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

Marjolein J. A. Weerts, Kristina Lanko, Francisco J. Guzman-Vega, Adam Jackson, Reshmi Ramakrishnan, Kelly J. Cardona-Londono, Karla A. Pena-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 JarvelaLeena Lauronen, Tuomo Maatta, 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, Marjolein Willemsen, Susanne Koning, Genomics England Research Consortium, Tahsin Stefan Barakat*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum.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.

Original languageEnglish
Pages (from-to)2122-2137
Number of pages16
JournalGenetics in Medicine
Issue number11
Early online date3 Aug 2021
Publication statusPublished - Nov 2021


  • 12Q24.31
  • SETD1B

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