, Rimas V. Lukas, L. Dade Lunsford, Neal Luther, Pedro Lylyk, Andrew I.R. Maas, R. Loch Macdonald, Andre Machado, Raul Macias, Robert J. Maciunas, Brian N. Maddux, Pierre Magistretti, Martijn J.A. Malessy, Neil R. Malhotra, Donald A. Malone, Adam N. Mamelak, Christopher E. Mandigo, Francesco T. Mangano, Allen H. Maniker, Geoffrey T. Manley, Daniel Marchac, Anthony Marmarou, Joseph C. Maroon, Lawrence F. Marshall, Neil A. Martin, Timothy J. Martin, Alexander M. Mason, Marlon S. Mathews, Helen S. Mayberg, James P. McAllister, J. Gordon McComb, Paul C. McCormick, Ian E. McCutcheon, Michael W. McDermott, Cameron G. McDougall, Matthew McGehee, Cameron C. McIntyre, Guy M. McKhann, M. Sean McKisic, David F. Meaney, Minesh P. Mehta, Vivek Mehta, William P. Melega, Arnold H. Menezes, Patrick Mertens, Fredric B. Meyer, Scott A. Meyer, Philip M. Meyers, Costas Michaelides, Karine Michaud, Rajiv Midha, Vincent J. Miele, Jonathan Miller, Matthew L. Miller, Neil R. Miller, John Mitrofanis, Kevin Y. Miyashiro, J. Mocco, Michael T. Modic, Parham Moftakhar, Avinash Mohan, Stephen J. Monteith, Jacques J. Morcos, Michael Morgan, David E. Morris, S. David Moss, J. Paul Muizelaar, Karim Mukhida, Praveen V. Mummaneni, Gregory J.A. Murad, Karin Muraszko, Antônio C.M. Mussi, Imad Najm, Peter Nakaji, Sandra Narayanan, David W. Newell, M. Kelly Nicholas, Yasunari Niimi, Shahid M. Nimjee, Ajay Niranjan, Richard B. North, Josef Novotny, Turo Nurmikko, Samuel E. Nutt, W. Jerry Oakes, José A. Obeso, Alfred T. Ogden, Lissa Ogieglo, Christopher S. Ogilvy, David O. Okonkwo, Michael S. Okun, Edward H. Oldfield, Alessandro Olivi, Stephen E. Olvey, David Omahen, Brent O'Neill, Rod J. Oskouian, Robert Owen, Koray Özduman, Ali Kemal Ozturk, M. Necmettin Pamir, Dachling Pang, Jamie Pardini, Andrew D. Parent, T.S. Park, Michael D. Partington, Aman B. Patel, Parag G. Patil, Nicola Pavese, Richard D. Penn, Noel I. Perin, John A. Persing, Erika A. Petersen, Anthony L. Petraglia, Brigitte Piallat, Joseph H. Piatt, John D. Pickard, Joseph M. Piepmeier, Webster H. Pilcher, José Pineda, Joseph D. Pinter, Mary L. Pisculli, Thomas Pittman, Ian F. Pollack, Pierre Pollak, Bruce E. Pollock, Francisco A. Ponce, Alyx B. Porter, Randall W. Porter, Kalmon D. Post, Alexander K. Powers, Mark R. Proctor, Robert W. Prost, Jeffrey Pugh, Alfredo Quiñones-Hinojosa, Corey Raffel, Sharad Rajpal, Leonardo Rangel-Castilla, Ganesh Rao, Ahmed Raslan, Peter A. Rasmussen, Dibyendu K. Ray, Shaan M. Raza, Davis L. Reames, Chandan G. Reddy, Andy J. Redmond, Jean Régis, Peter L. Reilly, Dominique Renier, Daniel K. Resnick, Renee Reynolds, Ali R. Rezai, Laurence D. Rhines, Albert L. Rhoton, Teresa Ribalta, R. Mark Richardson, Daniele Rigamonti, Gregory J. Riggins, Jay Riva-Cambrin, Paolo Rizzo, David W. Roberts, Claudia Robertson, Lawrence Robinson, Shenandoah Robinson, Pierre-Hugues Roche, Mark A. Rockoff, Gerald E. Rodts, Pantaleo Romanelli, Mark L. Rosenblum, Joshua M. Rosenow, Michael K. Rosner, Eric S. Rovner, Christina L. Runge-Samuelson, Stephen M. Russell, James T. Rutka, Oren Sagher, Eric G. St. Clair, Madjid Samii, Prakash Sampath, Srinath Samudrala, Nader Sanai, Robert A. Sanford, Paul Santiago, Teresa Santiago-Sim, Harvey B. Sarnat, Raymond Sawaya, W. Michael Scheld, Wouter I. Shirzadi, Nicholas D. Schiff, Clemens M. Schirmer, David Schlesinger, Meic H. Schmidt, Joost W. Schouten, Johannes Schramm, Thomas C. Schuler, James M. Schuster, Theodore H. Schwartz, Judith A. Schwartzbaum, Patrick M. Schweder, R. Michael Scott, Eric Seigneuret, Nathan R. Selden, Warren R. Selman, Christopher I. Shaffrey, Manish N. Shah, Kiarash Shahlaie, William R. Shapiro, Deepak Sharma, Jason P. Sheehan, Jonas M. Sheehan, Arun K. Sherma, James M. Shiflett, Helen A. Shih, Jay L. Shils, Alexander Y. Shin, Ali Shirzadi, Adnan H. Siddiqui, Marc Sindou, Konstantin V. Slavin, Edward R. Smith, Justin S. Smith, Yoland Smith, Matthew D. Smyth, Penny K. Sneed, Brian J. Snyder, Kenneth V. Snyder, Robert A. Solomon, Volker K.H. Sonntag, Leif Sørensen, Sulpicio G. Soriano, Mark M. Souweidane, Julian Spears, David Spencer, Dennis D. Spencer, Robert F. Spetzler, Robert J. Spinner, Brett R. Stacey, William C. Stacey, Robert M. Starke, Philip A. Starr, Gary K. Steinberg, Frederick L. Stephens, Barney J. Stern, Charles B. Stevenson, Eric Stiner, Scellig Stone, Nicole L. Stroud, Robert Morgan Stuart, Brian R. Subach, Patrick A. Sugrue, Dima Suki, Wale A.R. Sulaiman, Daniel L. Surdell, William W. Sutherling, Leslie N. Sutton, Omar N. Syed, Michele Tagliati, Yasushi Takagi, Rafael J. Tamargo, Caroline C. Tan, Nitin Tandon, Marcos Tatagiba, Michael D. Taylor, Steven A. Telian, Charles Teo, Jeffrey M. Tessier, Khoi D. Than, Kamal Thapar, Nicholas Theodore, B. Gregory Thompson, Robert Tiel, Tarik Tihan, Ann Tilton, Shelly D. Timmons, Maria Toledo, Tadanori Tomita, Nestor D. Tomycz, Napoleon Torres, Charles P. Toussaint, Bruce D. Trapp, Vincent C. Traynelis, R. Shane Tubbs, Luis M. Tumialán, Allan R. Tunkel, Atsushi Umemura, Alexander R. Vaccaro, Koen van Besien, Jerrold L. Vitek, Kenneth P. Vives, Timothy W. Vogel, Michael A. Vogelbaum, Dennis G. Vollmer, Gretchen K. Von Allmen, Kajetan L. von Eckardstein, P. Ashley Wackym, Mark Wainwright, Ben Waldau, Marion L. Walker, M. Christopher Wallace, Brian Walsh, Huan Wang, Michael Y. Wang, Vincent Y. Wang, Ronald E. Warnick, Sharon Webb, Ralf Weigel, Robert J. Weil, Jon D. Weingart, Bryce Weir, Martin Weiss, Nirit Weiss, William C. Welch, John C. Wellons, Hung Tzu Wen, Christian Wess, G. Alexander West, Nicholas M. Wetjen, Robert G. Whitmore, Louis A. Whitworth, Thomas Wichmann, Joseph L. Wiemels, Eelco F.M. Wijdicks, Adam C. Wilberger, Jack Wilberger, David M. Wildrick, Jason Wilson, Christopher J. Winfree, H. Richard Winn, Christopher Wolfla, Eric T. Wong, Peter J. Wormald, Margaret Wrensch, Neill M. Wright, Zachary Wright, David Yam, Shinya Yamada, Yoshiya Yamada, Isaac Yang, Victor X.D. Yang, Tom Yao, Chun-Po Yen, H. Kwang Yeoh, Yasuhiro Yonekawa, Alice Yoo, David M. Yousem, Eric C. Yuen, Joseph M. Zabramski, Andrew C. Zacest, J. Christopher Zacko, Gabriel Zada, Ross Zafonte, Eric L. Zager, Hasan A. Zaidi, Hekmat Zarzour, Vasilios A. Zerris, Justin A. Zivin, John G. Zovickian, Alexander Y. Zubkov, and Marike Zwienenberg-Lee

Published
2011
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22. Sequencing of TGF-β pathway genes in familial cases of intracranial aneurysm

Author

Sumy Mathew-Joseph, Hariyadarshi Pannu, Christine E. Seidman, Dianna M. Milewicz, Jon G. Seidman, Dong H. Kim, and Teresa Santiago-Sim

Subjects
Male, Receptor, Transforming Growth Factor-beta Type I, Single-nucleotide polymorphism, Receptors, Cell Surface, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Article, Pathogenesis, Antigens, CD, Transforming Growth Factor beta, Medicine, Humans, Allele, Allele frequency, Gene, Alleles, Aged, DNA Primers, Advanced and Specialized Nursing, Genetics, biology, business.industry, Endoglin, Receptor, Transforming Growth Factor-beta Type II, Family aggregation, Intracranial Aneurysm, Transforming growth factor beta, DNA, Middle Aged, Pedigree, Stroke, Immunology, biology.protein, Female, Proteoglycans, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Activin Receptors, Type I, Receptors, Transforming Growth Factor beta, Signal Transduction
Abstract

Background and Purpose— Familial aggregation of intracranial aneurysms (IA) strongly suggests a genetic contribution to pathogenesis. However, genetic risk factors have yet to be defined. For families affected by aortic aneurysms, specific gene variants have been identified, many affecting the receptors to transforming growth factor-beta (TGF-β). In recent work, we found that aortic and intracranial aneurysms may share a common genetic basis in some families. We hypothesized, therefore, that mutations in TGF-β receptors might also play a role in IA pathogenesis. Methods— To identify genetic variants in TGF-β and its receptors, TGFB1 , TGFBR1 , TGFBR2 , ACVR1 , TGFBR3 , and ENG were directly sequenced in 44 unrelated patients with familial IA. Novel variants were confirmed by restriction digestion analyses, and allele frequencies were analyzed in cases versus individuals without known intracranial disease. Similarly, allele frequencies of a subset of known SNPs in each gene were also analyzed for association with IA. Results— No mutations were found in TGFB1 , TGFBR1 , TGFBR2 , or ACVR1 . Novel variants identified in ENG (p.A60E) and TGFBR3 (p.W112R) were not detected in at least 892 reference chromosomes. ENG p.A60E showed significant association with familial IA in case-control studies ( P =0.0080). No association with IA could be found for any of the known polymorphisms tested. Conclusions— Mutations in TGF-β receptor genes are not a major cause of IA. However, we identified rare variants in ENG and TGFBR3 that may be important for IA pathogenesis in a subset of families.

Published
2009

23. Genomewide Linkage in a Large Caucasian Family Maps a New Locus for Intracranial Aneurysms to Chromosome 13q

Author

Steven R. DePalma, Jonathan G. Seidman, Dong H. Kim, Christine E. Seidman, Teresa Santiago-Sim, Barbara McDonough, and Kevin L. Ju

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Genetic Linkage, Locus (genetics), Disease, Polymorphism, Single Nucleotide, White People, Genetic linkage, medicine, Humans, Genetic Predisposition to Disease, Gene, Aged, Advanced and Specialized Nursing, Genetics, Chromosomes, Human, Pair 13, business.industry, Family aggregation, Chromosome, Intracranial Aneurysm, Middle Aged, Pedigree, Genetic marker, Susceptibility locus, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business
Abstract

Background and Purpose— Familial aggregation of intracranial aneurysms (IAs) indicates a genetic role in the pathogenesis of this disease. Despite a number of reported susceptibility loci, no disease-causing gene variants have been identified. In this study, we used a parametric genomewide linkage approach to search for new IA susceptibility loci in a large Caucasian family. Methods— The affection status of family members with clinical signs of IA was confirmed with medical records or through radiological or surgical examinations. All other relatives were screened using MR angiography. Genomewide linkage analysis was performed on 35 subjects using approximately 250 000 single nucleotide polymorphic markers. Results— Ten individuals had an IA. Linkage analysis using a dominant model showed significant linkage to a 7-cM region in 13q14.12–21.1 with a maximum logarithm of odds score of 4.56. Conclusion— A new IA susceptibility locus on 13q was identified, adding to the number of IA loci already reported. Given that no coding variants have been reported to date, it is possible that alternative genetic variants such as regulatory elements or copy number variation are important in IA pathogenesis. We are proceeding with attempts to identify such variants in our locus.

Published
2009
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24. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Author

Antonio Vitobello, Christel Depienne, Kelly Radtke, Bruria Ben-Zeev, Vaidutis Kučinskas, Hirofumi Kashii, Leslie Granger, Florence Demurger, Adi Vaknin-Dembinsky, Androu Waheeb, Takeshi Mizuguchi, Lip H. Moey, Urania Kotzaeridou, Frédérique Béna, Fernando Kok, Timothy Blake Palculict, Yasmin Hamzavi Abedi, Satoko Miyatake, Anne-Sophie Denommé-Pichon, Linda Manwaring, Laura Elena Orec, Laurens Wiel, Han G. Brunner, Sylvie Odent, Eric Vilain, Linh Tran, Simon E. Fisher, Emmanuèlle C. Délot, Vidya Krishnamurthy, Rebecca C. Spillmann, Hilary Coon, Shelagh Joss, Hui B. Chew, Matias Wagner, David A. Dyment, Kirsty McWalter, Michael W. Parker, Adam Jackson, Margje Sinnema, Pengfei Liu, Elke de Boer, Alma Kuechler, Christoffer Nellåker, Christian Gilissen, Yasuo Hachiya, Marcia C. Willing, Shivarajan M. Amudhavalli, Alexander P.A. Stegmann, Ange-Line Bruel, Siddharth Banka, Joery den Hoed, Vardiella Meiner, Rosalyn Jewell, Britton D Zuccarelli, Alexander J. M. Dingemans, Kelly L. Jones, Anja A. Kattentidt-Mouravieva, Matthew Osmond, Orly Elpeleg, Andrea K. Petersen, Nicolas Guex, Dianne F. Newbury, Jill A. Rosenfeld, Alexandre Reymond, Mohamad A. Mikati, Tjitske Kleefstra, Lisenka E.L.M. Vissers, Naomichi Matsumoto, Vincent R. Bonagura, Loreta Cimbalistienė, Benoît Mazel, Hayley S. Mountford, Isabelle Thiffault, Rolph Pfundt, Ruth Newbury-Ecob, Teresa Santiago-Sim, Alinoë Lavillaureix, Eglė Preikšaitienė, Jacqueline Chrast, Toshiyuki Itai, Norine Voisin, Usha Kini, Emmanuelle Ranza, Caitlin Schwager, Brooke Horist, Samantha A. Schrier Vergano, Jennifer Hanebeck, Juliana H. Vedovato-dos-Santos, Mitsuhiro Kato, Theresa Brunet, Lot Snijders Blok, Jayne Y. Hehir-Kwa, Shehla Mohammed, Benjamin Haber, Hagar Mor-Shaked, Laurence Faivre, Dian Donnai, Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft, Université de Lausanne = University of Lausanne (UNIL), Children's Mercy Hospital [Kansas City], University of Manchester [Manchester], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique et Développement de Rennes (IGDR), 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 ), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Radboud University [Nijmegen], Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, University of Lausanne (UNIL), 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), 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), Radboud university [Nijmegen], The DDD study, RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, and MUMC+: DA Klinische Genetica (5)

Subjects
0301 basic medicine, Male, Models, Molecular, MISSENSE MUTATIONS, CHROMATIN, Transcription, Genetic, Cell, Medizin, Disease, Haploinsufficiency, medicine.disease_cause, 0302 clinical medicine, Missense mutation, de novo variants, Genetics (clinical), INTERLEUKIN-2, seizures, Genetics, 0303 health sciences, Mutation, Chromatin binding, neurodevelopmental disorders, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], SATB1, Phenotype, medicine.anatomical_structure, intellectual disability, Female, teeth abnormalities, Protein Binding, Neuroinformatics, EXPRESSION, GENES, Mutation, Missense, Biology, BINDING PROTEIN, REGION, 03 medical and health sciences, Protein Domains, Report, medicine, HPO-based analysis, Humans, Genetic Association Studies, Hpo-based Analysis, Satb1, Cell-based Functional Assays, De Novo Variants, Intellectual Disability, Neurodevelopmental Disorders, Seizures, Teeth Abnormalities, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Matrix Attachment Region Binding Proteins, 030104 developmental biology, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], 030217 neurology & neurosurgery, cell-based functional assays
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 carryingSATB1variants 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. Contrastingly, 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 and encode truncated proteins, 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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