EBioMedicine (Jul 2022)
KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism
- Francesco Miceli,
- Charissa Millevert,
- Maria Virginia Soldovieri,
- Ilaria Mosca,
- Paolo Ambrosino,
- Lidia Carotenuto,
- Dewi Schrader,
- Hyun Kyung Lee,
- James Riviello,
- William Hong,
- Sarah Risen,
- Lisa Emrick,
- Hitha Amin,
- Dorothée Ville,
- Patrick Edery,
- Julitta de Bellescize,
- Vincent Michaud,
- Julien Van-Gils,
- Cyril Goizet,
- Marjolein H. Willemsen,
- Tjitske Kleefstra,
- Rikke S Møller,
- Allan Bayat,
- Orrin Devinsky,
- Tristan Sands,
- G. Christoph Korenke,
- Gerhard Kluger,
- Heather C. Mefford,
- Eva Brilstra,
- Gaetan Lesca,
- Mathieu Milh,
- Edward C. Cooper,
- Maurizio Taglialatela,
- Sarah Weckhuysen
Affiliations
- Francesco Miceli
- Department of Neuroscience, University of Naples “Federico II”, Naples, Italy
- Charissa Millevert
- Applied & Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Neurology, University Hospital, Antwerp, Belgium
- Maria Virginia Soldovieri
- Department of Medicine and Health Science “V. Tiberio”, University of Molise, Campobasso, Italy
- Ilaria Mosca
- Department of Medicine and Health Science “V. Tiberio”, University of Molise, Campobasso, Italy
- Paolo Ambrosino
- Department of Science and Technology (DST), University of Sannio, Benevento, Italy
- Lidia Carotenuto
- Department of Neuroscience, University of Naples “Federico II”, Naples, Italy
- Dewi Schrader
- Division of Neurology, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
- Hyun Kyung Lee
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
- James Riviello
- Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- William Hong
- Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA
- Sarah Risen
- Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA
- Lisa Emrick
- Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
- Hitha Amin
- Pediatric Neurology at Cortica Care, Irvine, CA, USA
- Dorothée Ville
- Pediatric Neurology Department, Lyon University Hospital, France
- Patrick Edery
- Department of Genetics, Lyon University Hospital, France; Centre for Neuroscience Research Lyon, Lyon, France
- Julitta de Bellescize
- Department of Pediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, Member of the European Reference Network EpiCARE, University Hospitals of Lyon (HCL), Lyon, France
- Vincent Michaud
- Reference Center for Rare “Neurogenetic” Diseases, Department of Medical Genetics, Pellegrin Hospital, Bordeaux University Hospital, France
- Julien Van-Gils
- Reference Center for Rare “Neurogenetic” Diseases, Department of Medical Genetics, Pellegrin Hospital, Bordeaux University Hospital, France
- Cyril Goizet
- Reference Center for Rare “Neurogenetic” Diseases, Department of Medical Genetics, Pellegrin Hospital, Bordeaux University Hospital, France; Rare Diseases Laboratory: Genetics and Metabolism (MRGM), Bordeaux University, Bordeaux, France
- Marjolein H. Willemsen
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
- Tjitske Kleefstra
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Vincent Van Gogh Instituut, Center for Neuropsychiatry, Venray, Limburg, the Netherlands
- Rikke S Møller
- Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark; Department Regional Health Research, University of Southern Denmark, Odense, Denmark
- Allan Bayat
- Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark; Department Regional Health Research, University of Southern Denmark, Odense, Denmark
- Orrin Devinsky
- Department of Neurology, NYU Langone Health and Grossman School of Medicine, New York, NY, USA
- Tristan Sands
- Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA
- G. Christoph Korenke
- Department of Neuropediatrics, University Children's Hospital, Klinikum Oldenburg, Oldenburg, Germany
- Gerhard Kluger
- Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany; Research Institute for Rehabilitation, Transition and Palliation, Paracelsus Medical University Salzburg, Salzburg, Austria
- Heather C. Mefford
- Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA
- Eva Brilstra
- Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
- Gaetan Lesca
- Department of Medical Genetics, Lyon University Hospital, Lyon, France; Neuromyogene Institute, University of Lyon, Lyon, France
- Mathieu Milh
- Aix Marseille University, Pediatric neurology unit, Timone Children Hospital, Marseille, France
- Edward C. Cooper
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Departments of Neurology and Neuroscience, Baylor College of Medicine, Houston, TX, USA
- Maurizio Taglialatela
- Department of Neuroscience, University of Naples “Federico II”, Naples, Italy; Corresponding author at: Department of Neuroscience, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy.
- Sarah Weckhuysen
- Applied & Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Neurology, University Hospital, Antwerp, Belgium; µNEURO Research Centre of Excellence, University of Antwerp, Antwerp, Belgium; Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium; Corresponding author at: VIB-UAntwerp Center for Molecular Neurology, Universiteitsplein 1, 2610 Antwerp, Belgium.
- Journal volume & issue
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Vol. 81
p. 104130
Abstract
Summary: Background: Prior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline. Methods: Patients were identified using the RIKEE database and through clinical collaborators. Phenotypes were collected by a standardized questionnaire. Functional and pharmacological properties of variant subunits were analyzed by whole-cell patch-clamp recordings. Findings: Detailed clinical information on fifteen patients (14 novel and 1 previously published) was analyzed. All patients had developmental delay with prominent language impairment. R144Q patients were more severely affected than R144W patients. Infantile to childhood onset epilepsy occurred in 40%, while 67% of sleep-EEGs showed sleep-activated epileptiform activity. Ten patients (67%) showed autistic features. Activation gating of homomeric Kv7.2 R144W/Q/G channels was left-shifted, suggesting gain-of-function effects. Amitriptyline blocked channels containing Kv7.2 and Kv7.2 R144Q subunits. Interpretation: Patients carrying KCNQ2 R144 gain-of-function variants have developmental delay with prominent language impairment, autistic features, often accompanied by infantile- to childhood-onset epilepsy and EEG sleep-activated epileptiform activity. The absence of neonatal seizures is a robust and important clinical differentiator between KCNQ2 gain-of-function and loss-of-function variants. The Kv7.2/7.3 channel blocker amitriptyline might represent a targeted treatment. Funding: Supported by FWO, GSKE, KCNQ2-Cure, Jack Pribaz Foundation, European Joint Programme on Rare Disease 2020, the Italian Ministry for University and Research, the Italian Ministry of Health, the European Commission, the University of Antwerp, NINDS, and Chalk Family Foundation.
