MED20 biallelic pathogenic variants cause a neurodevelopmental disorder altering both transcription activity and Transcription-Coupled Repair pathway
Abstract
Defects in transcription and DNA repair pathways underlie a growing spectrum of rare neurodevelopmental disorders, including MEDopathies and transcription-coupled repair (TCR)-related syndromes like Cockayne Syndrome (CS). Here, we report biallelic variants in MED20, encoding a core subunit of Mediator, in eight individuals presenting intellectual disability, brain atrophy, dystonia and developmental delay. Patient-derived fibroblasts exhibit mild but consistent defects in TCR, alongside transcriptional abnormalities reminiscent of CS. Functional modeling of MED20 variants in yeast and nematode recapitulates UV sensitivity, transcriptional impairment and neurodevelopmental defects. At the molecular level, MED20 variants disrupt interactions within the Mediator complex, disturbing the pre-initiation complex and reducing transcriptional output. Collectively, these findings identify MED20 pathogenic variants as a cause of neurodevelopmental disorder at the interface of transcription and DNA repair and position Mediator-dependent transcriptional regulation upstream of TCR. This work establishes a direct link between inherited defects in basal transcription machinery and human transcription-DNA repair syndromes.
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BibTeX
@misc{may2026med20,
title = {{MED20 biallelic pathogenic variants cause a neurodevelopmental disorder altering both transcription activity and Transcription-Coupled Repair pathway}},
author = {Nicolas Le May and Raphaël Leconte and Adriana Alberti and Valeria Ramirez-Ramirez and Thanh Vuong-Bender and Judit Osz and Eléonore Réal and Christelle Maalouf and Carole Peluso-Iltis and Cathy Obringer and Sylviane Peudenier and Moustapha Ndiaye and Marietou Traore and Ainara Salazar-Villacorta and Shira Ziegler and Carolyn Applegate and Ada Hamosh and Imène Boujelbene and Samuel Nicaise and Elise Hameau and Sophie Scheidecker and Gaétan Caravello and Véronique Geoffroy and Jean Muller and Hélène Dollfus and Pedro Rodriguez Cruz and Ingrid Wentzensen and Julia Vodopiutz and Andreas Janecke and Nadège Calmels and Vincent Laugel and Björn Schumacher and Natacha Rochel and Julie Soutourina},
howpublished = {HAL},
year = {2026},
month = jun,
doi = {10.21203/rs.3.rs-9516499/v1},
url = {https://hal.science/hal-05780827v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - MED20 biallelic pathogenic variants cause a neurodevelopmental disorder altering both transcription activity and Transcription-Coupled Repair pathway
AU - Nicolas Le May
AU - Raphaël Leconte
AU - Adriana Alberti
AU - Valeria Ramirez-Ramirez
AU - Thanh Vuong-Bender
AU - Judit Osz
AU - Eléonore Réal
AU - Christelle Maalouf
AU - Carole Peluso-Iltis
AU - Cathy Obringer
AU - Sylviane Peudenier
AU - Moustapha Ndiaye
AU - Marietou Traore
AU - Ainara Salazar-Villacorta
AU - Shira Ziegler
AU - Carolyn Applegate
AU - Ada Hamosh
AU - Imène Boujelbene
AU - Samuel Nicaise
AU - Elise Hameau
AU - Sophie Scheidecker
AU - Gaétan Caravello
AU - Véronique Geoffroy
AU - Jean Muller
AU - Hélène Dollfus
AU - Pedro Rodriguez Cruz
AU - Ingrid Wentzensen
AU - Julia Vodopiutz
AU - Andreas Janecke
AU - Nadège Calmels
AU - Vincent Laugel
AU - Björn Schumacher
AU - Natacha Rochel
AU - Julie Soutourina
PY - 2026
DA - 2026/06/03
PB - HAL
DO - 10.21203/rs.3.rs-9516499/v1
UR - https://hal.science/hal-05780827v1
AB - Defects in transcription and DNA repair pathways underlie a growing spectrum of rare neurodevelopmental disorders, including MEDopathies and transcription-coupled repair (TCR)-related syndromes like Cockayne Syndrome (CS). Here, we report biallelic variants in MED20, encoding a core subunit of Mediator, in eight individuals presenting intellectual disability, brain atrophy, dystonia and developmental delay. Patient-derived fibroblasts exhibit mild but consistent defects in TCR, alongside transcriptional abnormalities reminiscent of CS. Functional modeling of MED20 variants in yeast and nematode recapitulates UV sensitivity, transcriptional impairment and neurodevelopmental defects. At the molecular level, MED20 variants disrupt interactions within the Mediator complex, disturbing the pre-initiation complex and reducing transcriptional output. Collectively, these findings identify MED20 pathogenic variants as a cause of neurodevelopmental disorder at the interface of transcription and DNA repair and position Mediator-dependent transcriptional regulation upstream of TCR. This work establishes a direct link between inherited defects in basal transcription machinery and human transcription-DNA repair syndromes.
ER -