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Ann Neurol. 2019 Aug;86(2):181-192. doi: 10.1002/ana.25522. Epub 2019 Jun 26.

Autism and developmental disability caused by KCNQ3 gain-of-function variants.

Author information

1
Department of Neurology, Columbia University Medical Center, New York, NY.
2
Institute for Genomic Medicine, Columbia University Medical Center, New York, NY.
3
Section of Pharmacology, Department of Neuroscience, University of Naples "Federico II,", Naples, Italy.
4
Department of Medical Genetics, Reference Center for Developmental Anomalies, Civil Hospices of Lyon, Lyon, France.
5
French Institute of Health and Medical Research U1028, French National Center for Scientific Research UMR5292, Center for Research in Neuroscience in Lyon, Genetics of Neurodevelopment Team, Claude Bernard University Lyon 1, Lyon, France.
6
Claude Bernard University Lyon 1, Lyon, France.
7
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA.
8
Seattle Children's Hospital, Seattle, WA.
9
Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
10
Children's Neurology, St Luke's Children's Hospital, Boise, ID.
11
Center for Rett Syndrome, Department of Pediatrics and Adolescent Medicine, National Hospital, Copenhagen, Denmark.
12
Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet and Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
13
French Institute of Health and Medical Research U1231, Laboratory of Cognitive Neuroscience UMR1231, Genetics of Developmental Anomalies, Burgundy University, F-21000, Dijon, France.
14
Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, Campobasso, Italy.
15
University of Melbourne, Austin Health, Royal Children's Hospital, Florey and Murdoch Institutes, Melbourne, Victoria, Australia.
16
Department of Neurology, University of California, San Francisco, San Francisco, CA.
17
Departments of Pediatrics and Neurology, Johns Hopkins School of Medicine, Baltimore, MD.
18
Pediatric Neurology, INTEGRIS Baptist Medical Center, Oklahoma City, OK.
19
Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC.
20
Molecular Genetic Unit, Strasbourg University Hospital, Strasbourg, France.
21
Genetics Department, Reference Center for Developmental Anomalies, Clermont-Ferrand University Hospital, Clermont-Ferrand, France.
22
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
23
Reference Center for Developmental Disorders, Department of Medical Genetics, Arnaud de Villeneuve Hospital, Montpellier University Hospital, Montpellier, France.
24
Department of Pediatric Neurology, University Hospital of Montpellier, and Physiology and Experimental Medicine of Heart and Muscle Unit, University of Montpellier, National Institute for Health and Medical Research, French National Center for Scientific Research, Montpellier, France.
25
Functional Unit 12, Innovation in Genomic Diagnosis of Rare Diseases, University Hospital Dijon-Bourgogne, Dijon, France.
26
Division of Neurology, Department of Pediatrics, Children's Hospital of Pittsburgh and University of Pittsburgh School of Medicine, Pittsburgh, PA.
27
Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA.
28
Neurogenetics Group, University of Antwerp, Antwerp, Belgium.
29
Neurology Department, University Hospital Antwerp, Antwerp, Belgium.
30
Departments of Neurology, Neuroscience, and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
31
Departments of Pediatrics and Institute of Experimental and Clinical Research, University of Louvain, Brussels, Belgium.

Abstract

OBJECTIVE:

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.

METHODS:

Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording.

RESULTS:

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 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 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.

INTERPRETATION:

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. ANN NEUROL 2019;86:181-192.

PMID:
31177578
DOI:
10.1002/ana.25522

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