The Role of a Novel TRIP12 Mutation in Intellectual Disability: A Molecular and Clinical Investigation in Multiplex Family.

Thyroid hormone receptor interactor 12 (TRIP12; MIM #617,752) is an autosomal dominant hereditary disorder involved in the ubiquitin fusion degradation pathway and the regulation of DNA damage-induced chromatin ubiquitination. Positioned on chromosome 2 at position 2q36.3, TRIP12 is a member of the E3 ubiquitin ligase family. This gene plays a vital role in proteasomal degradation by catalyzing substrate ubiquitination and regulating processes such as cell cycle progression, DNA damage repair, and chromatin remodeling. Mutations in TRIP12 can result in intellectual disability (ID), Clark-Baraitser syndrome, and various physical and behavioral abnormalities. The proband, a 32-year-old male, exhibited intellectual disability, delayed speech, and behavioral abnormalities without autistic spectrum disorders. The novel TRIP12 variant was detected through WES and validated by Sanger sequencing in affected family members. In silico tools predicted the deleterious effect of the variant, and protein modeling indicated significant structural changes. RT-qPCR demonstrated increased TRIP12 mRNA levels, suggesting a compensatory mechanism for decreased protein stability. This study examines the role of the TRIP12 gene in the ubiquitin pathway and associated pathologies such as intellectual disability and developmental delay.