Genotype-phenotype correlations in patients with de novo KCNQ2 pathogenic variants

Federica Malerba, Giulio Alberini, Ganna Balagura, Francesca Marchese, Elisabetta Amadori, Antonella Riva, Maria Stella Vari, Elena Gennaro, Francesca Madia, Vincenzo Salpietro, Marco Angriman, Lucio Giordano, Patrizia Accorsi, Marina Trivisano, Nicola Specchio, Angelo Russo, Giuseppe Gobbi, Federico Raviglione, Tiziana Pisano, Carla MariniMaria M. Mancardi, Lino Nobili, Elena Freri, Barbara Castellotti, Giuseppe Capovilla, Antonietta Coppola, Alberto Verrotti, Paola Martelli, Francesco Miceli, Luca Maragliano, Fabio Benfenati, Maria R. Cilio, Kathrine M. Johannesen, Rikke S. Møller, Berten Ceulemans, Carlo Minetti, Sarah Weckhuysen, Federico Zara, Maurizio Taglialatela, Pasquale Striano

Research output: Contribution to journalArticlepeer-review


Objective Early identification of de novo KCNQ2 variants in patients with epilepsy raises prognostic issues toward optimal management. We analyzed the clinical and genetic information from a cohort of patients with de novo KCNQ2 pathogenic variants to dissect genotype-phenotype correlations. Methods Patients with de novo KCNQ2 pathogenic variants were identified from Italy, Denmark, and Belgium. Atomic resolution Kv7.2 structures were also generated using homology modeling to map the variants. Results We included 34 patients with a mean age of 4.7 years. Median seizure onset was 2 days, mainly with focal seizures with autonomic signs. Twenty-two patients (65%) were seizure free at the mean age of 1.2 years. More than half of the patients (17/32) displayed severe/profound intellectual disability; however, 4 (13%) of them had a normal cognitive outcome. A total of 28 de novo pathogenic variants were identified, most missense (25/28), and clustered in conserved regions of the protein; 6 variants recurred, and 7 were novel. We did not identify a relationship between variant position and seizure offset or cognitive outcome in patients harboring missense variants. Besides, recurrent variants were associated with overlapping epilepsy features but also variable evolution regarding the intellectual outcome. Conclusions We highlight the complexity of variant interpretation to assess the impact of a class of de novo KCNQ2 mutations. Genetic modifiers could be implicated, but the study paradigms to successfully address the impact of each single mutation need to be developed.

Original languageEnglish
Article numbere528
JournalNeurology: Genetics
Issue number6
Publication statusPublished - 2020

ASJC Scopus subject areas

  • Clinical Neurology
  • Genetics(clinical)


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