De novo variants in SP9 cause a novel form of interneuronopathy characterized by intellectual disability, autism spectrum disorder, and epilepsy with variable expressivity - Archive ouverte HAL Access content directly
Journal Articles Genetics in Medicine Year : 2024

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

Marine Tessarech
Florent Marguet
  • Function : Author
Maryline Lecointre
  • Function : Author
Morgane Le Mao
  • Function : Author
Rodrigo Muñoz Díaz
  • Function : Author
Cyril Mignot
  • Function : Author
Boris Keren
  • Function : Author
Bénédicte Héron
  • Function : Author
Charlotte de Bie
  • Function : Author
Koen van Gassen
  • Function : Author
Didier Loisel
  • Function : Author
Benoit Delorme
  • Function : Author
Steffen Syrbe
  • Function : Author
Annick Klabunde-Cherwon
  • Function : Author
Rami Abou Jamra
  • Function : Author
Meret Wegler
  • Function : Author
Bert Callewaert
  • Function : Author
Annelies Dheedene
  • Function : Author
Merzouka Zidane-Marinnes
  • Function : Author
Agnès Guichet
  • Function : Author
Céline Bris
  • Function : Author
Patrick van Bogaert
  • Function : Author
Florence Biquard
  • Function : Author
Guy Lenaers
  • Function : Author
Bruno Gonzalez
  • Function : Author
Antonio Vitobello
  • Function : Author
Dominique Bonneau
  • Function : Author
Annie Laquerriere
  • Function : Author
Salim Khiati
  • Function : Author
Estelle Colin
  • Function : Author
  • PersonId : 906473

Abstract

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 Kr¨uppel-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-offunction 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.
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hal-04530295 , version 1 (03-04-2024)

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Marine Tessarech, Gaëlle Friocourt, Florent Marguet, Maryline Lecointre, Morgane Le Mao, et al.. De novo variants in SP9 cause a novel form of interneuronopathy characterized by intellectual disability, autism spectrum disorder, and epilepsy with variable expressivity. Genetics in Medicine, 2024, 26 (5), pp.101087. ⟨10.1016/j.gim.2024.101087⟩. ⟨hal-04530295⟩
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