Browsing by Author "van Slegtenhorst, Marjon"

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    BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms
    (Elsevier, 2020-12-03) Barish, Scott; Barakat, Tahsin Stefan; Michel, Brittany C.; Mashtalir, Nazar; Phillips, Jennifer B.; Valencia, Alfredo M.; Ugur, Berrak; Wegner, Jeremy; Scott, Tiana M.; Bostwick, Brett; Murdock, David R.; Dai, Hongzheng; Perenthaler, Elena; Nikoncuk, Anita; van Slegtenhorst, Marjon; Brooks, Alice S.; Keren, Boris; Nava, Caroline; Mignot, Cyril; Douglas, Jessica; Rodan, Lance; Nowak, Catherine; Ellard, Sian; Stals, Karen; Lynch, Sally Ann; Faoucher, Marie; Lesca, Gaetan; Edery, Patrick; Engleman, Kendra L.; Zhou, Dihong; Thiffault, Isabelle; Herriges, John; Gass, Jennifer; Louie, Raymond J.; Stolerman, Elliot; Washington, Camerun; Vetrini, Francesco; Otsubo, Aiko; Pratt, Victoria M.; Conboy, Erin; Treat, Kayla; Shannon, Nora; Camacho, Jose; Wakeling, Emma; Yuan, Bo; Chen, Chun-An; Rosenfeld, Jill A.; Westerfield, Monte; Wangler, Michael; Yamamoto, Shinya; Kadoch, Cigall; Scott, Daryl A.; Bellen, Hugo J.; Medical and Molecular Genetics, School of Medicine
    SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.
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    Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome
    (Elsevier, 2021-11) 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, Jeffery; Yang, Lin; Huang, Shaoping; Wang, Xiaodong; Jewett, Tamison; Rosso, Gretchen; Lin, Xi; Mohammed, Shehla; Merritt, J. Lawrence, II.; Mirzaa, Ghayda M.; Timms, Andrew E.; Scheck, Joshua; Elting, Mariet W.; Polstra, Abeltje M.; Schenck, Lauren; Ruzhnikov, Maura R.Z.; Vetro, Annalisa; Montomoli, Martino; Guerrini, Renzo; Koboldt, Daniel C.; Mihalic Mosher, Theresa; 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 E.; Quindipan, Catherine; Deardorff, Matthew A.; Hamm, J. Austin; 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; Maroofian, Reza; Sadikovic, Bekim; Banka, Siddharth; Arold, Stefan T.; Barakat, Tahsin Stefan; Medical and Molecular Genetics, School of Medicine
    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.