Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Purpose Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome

Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant pachygyria in the Finnish population

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Developing a Set of Health Indicators for People with Intellectual Disabilities: Pomona Project

The European Commission's Health Monitoring Programme culminated in the development of a set of European Community Health Indicators (ECHI) for the general population. Despite evidence of marked disparities between the health of people with intellectual disabilities (ID) and their peers in the general population, the ECHI contain no significant reference to people with ID. To address this deficit, a two-year grant from the Health Monitoring Programme was awarded to the Pomona project (a collection of researchers from 13 European countries). The project comprised exchanges of expertise; a critical review of published evidence about health and ID; and consultative processes in member states. The project's finding was that there was no systematic monitoring of the health of people with ID in EU member states and, as a consequence, a set of health indicators specific to people with ID was proposed that could lead to such systemic monitoring