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.

Pathogenic variants in the TRIP12 gene are associated with Clark-Baraitser syndrome, a condition characterized by neurodevelopmental disorders, including intellectual disability, autism spectrum disorder (ASD), and speech delay. Phenotypic expression is variable, and facial features are not consistently present. Familial inheritance is rare. Whole-exome sequencing (WES) was performed on a proband with speech disorder and ASD, as well as on her parents. Clinical assessment included developmental, cognitive, and physical evaluations. A heterozygous missense variant c.3404A>T (p. Asp1135Val) in the TRIP12 gene was identified in both the proband and her father. Both presented with speech disorder and ASD without facial features or severe intellectual disability. In line with recent genotype-phenotype studies, missense TRIP12 variants tend to be associated with milder neurodevelopmental presentations, typically characterized by mild to moderate intellectual impairment, variable autistic traits, limited or absent facial features, and a low incidence of epilepsy. This familial case further presents the phenotypic spectrum of TRIP12 missense variants and highlights that ASD and speech disorder may occur as isolated neurodevelopmental findings without syndromic features. The report reinforces the relevance of TRIP12 analysis in the differential diagnosis of ASD and language disorders, even in individuals lacking physical traits, supporting more accurate genetic counseling and broader awareness of inherited TRIP12-related conditions.

The TRIP12 gene, encoding an E3 ligase involved in the ubiquitin-proteasome pathway, is implicated in Clark-Baraitser syndrome which causes neurodevelopmental delay and intellectual disability (ID). This study aims to present and characterize two distinct novel TRIP12 variants in two unrelated Lebanese children with neurodevelopmental delay. Exome sequencing (ES) was performed, followed by in silico assessment of variant impact on protein structure. Clinical and molecular findings were described. Literature review was carried out on previously published TRIP12 variants. Patients demonstrated hypotonia, speech and motor delay. ES uncovered a paternally inherited missense variant in the TRIP12 gene (c.5905T > A nucleotide substitution) in patient 1, and a de novo indel variant causing an in-frame change (c.4532_4538delinsC) in patient 2. Affected amino acids in both variants were highly conserved, and structural analyses of mutant variants suggested altered TRIP12 protein structure. No phenotypic distinction emerged in comparison to 70 published TRIP12 variants. This study introduces the first Lebanese TRIP12 variants in developmentally delayed patients. It expands the genotypic spectrum of TRIP12-related neurodevelopmental disorders and underscores their variable expressivity. The online version contains supplementary material available at 10.1186/s12920-025-02299-x.

Clark-Baraitser syndrome is a rare neurodevelopmental disorder associated with the E3 ubiquitin-protein ligase gene TRIP12. Using chromosomal microarray analysis (CMA), long-range PCR, breakpoint sequencing, and RNA analyses, we studied a 6-year-old female presenting with developmental delay, aggressive behavior, attention-deficit hyperactivity disorder, and mild dysmorphic features. CMA revealed a de novo ~87 kb copy-number variant (CNV) duplication at 2q36.3, involving Exons 3-14 of TRIP12. Long-range PCR and Sanger sequencing showed a head-to-tail tandem duplication with breakpoints in Introns 2 and 14. RNA analysis identified a novel splicing junction between the coding Exon 14 and the stop codon of the noncoding portion of Exon 3, resulting in a premature translation termination. This suggests the neo-transcript undergoes nonsense-mediated decay and/or produces a truncated protein lacking the critical E6AP-type E3 ubiquitin-protein ligase domain. This case further highlights the challenges with the clinical interpretation of CNV gains and the usefulness of RNA sequencing in the clarification of the impacts of intragenic duplications.

The oxidative stress response is centered on the transcription factor NRF2 and protects cells from reactive oxygen species (ROS). While ROS inhibit the E3 ligase CUL3 KEAP1 to stabilize NRF2 and elicit antioxidant gene expression, cells recovering from stress must rapidly reactivate CUL3 KEAP1 to prevent reductive stress and oxeiptosis-dependent cell death. How cells restore efficient NRF2-degradation upon ROS clearance remains poorly understood. Here, we identify TRIP12, an E3 ligase dysregulated in Clark-Baraitser Syndrome and Parkinson's Disease, as a component of the oxidative stress response. TRIP12 is a ubiquitin chain elongation factor that cooperates with CUL3 KEAP1 to ensure robust NRF2 degradation. In this manner, TRIP12 accelerates stress response silencing as ROS are being cleared, but limits NRF2 activation during stress. The need for dynamic control of NRF2-degradation therefore comes at the cost of diminished stress signaling, suggesting that TRIP12 inhibition could be used to treat degenerative pathologies characterized by ROS accumulation.