Delineating the molecular and phenotypic spectrum of theSETD1B-related syndrome
Authors: Weerts Marjolein J.A. , Lanko Kristina , Guzmán-Vega Francisco J. , Jackson Adam , Ramakrishnan Reshmi , Cardona-Londoño Kelly J. , Peña-Guerra Karla A. , van Bever Yolande , van Paassen Barbara W. , Kievit Anneke , van Slegtenhorst Marjon , Allen Nicholas M. , Kehoe Caroline M. , Robinson Hannah K. , Pang Lewis , Banu Selina H. , Zaman Mashaya , Efthymiou Stephanie , Houlden Henry , Järvelä Irma , Lauronen Leena , Määttä Tuomo , Schrauwen Isabelle , Leal Suzanne M , Ruivenkamp Claudia A.L , Barge-Schaapveld Daniela Q.C.M. , Peeters-Scholte Cacha M.P.C.D. , Galehdari Hamid , Mazaheri Neda , Sisodiya Sanjay M , Harrison Victoria , Sun Angela , Thies Jenny , Pedroza Luis Alberto , Lara-Taranchenko Yana , Chinn Ivan K. , Lupski James R. , Garza-Flores Alexandra , McGlothlin Jefferey , Yang Lin , Huang Shaoping , Wang Xiaodong , Jewett Tamison , Rosso Gretchen , Lin Xi , Mohammed Shehla , Merritt J. Lawrence , Mirzaa Ghayda M. , Timms Andrew E. , Scheck Joshua , Elting Mariet , Polstra Abeltje M. , Schenck Lauren , Ruzhnikov Maura R.Z. , Vetro Annalisa , Montomoli Martino , Guerrini Renzo , Koboldt Daniel C. , Mosher Theresa Mihalic , Pastore Matthew T. , McBride Kim L. , Peng Jing , Pan Zou , Willemsen Marjolein , Koning Susanne , Turnpenny Peter D. , de Vries Bert B.A. , Gilissen Christian , Pfundt Rolph , Lees Melissa , Braddock Stephen R. , Klemp Kara C. , Vansenne Fleur , van Gijn Marielle , Quindipan Catherine , Deardorff Matthew A. , Austin Hamm J. , Putnam Abbey M. , Baud Rebecca , Walsh Laurence , Lynch Sally A. , Baptista Julia , Person Richard E. , Monaghan Kristin G. , Crunk Amy , Keller-Ramey Jennifer , Reich Adi , Elloumi Houda Zghal , Alders Marielle , Kerkhof Jennifer , McConkey Haley , Haghshenas Sadegheh ,   Genomics England Research Consortium, Maroofian Reza , Sadikovic Bekim , Banka Siddharth , Arold Stefan T. , Barakat Tahsin Stefan 
Published: February 2021

Pathogenic variants inSETD1Bhave been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay and seizures. To date, clinical features have been described for eleven patients with (likely) pathogenicSETD1Bsequence variants. We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals withSETD1Bsequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested usingin vitroand genome-wide methylation assays. Our data present evidence for a loss-of-function mechanism ofSETD1Bvariants, 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, suggestingSETD1Bdysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Interestingly, males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum ofSETD1Bvariants. Finally, despite the possibility of non-redundant contributions ofSETD1Band its paralogue SETD1A to epigenetic control, the clinical phenotypes of the related disorders share many similarities, indicating that elucidating shared and divergent downstream targets of both genes will help to understand the mechanism leading to the neurobehavioral phenotypes. Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with theSETD1B-related syndrome.