Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/20971
Title: Autism and developmental disability caused by KCNQ3 gain-of-function variants.
Austin Authors: Sands, Tristan T;Miceli, Francesco;Lesca, Gaetan;Beck, Anita E;Sadleir, Lynette G;Arrington, Daniel K;Schönewolf-Greulich, Bitten;Moutton, Sébastien;Lauritano, Anna;Nappi, Piera;Soldovieri, Maria Virginia;Scheffer, Ingrid E ;Mefford, Heather C;Stong, Nicholas;Heinzen, Erin L;Goldstein, David B;Grijalvo Perez, Ana;Kossoff, Eric H;Stocco, Amber;Sullivan, Jennifer A;Shashi, Vandana;Gerard, Benedicte;Francannet, Christine;Bisgaard, Anne-Marie;Tümer, Zeynep;Willems, Marjolaine;Rivier, François;Vitobello, Antonio;Thakkar, Kavita;Rajan, Deepa S;Barkovich, A James;Weckhuysen, Sarah;Cooper, Edward C;Taglialatela, Maurizio;Cilio, M Roberta
Affiliation: Departments of Pediatrics and Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA
Departments of Pediatrics and Institute of Experimental and Clinical Research, University of Louvain, Brussels, Belgium
Neurogenetics Group, University of Antwerp, Antwerp, Belgium
Neurology Department, University Hospital Antwerp, Antwerp, Belgium
Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet and Department of Clinical Medicine, University of Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
Center for Rett Syndrome, Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Denmark
Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet and Department of Clinical Medicine, University of Copenhagen, Denmark
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA
Service de Génétique, Centre de Référence Anomalies du Développement, Hospices Civils de Lyon, Bron, France
INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, GENDEV Team, Université Claude Bernard Lyon 1, Bron, France
Université Claude Bernard Lyon 1, Lyon, France
Department of Neurology, Columbia University Medical Center, New York, NY, USA
The University of Melbourne, Royal Children's Hospital, Florey and Murdoch Institutes, Melbourne, Australia
Children's Neurology, St. Luke's Children's Hospital, Boise, ID, USA
Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA
Seattle Children's Hospital, Seattle, WA, USA
Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC, USA
Pediatric Neurology, INTEGRIS Baptist Medical Center, Oklahoma City, OK, USA
Section of Pharmacology, Department of Neuroscience, University of Naples "Federico II," Naples, Italy
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand
INSERM U1231, LNC UMR1231 GAD, Burgundy University, F-21000, Dijon
Section of Pharmacology, Department of Neuroscience, University of Naples "Federico II," Naples, Italy
Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, Campobasso, Italy
Molecular Genetic Unit, Strasbourg University Hospital, Strasbourg, France
Service de Génétique, Centre de Référence Anomalies du Développement, CHU de Clermont-Ferrand, Clermont-Ferrand, France
Center for Rett Syndrome, Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Denmark
Reference Center for Developmental Disorders, Department of Medical Genetics, Arnaud de Villeneuve Hospital, Montpellier University Hospital 371 avenue du Doyen Gaston Giraud. 34295 MONTPELLIER Cedex 05, France
Department of Pediatric Neurology, CHU Montpellier, PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France
12 UF Innovation en diagnostic génomique des maladies rares, CHU Dijon Bourgogne, Dijon, France
Division of Neurology, Department of Pediatrics, Children's Hospital of Pittsburgh and University of Pittsburgh School of Medicine, Pittsburgh, PA
Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, United States
Departments of Neurology, Neuroscience and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
Section of Pharmacology, Department of Neuroscience, University of Naples "Federico II," Naples, Italy
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Issue Date: 8-Jun-2019
metadata.dc.date: 2019-06-26
Publication information: Annals of neurology 2019; 86(2): 181-192
Abstract: Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms. Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts and EEG recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording. Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first two years of life. Most (8/11, 73%) were non-verbal or had a few words only. All patients had autistic features and autism spectrum disorder (ASD) was diagnosed in 5/11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8/11 (73%). For 6/9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects. Specific GoF variants in KCNQ3 cause NDD, ASD and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss-of-function, and with the neonatal or infantile-onset epileptic encephalopathies due to KCNQ2 GoF. This article is protected by copyright. All rights reserved.
URI: http://ahro.austin.org.au/austinjspui/handle/1/20971
DOI: 10.1002/ana.25522
ORCID: 0000-0001-7285-1195
0000-0002-7268-8559
PubMed URL: 31177578
Type: Journal Article
Appears in Collections:Journal articles

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