Suchergebnisse

PurposePathogenic 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on characterizing an expanded patient cohort.MethodsWe perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum.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.ResultsOur 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.ConclusionInsights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome. ; We thank all patients and families for participation in this study. Part of this research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. Family 2 was collected as part of the SYNaPS Study Group collaboration funded by The Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033aIA) and research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. HH is funded by The MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA). G.M.M. was supported by Jordan's Guardian Angels, the Brotman Baty Institute, and the Sunderland Foundation. J.R.L. acknowledges support by the Baylor Hopkins Center for Mendelian Genomics funded by the US National Human Genome Research Institute (UM1 HG006542). The DECODE-EE project (Health Research Call 2018, Tuscany Region) provided research funding to R.G. The Epilepsy Society supported this work, with funding to S.M.S. S.M.S. acknowledges that his work was partly carried out at NIHR University College London Hospitals Biomedical Research Centre, which receives a proportion of funding from the UK Department of Health's NIHR Biomedical Research Centres funding scheme. A.J. is supported by Solve-RD. The Solve-RD project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement number 779257. STA, R.R., K.J.C.L., K.A.P.G., and F.J.G.V. were supported by funding from King Abdullah University of Science and Technology (KAUST) through the baseline fund and award numbers FCC/1/1976-25 and REI/1/4446-01 from the Office of Sponsored Research (OSR). T.S.B.'s lab is supported by the Netherlands Organisation for Scientific Research (ZonMW Veni, grant 91617021), a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018.