Episignature Mapping of TRIP12 Provides Functional Insight into Clark–Baraitser Syndrome

Abstract

Clark–Baraitser syndrome is a rare autosomal dominant intellectual disability syndrome caused by pathogenic variants in the TRIP12 (Thyroid Hormone Receptor Interactor 12) gene. TRIP12 encodes an E3 ligase in the ubiquitin pathway. The ubiquitin pathway includes activating E1, conjugating E2 and ligating E3 enzymes which regulate the breakdown and sorting of proteins. This enzymatic pathway is crucial for physiological processes. A significant proportion of TRIP12 variants are currently classified as variants of unknown significance (VUS). Episignatures have been shown to represent a powerful diagnostic tool to resolve inconclusive genetic findings for Mendelian disorders and to re-classify VUSs. Here, we show the results of DNA methylation episignature analysis in 32 individuals with pathogenic, likely pathogenic and VUS variants in TRIP12. We identified a specific and sensitive DNA methylation (DNAm) episignature associated with pathogenic TRIP12 variants, establishing its utility as a clinical biomarker for Clark–Baraitser syndrome. In addition, we performed analysis of differentially methylated regions as well as functional correlation of the TRIP12 genome-wide methylation profile with the profiles of 56 additional neurodevelopmental disorders.

The intrinsically disordered region of the E3 ubiquitin ligase TRIP12 induces the formation of chromatin condensates and interferes with DNA damage response

“…Given the inhibitory effect on MDC1 foci formation, it is likely that the IDR of TRIP12 simultaneously participates in the chemosensitivity of cancer cells. Finally, numerous studies have reported an association between Trip12 mutations and intellectual deficiencies such as Clark-Baraister syndrome 21,54 . The molecular mechanisms involved are currently unknown.…”

“…TRIP12 alterations have been involved in several pathologies. Indeed, TRIP12 gene mutations are tightly associated with intellectual disabilities such as Clark-Baraitser syndrome 20,21 and autism spectrum disorders 22–24 . It is also reported that TRIP12 protein is overexpressed in several types of cancer and preneoplastic lesions 3,25 .…”

Identification of the DNA methylation signature of Mowat-Wilson syndrome

“…Previously published articles were used as a basis for functional annotation and episignature cohort comparison [ 22 – 24 ]. We assessed the percentage of differentially methylated probes (DMPs) shared between the MOWS episignature and those referring to 56 neurodevelopmental disorder episignatures included in the EpiSign v3 clinical classifier, and produced heatmaps and circos plots.…”

“…In particular, the EpiSign classifier has proven to be a useful tool for the reclassification of VUS as well as to confirm/reject a clinical diagnosis [ 21 ]. EpiSign v3 assay has been reported to detect over 58 episignatures across more than 65 diseases, in particular NDDs [ 22 – 24 ].…”