Browsing by Author "Tan, Tiong Yang"

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    A dyadic approach to the delineation of diagnostic entities in clinical genomics
    (Cell Press, 2021-01-07) Biesecker, Leslie G.; Adam, Margaret P.; Alkuraya, Fowzan S.; Amemiya, Anne R.; Bamshad, Michael J.; Beck, Anita E.; Bennett, James T.; Bird, Lynne M.; Carey, John C.; Chung, Brian; Clark, Robin D.; Cox, Timothy C.; Curry, Cynthia; Palko Dinulos, Mary Beth; Dobyns, William B.; Giampietro, Philip F.; Girisha, Katta M.; Glass, Ian A.; Graham, John M., Jr.; Gripp, Karen W.; Haldeman-Englert, Chad R.; Hall, Bryan D.; Innes, A. Micheil; Kalish, Jennifer M.; Keppler-Noreuil, Kim M.; Kosaki, Kenjiro; Kozel, Beth A.; Mirzaa, Ghayda M.; Mulvihill, John J.; Nowaczyk, Malgorzata J.M.; Pagon, Roberta A.; Retterer, Kyle; Rope, Alan F.; Sanchez-Lara, Pedro A.; Seaver, Laurie H.; Shieh, Joseph T.; Slavotinek, Anne M.; Sobering, Andrew K.; Stevens, Cathy A.; Stevenson, David A.; Tan, Tiong Yang; Tan, Wen-Hann; Tsai, Anne C.; Weaver, David D.; Williams, Marc S.; Zackai, Elaine; Zarate, Yuri A.; Medical and Molecular Genetics, School of Medicine
    The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.
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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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    Response to Hamosh et al
    (Elsevier, 2021) Biesecker, Leslie G.; Adam, Margaret P.; Alkuraya, Fowzan S.; Amemiya, Anne R.; Bamshad, Michael J.; Beck, Anita E.; Bennett, James T.; Bird, Lynne M.; Carey, John C.; Chung, Brian; Clark, Robin D.; Cox, Timothy C.; Curry, Cynthia; Dinulos, Mary Beth Palko; Dobyns, William B.; Giampietro, Philip F.; Girisha, Katta M.; Glass, Ian A.; Graham, John M., Jr.; Gripp, Karen W.; Haldeman-Englert, Chad R.; Hall, Bryan D.; Innes, A. Micheil; Kalish, Jennifer M.; Keppler-Noreuil, Kim M.; Kosaki, Kenjiro; Kozel, Beth A.; Mirzaa, Ghayda M.; Mulvihill, John J.; Nowaczyk, Malgorzata J.M.; Pagon, Roberta A.; Retterer, Kyle; Rope, Alan F.; Sanchez-Lara, Pedro A.; Seaver, Laurie H.; Shieh, Joseph T.; Slavotinek, Anne M.; Sobering, Andrew K.; Stevens, Cathy A.; Stevenson, David A.; Tan, Tiong Yang; Tan, Wen-Hann; Tsai, Anne C.; Weaver, David D.; Williams, Marc S.; Zackai, Elaine; Zarate, Yuri A.; Medical and Molecular Genetics, School of Medicine