MED17 encodes a critical component of the Mediator complex that serves as a transcriptional coactivator for RNA polymerase II-dependent gene expression 1. The protein functions as a structural hinge connecting different regions of the Mediator head module and facilitates preinitiation complex assembly through direct interactions with RNA polymerase II and general transcription factors including TFIIB, TBP, TFIIE, and TFIIH 12. Beyond transcriptional regulation, MED17 plays essential roles in DNA repair by physically interacting with nucleotide excision repair proteins XPB and XPG, particularly following UV damage 13. Disease-causing mutations in MED17 result in a severe neurodevelopmental disorder characterized by postnatal progressive microcephaly, seizures, spasticity, and profound intellectual disability 45. The most well-characterized pathogenic variant is a founder mutation (p.L371P) in Caucasus Jewish populations that causes infantile cerebral and cerebellar atrophy with distinctive neuroimaging features including marked brain atrophy and myelination defects 54. Recent studies suggest that MED17 mutations may contribute to disease pathogenesis through increased unfolded protein responses, indicating disrupted cellular stress responses 6. The clinical phenotype is uniformly severe, with most patients requiring supportive care and experiencing early mortality 4.