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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.

Dysmorphology is the study of human congenital malformations and combines concepts and knowledge of different medical fields, including embryology and clinical genetics. Syndromology specialises in the diagnosis of multiple congenital anomalies through the recognition of patterns of human malformations. This article provides a theoretical framework of dysmorphism and a clinical and molecular diagnostic approach to the child that presents with a congenital malformation. The assessment of a dysmorphic child must contain a detailed family, prenatal and birth history, an evaluation of the psychomotor development and a good clinical examination, including biometry, neurology and detailed description of minor and major anomalies. Dysmorphic syndromes often present variable phenotypes and may escape clinical diagnosis even when causative molecular defects are similar. Alternatively, locus heterogeneity or mutations in different genes can underlie similar phenotypes. Therefore, technical advances are shifting the field of dysmorphology from gestalt diagnoses to broad molecular diagnostics and reverse phenotyping. Key Concepts Dysmorphism refers to any observable structural abnormality of the body but colloquially is often used to indicate facial dysmorphism. The phenotype refers to the totality of the presentation including facial gestalt, congenital anomalies, psychomotor development and behavioural patterns. Pathognomonic features can be subtle but are very specific for one disorder and confirm a clinical diagnosis. Congenital anomalies are categorized into deformations, disruptions, dysplasias and malformations. Multiple congenital anomalies can be categorized as associations, syndromes or sequences. Continuous technical advances have greatly improved the diagnostic yield of molecular investigations in human malformations. Accurate diagnosis can reduce uncertainty, offer prognostic predictions, allow counselling of recurrence risk and earlier recognition of care needs through screening for additional comorbidities and better follow‐up, and guide therapeutic strategies.