RESUMEN
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 METHODS: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum.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.
Asunto(s)
Epilepsia , N-Metiltransferasa de Histona-Lisina , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Epilepsia/diagnóstico , Epilepsia/genética , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Masculino , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Fenotipo , Convulsiones/diagnóstico , Convulsiones/genéticaRESUMEN
Metagenomic analysis is a powerful approach for wholesale characterizations of microbial populations like those that operate within municipal wastewater treatment plants. It is well known that many problems are associated with the overgrowth or undergrowth of specific bacterial genera. We describe a database of the combined metagenomes of activated sludge aeration basins from around the globe and use it as a reference to study the population of a foamy activated sludge aeration basin. We show that foam production is associated with blooms of mycolic acid producing genera, especially Mycobacterium. We confirm this bloom using the acid-fast stain, and we show that genes involved with mycolic acid production are enriched in the foam-producing sample. In addition, we show that this sample has unusual nitrifying populations. We suggest that low-cost DNA sequencing and publicly available tools for shotgun metagenomic analyses, including those described here, might broadly facilitate wastewater treatment plant operation.