Browsing by Author "Marcelis, Carlo"

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    Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome
    (Elsevier, 2022) Stephenson, Sarah E.M.; Costain, Gregory; Blok, Laura E.R.; Silk, Michael A.; Nguyen, Thanh Binh; Dong, Xiaomin; Alhuzaimi, Dana E.; Dowling, James J.; Walker, Susan; Amburgey, Kimberly; Hayeems, Robin Z.; Rodan, Lance H.; Schwartz, Marc A.; Picker, Jonathan; Lynch, Sally A.; Gupta, Aditi; Rasmussen, Kristen J.; Schimmenti, Lisa A.; Klee, Eric W.; Niu, Zhiyv; Agre, Katherine E.; Chilton, Ilana; Chung, Wendy K.; Revah-Politi, Anya; Au, P.Y. Billie; Griffith, Christopher; Racobaldo, Melissa; Raas-Rothschild, Annick; Zeev, Bruria Ben; Barel, Ortal; Moutton, Sebastien; Morice-Picard, Fanny; Carmignac, Virginie; Cornaton, Jenny; Marle, Nathalie; Devinsky, Orrin; Stimach, Chandler; Burns Wechsler, Stephanie; Hainline, Bryan E.; Sapp, Katie; Willems, Marjolaine; Bruel, Ange-Line; Dias, Kerith-Rae; Evans, Carey-Anne; Roscioli, Tony; Sachdev, Rani; Temple, Suzanna E.L.; Zhu, Ying; Baker, Joshua J.; Scheffer, Ingrid E.; Gardiner, Fiona J.; Schneider, Amy L.; Muir, Alison M.; Mefford, Heather C.; Crunk, Amy; Heise, Elizabeth M.; Millan, Francisca; Monaghan, Kristin G.; Person, Richard; Rhodes, Lindsay; Richards, Sarah; Wentzensen, Ingrid M.; Cogné, Benjamin; Isidor, Bertrand; Nizon, Mathilde; Vincent, Marie; Besnard, Thomas; Piton, Amelie; Marcelis, Carlo; Kato, Kohji; Koyama, Norihisa; Ogi, Tomoo; Suk-Ying Goh, Elaine; Richmond, Christopher; Amor, David J.; Boyce, Jessica O.; Morgan, Angela T.; Hildebrand, Michael S.; Kaspi, Antony; Bahlo, Melanie; Friðriksdóttir, Rún; Katrínardóttir, Hildigunnur; Sulem, Patrick; Stefánsson, Kári; Björnsson, Hans Tómas; Mandelstam, Simone; Morleo, Manuela; Mariani, Milena; TUDP Study Group; Scala, Marcello; Accogli, Andrea; Torella, Annalaura; Capra, Valeria; Wallis, Mathew; Jansen, Sandra; Weisfisz, Quinten; de Haan, Hugoline; Sadedin, Simon; Broad Center for Mendelian Genomics; Lim, Sze Chern; White, Susan M.; Ascher, David B.; Schenck, Annette; Lockhart, Paul J.; Christodoulou, John; Tan, Tiong Yang; Medical and Molecular Genetics, School of Medicine
    Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.
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    De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder
    (Elsevier, 2018-06-07) Reijnders, Margot R.F.; Miller, Kerry A.; Alvi, Mohsan; Goos, Jacqueline A.C.; Lees, Melissa M.; de Burca, Anna; Henderson, Alex; Kraus, Alison; Mikat, Barbara; de Vries, Bert B.A.; Isidor, Bertrand; Kerr, Bronwyn; Marcelis, Carlo; Schluth-Bolard, Caroline; Deshpande, Charu; Ruivenkamp, Claudia A.L.; Wieczorek, Dagmar; Baralle, Diana; Blair, Edward M.; Engels, Hartmut; Lüdecke, Hermann-Josef; Eason, Jacqueline; Santen, Gijs W.E.; Clayton-Smith, Jill; Chandler, Kate; Tatton-Brown, Katrina; Payne, Katelyn; Helbig, Katherine; Radtke, Kelly; Nugent, Kimberly M.; Cremer, Kirsten; Strom, Tim M.; Bird, Lynne M.; Sinnema, Margje; Bitner-Glindzicz, Maria; van Dooren, Marieke F.; Alders, Marielle; Koopmans, Marije; Brick, Lauren; Kozenko, Mariya; Harline, Megan L.; Klaassens, Merel; Steinraths, Michelle; Cooper, Nicola S.; Edery, Patrick; Yap, Patrick; Terhal, Paulien A.; van der Spek, Peter J.; Lakeman, Phillis; Taylor, Rachel L.; Littlejohn, Rebecca O.; Pfundt, Rolph; Mercimek-Andrews, Saadet; Stegmann, Alexander P.A.; Kant, Sarina G.; McLean, Scott; Joss, Shelagh; Swagemakers, Sigrid M.A.; Douzgou, Sofia; Wall, Steven A.; Küry, Sebastian; Calpena, Eduardo; Koelling, Nils; McGowan, Simon J.; Twigg, Stephen R.F.; Mathijssen, Irene M.J.; Nellaker, Christoffer; Brunner, Han G.; Wilkie, Andrew O.M.; Medical and Molecular Genetics, School of Medicine
    Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.