TY - JOUR
T1 - Autism and developmental disability caused by KCNQ3 gain-of-function variants
AU - Sands, Tristan T.
AU - Miceli, Francesco
AU - Lesca, Gaetan
AU - Beck, Anita E.
AU - Sadleir, Lynette G.
AU - Arrington, Daniel K.
AU - Schönewolf-Greulich, Bitten
AU - Moutton, Sébastien
AU - Lauritano, Anna
AU - Nappi, Piera
AU - Soldovieri, Maria Virginia
AU - Scheffer, Ingrid E.
AU - Mefford, Heather C.
AU - Stong, Nicholas
AU - Heinzen, Erin L.
AU - Goldstein, David B.
AU - Perez, Ana Grijalvo
AU - Kossoff, Eric H.
AU - Stocco, Amber
AU - Sullivan, Jennifer A.
AU - Shashi, Vandana
AU - Gerard, Benedicte
AU - Francannet, Christine
AU - Bisgaard, Anne Marie
AU - Tümer, Zeynep
AU - Willems, Marjolaine
AU - Rivier, François
AU - Vitobello, Antonio
AU - Thakkar, Kavita
AU - Rajan, Deepa S.
AU - Barkovich, A. James
AU - Weckhuysen, Sarah
AU - Cooper, Edward C.
AU - Taglialatela, Maurizio
AU - Cilio, M. Roberta
N1 - Publisher Copyright:
© 2019 American Neurological Association
PY - 2019/8
Y1 - 2019/8
N2 - 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.
AB - 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.
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U2 - 10.1002/ana.25522
DO - 10.1002/ana.25522
M3 - Article
C2 - 31177578
AN - SCOPUS:85068128686
SN - 0364-5134
VL - 86
SP - 181
EP - 192
JO - Annals of neurology
JF - Annals of neurology
IS - 2
ER -