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

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 Kievit, Marjon van Slegtenhorst, Nicholas M Allen, Caroline M Kehoe, Hannah K Robinson, Lewis Pang, Selina H Banu, Mashaya Zaman, Stephanie Efthymiou, Henry Houlden, Irma JärveläLeena Lauronen, Tuomo Määttä, Isabelle Schrauwen, Suzanne M Leal, Claudia A L Ruivenkamp, Daniela Q C M Barge-Schaapveld, Cacha M P C D Peeters-Scholte, Hamid Galehdari, Neda Mazaheri, Sanjay M Sisodiya, Victoria Harrison, Angela Sun, Jenny Thies, Luis Alberto Pedroza, Yana Lara-Taranchenko, Ivan 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 M Mirzaa, Andrew E Timms, Joshua Scheck, Mariet W Elting, Abeltje M Polstra, Lauren Schenck, Maura R Z Ruzhnikov, Annalisa Vetro, Martino Montomoli, Renzo Guerrini, Daniel C Koboldt, Theresa Mihalic Mosher, Matthew T Pastore, Kim L McBride, Jing Peng, Zou Pan, Marjolein 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, Marielle E van Gijn, Catherine Quindipan, Matthew A Deardorff, J Austin Hamm, Abbey M Putnam, Rebecca Baud, Laurence Walsh, Sally A Lynch, Julia Baptista, Richard E Person, Kristin G Monaghan, Amy Crunk, Jennifer Keller-Ramey, Adi Reich, Houda Zghal Elloumi, Marielle Alders, Jennifer Kerkhof, Haley McConkey, Sadegheh Haghshenas, Genomics England Research Consortium, Reza Maroofian, Bekim Sadikovic, Siddharth Banka, Tahsin Stefan Barakat, Tahsin Stefan Barakat

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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on characterizing an expanded patient cohort.MethodsWe perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum.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.

ASJC Scopus subject areas

  • Genetics(clinical)


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