1. De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder
- Author
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Yoeri Sleyp, Irene Valenzuela, Andrea Accogli, Katleen Ballon, Bruria Ben-Zeev, Samuel F. Berkovic, Martin Broly, Patrick Callaerts, Raymond C. Caylor, Perrine Charles, Nicolas Chatron, Lior Cohen, Antonietta Coppola, Dawn Cordeiro, Claudia Cuccurullo, Ivon Cuscó, null Janette diMonda, Ramon Duran-Romaña, Nina Ekhilevitch, Paula Fernández-Alvarez, Christopher T. Gordon, Bertrand Isidor, Boris Keren, Gaetan Lesca, Jarymke Maljaars, Saadet Mercimek-Andrews, Michelle M. Morrow, Alison M. Muir, Frederic Rousseau, Vincenzo Salpietro, Ingrid E. Scheffer, Rhonda E. Schnur, Joost Schymkowitz, Erika Souche, Jean Steyaert, Elliot S. Stolerman, Jaime Vengoechea, Dorothée Ville, Camerun Washington, Karin Weiss, Rinat Zaid, Lynette G. Sadleir, Heather C. Mefford, and Hilde Peeters
- Subjects
Epilepsy ,Autism Spectrum Disorder ,Developmental Disabilities ,Intellectual Disability ,Ubiquitin-Protein Ligases ,Mutation, Missense ,Humans ,Child ,Seizures, Febrile ,Genetics (clinical) ,Adaptor Proteins, Signal Transducing - Abstract
KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20.Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed.We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069GA p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type β-propeller domain of the KLHL20 protein, which shapes the substrate binding surface.Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity.
- Published
- 2022
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