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 (US) |
|---|---|
| Pages (from-to) | 181-192 |
| Number of pages | 12 |
| Journal | Annals of neurology |
| Volume | 86 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 2019 |
Funding
and S.W.), and the Miles Family Fund (E.C.C.). The present work was also supported by the University Research Fund–University of Antwerp (FFB180053) and Scientific Research Flanders (1861419N) to S.W. and by the NIH National Institute of Neurological Disorders and Stroke (R01 NS069605) to H.C.M. Genome sequencing for Patient 11 was performed by the SNP&SEQ Technology Platform in Uppsala, Sweden, in collaboration with Lars Feuk. This facility is part of the National Genomics Infrastructure Sweden and Science for Life Technologies. The platform is supported by the Swedish Research Council and the Knut and Alice Wallenberg Foundation. Exome sequencing for Patient 4 was ascertained in the Duke Genome Sequencing Clinic, supported by the Duke University Health System, Durham, NC. The present work was supported by the Telethon Foundation (GGP15113) and by the Italian Ministry for University and Research (PRIN 2017ALCR7C) to M.T.; the Italian Ministry for University and Research (Project Scientific Independence of Researchers 2014 RBSI1444EM and PRIN 2017YH3SXK) and the University of Naples ?Federico II? and Compagnia di San Paolo within the STAR Program ?Sostegno Territoriale alle Attivit? di Ricerca? (project number 6-CSP-UNINA-120) to F.M.; the Italian Ministry of Health Ricerca Finalizzata Giovani Ricercatori 2016 (project GR-2016-02363337) and the Italian Ministry for University and Research (PRIN 2017ALCR7C) to M.V.S.; National Institute of Neurological Disorders and Stroke (R01 NS49119 and U54 NS108874) to E.C.C.; the Jack Pribaz Foundation (E.C.C. and S.W.), the KCNQ2 Cure Alliance (E.C.C. and S.W.), and the Miles Family Fund (E.C.C.). The present work was also supported by the University Research Fund?University of Antwerp (FFB180053) and Scientific Research Flanders (1861419N) to S.W. and by the NIH National Institute of Neurological Disorders and Stroke (R01 NS069605) to H.C.M. Genome sequencing for Patient 11 was performed by the SNP&SEQ Technology Platform in Uppsala, Sweden, in collaboration with Lars Feuk. This facility is part of the National Genomics Infrastructure Sweden and Science for Life Technologies. The platform is supported by the Swedish Research Council and the Knut and Alice Wallenberg Foundation. Exome sequencing for Patient 4 was ascertained in the Duke Genome Sequencing Clinic, supported by the Duke University Health System, Durham, NC. We thank the patients and their families for participation in this research, and the KCNQ2 Cure Alliance and Jack Pribaz Foundation for collaboration and parent referrals. The present work was supported by the Telethon Foundation (GGP15113) and by the Italian Ministry for University and Research (PRIN 2017ALCR7C) to M.T.; the Italian Ministry for University and Research (Project Scientific Independence of Researchers 2014 RBSI1444EM and PRIN 2017YH3SXK) and the University of Naples “Federico II” and Compagnia di San Paolo within the STAR Program “Sostegno Territoriale alle Attività di Ricerca” (project number 6-CSP-UNINA-120) to F.M.; the Italian Ministry of Health Ricerca Finalizzata Giovani Ricercatori 2016 (project GR-2016-02363337) and the Italian Ministry for University and Research (PRIN 2017ALCR7C) to M.V.S.; National Institute of Neurological Disorders and Stroke (R01 NS49119 and U54 NS108874) to E.C.C.; the Jack Pribaz Foundation (E.C.C. and S.W.), the KCNQ2 Cure Alliance (E.C.C.
ASJC Scopus subject areas
- Neurology
- Clinical Neurology