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.

Screening for hypo- or hyperthyroidism in adults is generally done by measuring the serum thyrotropin (thyroid-stimulating hormone, TSH) concentration. This is an efficient approach in case of suspected acquired thyroid disease. However, in infants and children, congenital hypothalamus-pituitary-thyroid (HPT) axis disorders also need to be considered, including primary and central congenital hypothyroidism, and even rarer thyroid hormone receptor and transporter defects. In primary congenital hypothyroidism, TSH will be elevated, but in the other congenital HPT axis disorders, TSH is usually within the normal range. Free thyroxine (FT4) assessment is essential for the diagnosis in these conditions.Conclusion: Here we discuss a number of rare congenital HPT axis disorders in which TSH is normal, but FT4 is low, and provide a clinical algorithm to distinguish between these disorders. What is Known:• A single thyroid-stimulating hormone (TSH) measurement is an appropriate screening method for primary hypothyroidism.• For central hypothyroidism and rare thyroid hormone receptor and transporter defects a free thyroxine (FT4) measurement is essential for the diagnosis because TSH is usually normal. What is New:• Here we present a new problem-oriented clinical algorithm including a diagnostic flow-chart for low FT4 and normal TSH in infants and children.