KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism.
eBioMedicine. 2022-07-01; 81: 104130
DOI: 10.1016/j.ebiom.2022.104130
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Miceli F(1), Millevert C(2), Soldovieri MV(3), Mosca I(3), Ambrosino P(4),
Carotenuto L(1), Schrader D(5), Lee HK(6), Riviello J(7), Hong W(8), Risen S(9),
Emrick L(10), Amin H(11), Ville D(12), Edery P(13), de Bellescize J(14), Michaud
V(15), Van-Gils J(15), Goizet C(16), Willemsen MH(17), Kleefstra T(18), Møller
RS(19), Bayat A(19), Devinsky O(20), Sands T(21), Korenke GC(22), Kluger G(23),
Mefford HC(24), Brilstra E(25), Lesca G(26), Milh M(27), Cooper EC(28),
Taglialatela M(29), Weckhuysen S(30).
Author information:
(1)Department of Neuroscience, University of Naples « Federico II », Naples, Italy.
(2)Applied & Translational Neurogenomics Group, VIB Center for Molecular
Neurology, VIB, Antwerp, Belgium; Department of Neurology, University Hospital,
Antwerp, Belgium.
(3)Department of Medicine and Health Science « V. Tiberio », University of Molise,
Campobasso, Italy.
(4)Department of Science and Technology (DST), University of Sannio, Benevento,
Italy.
(5)Division of Neurology, Department of Pediatrics, BC Children’s Hospital,
University of British Columbia, Vancouver, British Columbia, Canada.
(6)Department of Medical Genetics, University of British Columbia, Vancouver,
British Columbia, Canada.
(7)Section of Neurology and Developmental Neuroscience, Department of Pediatrics,
Baylor College of Medicine, Houston, TX, USA.
(8)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.
(9)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.
(10)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.
(11)Pediatric Neurology at Cortica Care, Irvine, CA, USA.
(12)Pediatric Neurology Department, Lyon University Hospital, France.
(13)Department of Genetics, Lyon University Hospital, France; Centre for
Neuroscience Research Lyon, Lyon, France.
(14)Department of Pediatric Clinical Epileptology, Sleep Disorders and Functional
Neurology, Member of the European Reference Network EpiCARE, University Hospitals
of Lyon (HCL), Lyon, France.
(15)Reference Center for Rare « Neurogenetic » Diseases, Department of Medical
Genetics, Pellegrin Hospital, Bordeaux University Hospital, France.
(16)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.
(17)Department of Human Genetics, Radboud University Medical Center, Nijmegen,
the Netherlands.
(18)Department of Human Genetics, Radboud University Medical Center, Nijmegen,
the Netherlands; Vincent Van Gogh Instituut, Center for Neuropsychiatry, Venray,
Limburg, the Netherlands.
(19)Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy
Centre, Dianalund, Denmark; Department Regional Health Research, University of
Southern Denmark, Odense, Denmark.
(20)Department of Neurology, NYU Langone Health and Grossman School of Medicine,
New York, NY, USA.
(21)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.
(22)Department of Neuropediatrics, University Children’s Hospital, Klinikum
Oldenburg, Oldenburg, Germany.
(23)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.
(24)Department of Pediatrics, Division of Genetic Medicine, University of
Washington, Seattle, WA, USA.
(25)Department of Medical Genetics, University Medical Center Utrecht, Utrecht,
the Netherlands.
(26)Department of Medical Genetics, Lyon University Hospital, Lyon, France;
Neuromyogene Institute, University of Lyon, Lyon, France.
(27)Aix Marseille University, Pediatric neurology unit, Timone Children Hospital,
Marseille, France.
(28)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.
(29)Department of Neuroscience, University of Naples « Federico II », Naples,
Italy. Electronic address: .
(30)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. Electronic address:
.
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.
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
Conflict of interest statement: Declaration of interests SW received consultancy
and speaker fees from UCB, Biocodex, Xenon, Zogenix, Lundbeck, Knopp Biosciences,
Encoded MT received consultancy fees from Xenon. ECC received consultancy fees
from Xenon, Knopp, these activities have been reviewed and approved by Baylor
College of Medicine according to its policy on disclosure of outside interests.
RSM received consultancy and speaker fees from EISAI and UCB. The remaining
authors have no conflicts of interest.