Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Thyroid hormone receptor interactor 12 (TRIP12) encodes an E3 ubiquitin-protein ligase essential for proteasomal degradation and chromatin remodeling. Haploinsufficiency of TRIP12 is established as the molecular basis of Clark-Baraitser syndrome, an autosomal dominant neurodevelopmental disorder characterized by intellectual disability, speech and motor delay, and distinctive facial gestalt. Functional evidence implicates loss of critical E6AP-type ligase activity underlying the phenotype.
Initial reports identified nine inactivating TRIP12 variants—including two frameshifts, one missense, one splice, and five deletion CNVs—with seven confirmed de novo, in probands presenting with intellectual disability and dysmorphic features, supporting a loss-of-function mechanism (PMID:28251352). Subsequent detailed analysis of two unrelated Chinese patients uncovered one de novo frameshift duplication and one synonymous variant inducing exon 12 skipping, both leading to truncated transcripts escaping nonsense-mediated decay (PMID:36275919).
A cohort of 38 individuals (37 novel, one previously published) further delineated the TRIP12-associated phenotype, reporting 35 frameshift (n=15), nonsense (n=6), missense (n=5), splice (n=3), intragenic deletion (n=4) and multigene deletion (n=2) variants with universal global developmental delay and variable autism, obesity susceptibility, and facial features (PMID:36747006). DNA methylation episignature analysis in 32 affected individuals demonstrated a specific and sensitive DNAm signature, reclassifying VUSs and serving as a robust clinical biomarker for Clark-Baraitser syndrome (PMID:36430143).
More recently, a de novo ~87 kb intragenic tandem duplication spanning exons 3–14 was shown to create a neo-junction that triggers transcript degradation or produces a truncated protein lacking the ligase domain in a 6-year-old with developmental delay, aggression, ADHD, and dysmorphism (PMID:40062706). A multiplex family study also reported a novel TRIP12 variant segregating with intellectual disability and behavioral abnormalities, with increased TRIP12 mRNA levels suggesting compensatory upregulation in response to protein instability (PMID:40172777).
Mechanistic studies across models confirm haploinsufficiency as the pathogenic mechanism: quantitative PCR of splicing mutations reveals markedly reduced TRIP12 mRNA, episignature profiling aligns genome-wide methylation alterations with other neurodevelopmental disorders, and RT-qPCR assays show dysregulated expression of proteasome targets. These findings converge to validate TRIP12 loss-of-function and its downstream epigenetic impact in Clark-Baraitser syndrome.
Collectively, TRIP12 demonstrates a definitive gene–disease relationship with Clark-Baraitser syndrome, supported by extensive de novo LoF variant data, segregation, and concordant functional assays. Genetic testing for TRIP12 variants alongside DNA methylation episignature profiling provides a reliable diagnostic approach and reclassification avenue for uncertain variants.
Gene–Disease AssociationDefinitiveOver 70 unrelated probands across multiple studies, including de novo loss-of-function and CNV variants, with consistent segregation and functional concordance Genetic EvidenceStrongDe novo variants in >70 probands spanning LoF and CNV classes, fulfilling case-level and segregation criteria Functional EvidenceModerateConcordant RNA analyses, episignature profiling, and quantitative PCR demonstrate haploinsufficiency mechanism |