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

Tristan T Sands; Francesco Miceli; Gaetan Lesca; Anita E Beck; Lynette G Sadleir; Daniel K Arrington; Bitten Schönewolf-Greulich; Sébastien Moutton; Anna Lauritano; Piera Nappi; Maria Virginia Soldovieri; Ingrid E Scheffer; Heather C Mefford; Nicholas Stong; Erin L Heinzen; David B Goldstein; Ana Grijalvo Perez; Eric H Kossoff; Amber Stocco; Jennifer A Sullivan; Vandana Shashi; Benedicte Gerard; Christine Francannet; Anne-Marie Bisgaard; Zeynep Tümer; Marjolaine Willems; François Rivier; Antonio Vitobello; Kavita Thakkar; Deepa S Rajan; A James Barkovich; Sarah Weckhuysen; Edward C Cooper; Maurizio Taglialatela; M Roberta Cilio

doi:10.1002/ana.25522

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

Tristan T Sands, Francesco Miceli, Gaetan Lesca, Anita E Beck, Lynette G Sadleir, Daniel K Arrington, Bitten Schönewolf-Greulich, Sébastien Moutton, Anna Lauritano, Piera Nappi, Maria Virginia Soldovieri, Ingrid E Scheffer, Heather C Mefford, Nicholas Stong, Erin L Heinzen, David B Goldstein, Ana Grijalvo Perez, Eric H Kossoff, Amber Stocco, Jennifer A SullivanVandana Shashi, Benedicte Gerard, Christine Francannet, Anne-Marie Bisgaard, Zeynep Tümer, Marjolaine Willems, François Rivier, Antonio Vitobello, Kavita Thakkar, Deepa S Rajan, A James Barkovich, Sarah Weckhuysen, Edward C Cooper, Maurizio Taglialatela, M Roberta Cilio

Department of Clinical Medicine

19 Citations (Scopus)

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.

Original language	English
Journal	Annals of Neurology
Volume	86
Issue number	2
Pages (from-to)	181-192
Number of pages	12
ISSN	0364-5134
DOIs	https://doi.org/10.1002/ana.25522
Publication status	Published - Aug 2019

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Sands, T. T., Miceli, F., Lesca, G., Beck, A. E., Sadleir, L. G., Arrington, D. K., Schönewolf-Greulich, B., Moutton, S., Lauritano, A., Nappi, P., Soldovieri, M. V., Scheffer, I. E., Mefford, H. C., Stong, N., Heinzen, E. L., Goldstein, D. B., Perez, A. G., Kossoff, E. H., Stocco, A., ... Cilio, M. R. (2019). Autism and developmental disability caused by KCNQ3 gain-of-function variants. Annals of Neurology, 86(2), 181-192. https://doi.org/10.1002/ana.25522

Sands, TT, Miceli, F, Lesca, G, Beck, AE, Sadleir, LG, Arrington, DK, Schönewolf-Greulich, B, Moutton, S, Lauritano, A, Nappi, P, Soldovieri, MV, Scheffer, IE, Mefford, HC, Stong, N, Heinzen, EL, Goldstein, DB, Perez, AG, Kossoff, EH, Stocco, A, Sullivan, JA, Shashi, V, Gerard, B, Francannet, C, Bisgaard, A-M, Tümer, Z, Willems, M, Rivier, F, Vitobello, A, Thakkar, K, Rajan, DS, Barkovich, AJ, Weckhuysen, S, Cooper, EC, Taglialatela, M & Cilio, MR 2019, 'Autism and developmental disability caused by KCNQ3 gain-of-function variants', Annals of Neurology, vol. 86, no. 2, pp. 181-192. https://doi.org/10.1002/ana.25522

@article{1f3bdd9a659d4ca086411de231029752,

title = "Autism and developmental disability caused by KCNQ3 gain-of-function variants",

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.",

author = "Sands, {Tristan T} and Francesco Miceli and Gaetan Lesca and Beck, {Anita E} and Sadleir, {Lynette G} and Arrington, {Daniel K} and Bitten Sch{\"o}newolf-Greulich and S{\'e}bastien Moutton and Anna Lauritano and Piera Nappi and Soldovieri, {Maria Virginia} and Scheffer, {Ingrid E} and Mefford, {Heather C} and Nicholas Stong and Heinzen, {Erin L} and Goldstein, {David B} and Perez, {Ana Grijalvo} and Kossoff, {Eric H} and Amber Stocco and Sullivan, {Jennifer A} and Vandana Shashi and Benedicte Gerard and Christine Francannet and Anne-Marie Bisgaard and Zeynep T{\"u}mer and Marjolaine Willems and Fran{\c c}ois Rivier and Antonio Vitobello and Kavita Thakkar and Rajan, {Deepa S} and Barkovich, {A James} and Sarah Weckhuysen and Cooper, {Edward C} and Maurizio Taglialatela and Cilio, {M Roberta}",

year = "2019",

month = aug,

doi = "10.1002/ana.25522",

language = "English",

volume = "86",

pages = "181--192",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "JohnWiley & Sons, Inc.",

number = "2",

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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

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.

U2 - 10.1002/ana.25522

DO - 10.1002/ana.25522

M3 - Journal article

C2 - 31177578

SN - 0364-5134

VL - 86

SP - 181

EP - 192

JO - Annals of Neurology

JF - Annals of Neurology

IS - 2

ER -

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

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