Cover Image

De novo variants in SP9 cause a novel form of interneuronopathy characterized by intellectual disability, autism spectrum disorder, and epilepsy with variable expressivity

Purpose - Interneuronopathies are a group of neurodevelopmental disorders characterized by deficient migration and differentiation of gamma-aminobutyric acidergic interneurons resulting in a broad clinical spectrum, including autism spectrum disorders, early-onset epileptic encephalopathy, intellect...

Full description

Saved in:
Bibliographic Details
Main Authors: Tessarech, Marine (Author) , Friocourt, Gaëlle (Author) , Marguet, Florent (Author) , Lecointre, Maryline (Author) , Le Mao, Morgane (Author) , Díaz, Rodrigo Muñoz (Author) , Mignot, Cyril (Author) , Keren, Boris (Author) , Héron, Bénédicte (Author) , De Bie, Charlotte (Author) , Van Gassen, Koen (Author) , Loisel, Didier (Author) , Delorme, Benoit (Author) , Syrbe, Steffen (Author) , Klabunde-Cherwon, Annick (Author) , Jamra, Rami Abou (Author) , Wegler, Meret (Author) , Callewaert, Bert (Author) , Dheedene, Annelies (Author) , Zidane-Marinnes, Merzouka (Author) , Guichet, Agnès (Author) , Bris, Céline (Author) , Van Bogaert, Patrick (Author) , Biquard, Florence (Author) , Lenaers, Guy (Author) , Marcorelles, Pascale (Author) , Ferec, Claude (Author) , Gonzalez, Bruno (Author) , Procaccio, Vincent (Author) , Vitobello, Antonio (Author) , Bonneau, Dominique (Author) , Laquerriere, Annie (Author) , Khiati, Salim (Author) , Colin, Estelle (Author)
Format: Article (Journal)
Language:English
Published: May 2024
In: Genetics in medicine
Year: 2024, Volume: 26, Issue: 5, Pages: 1-14
ISSN:1530-0366
DOI:10.1016/j.gim.2024.101087
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.gim.2024.101087
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S1098360024000200
Get full text
Author Notes:Marine Tessarech, Gaëlle Friocourt, Florent Marguet, Maryline Lecointre, Morgane Le Mao, Rodrigo Muñoz Díaz, Cyril Mignot, Boris Keren, Bénédicte Héron, Charlotte De Bie, Koen Van Gassen, Didier Loisel, Benoit Delorme, Steffen Syrbe, Annick Klabunde-Cherwon, Rami Abou Jamra, Meret Wegler, Bert Callewaert, Annelies Dheedene, Merzouka Zidane-Marinnes, Agnès Guichet, Céline Bris, Patrick Van Bogaert, Florence Biquard, Guy Lenaers, Pascale Marcorelles, Claude Ferec, Bruno Gonzalez, Vincent Procaccio, Antonio Vitobello, Dominique Bonneau, Annie Laquerriere, Salim Khiati, Estelle Colin
Description
Summary:Purpose - Interneuronopathies are a group of neurodevelopmental disorders characterized by deficient migration and differentiation of gamma-aminobutyric acidergic interneurons resulting in a broad clinical spectrum, including autism spectrum disorders, early-onset epileptic encephalopathy, intellectual disability, and schizophrenic disorders. SP9 is a transcription factor belonging to the Krüppel-like factor and specificity protein family, the members of which harbor highly conserved DNA-binding domains. SP9 plays a central role in interneuron development and tangential migration, but it has not yet been implicated in a human neurodevelopmental disorder. - Methods - Cases with SP9 variants were collected through international data-sharing networks. To address the specific impact of SP9 variants, in silico and in vitro assays were carried out. - Results - De novo heterozygous variants in SP9 cause a novel form of interneuronopathy. SP9 missense variants affecting the glutamate 378 amino acid result in severe epileptic encephalopathy because of hypomorphic and neomorphic DNA-binding effects, whereas SP9 loss-of-function variants result in a milder phenotype with epilepsy, developmental delay, and autism spectrum disorder. - Conclusion - De novo heterozygous SP9 variants are responsible for a neurodevelopmental disease. Interestingly, variants located in conserved DNA-binding domains of KLF/SP family transcription factors may lead to neomorphic DNA-binding functions resulting in a combination of loss- and gain-of-function effects.
Item Description:Online verfügbar 27 January 2024, Version des Artikels 12 March 2024
Gesehen am 27.11.2024
Physical Description:Online Resource
ISSN:1530-0366
DOI:10.1016/j.gim.2024.101087

Similar Items