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

2021; Elsevier BV; Volume: 23; Issue: 11 Linguagem: Inglês

10.1038/s41436-021-01246-2

1530-0366

Marjolein J.A. Weerts, Kristina Lanko, Francisco J. Guzmán‐Vega, Adam Jackson, Reshmi Ramakrishnan, Kelly J. Cardona‐Londoño, Karla A. Peña‐Guerra, Yolande van Bever, Barbara W. van Paassen, Anneke J.A. Kievit, Marjon van Slegtenhorst, Nicholas M. Allen, Caroline M. Kehoe, Hannah K. Robinson, Lewis Pang, Selina Banu, Mashaya Zaman, Stéphanie Efthymiou, Henry Houlden, Irma Järvelä, Leena Lauronen, Tuomo Määttä, Isabelle Schrauwen, Suzanne M. Leal, Claudia Ruivenkamp, Daniela Q.C.M. Barge‐Schaapveld, Cacha Peeters‐Scholte, Hamid Galehdari, Neda Mazaheri, Sanjay M. Sisodiya, Victoria Harrison, Angela Sun, Jenny Thies, Luis Alberto Pedroza, Yana Lara-Taranchenko, Iván K. Chinn, James R. Lupski, Alexandra Garza-Flores, Jeffery McGlothlin, Lin Yang, Shaoping Huang, Xiaodong Wang, Tamison Jewett, Gretchen Rosso, Xi Lin, Shehla Mohammed, J. Lawrence Merritt, Ghayda Mirzaa, Andrew E. Timms, Joshua Scheck, Mariet W. Elting, Abeltje M. Polstra, Lauren Schenck, Maura Ruzhnikov, Annalisa Vetro, Martino Montomoli, Renzo Guerrini, Daniel C. Koboldt, Theresa Mihalic Mosher, Matthew Pastore, Kim L. McBride, Jing Peng, Pan Zou, Marjolein H. Willemsen, Susanne Koning, Peter D. Turnpenny, Bert B.A. de Vries, Christian Gilissen, Rolph Pfundt, Melissa Lees, Stephen R. Braddock, Kara C. Klemp, Fleur Vansenne, Mariëlle van Gijn, Catherine Quindipan, Matthew A. Deardorff, J. Austin Hamm, Abbey M. Putnam, Rebecca Baud, Laurence E. Walsh, Sally Ann Lynch, Júlia Baptista, Richard Person, Kristin G. Monaghan, Amy Crunk, Jennifer Keller‐Ramey, Adi Reich, Houda Zghal Elloumi, Mariëlle Alders, Jennifer Kerkhof, Haley McConkey, Sadegheh Haghshenas, Reza Maroofian, Bekim Sadiković, Siddharth Banka, Stefan T. Arold, Tahsin Stefan Barakat,

Genomic variations and chromosomal abnormalities

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.