Browsing by Author "Slavotinek, Anne M."

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    De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations
    (Elsevier, 2022-09) Dias, Kerith-Rae; Carlston, Colleen M.; Blok, Laura E. R.; De Hayr , Lachlan; Nawaz, Urwah; Evans, Carey-Anne; Bayrak-Toydemir, Pinar; Htun, Stephanie; Zhu, Ying; Ma, Alan; Lynch, Sally Ann; Moorwood, Catherine; Stals , Karen; Ellard, Sian; Bainbridge, Matthew N.; Friedman, Jennifer; Pappas, John G.; Rabin , Rachel; Nowak, Catherine B.; Douglas, Jessica; Wilson, Theodore E.; Guillen Sacoto, Maria J.; Mullegama, Sureni V.; Palculict , Timothy Blake; Kirk, Edwin P.; Pinner, Jason R.; Edwards, Matthew; Montanari, Francesca; Graziano, Claudio; Pippucci, Tommaso; Dingmann, Bri; Glass , Ian; Mefford , Heather C.; Shimoji , Takeyoshi; Suzuki, Toshimitsu; Yamakawa, Kazuhiro; Streff, Haley; Schaaf, Christian P.; Slavotinek, Anne M.; Voineagu , Irina; Carey, John C.; Buckley, Michael F.; Schenck, Annette; Harvey, Robert J.; Roscioli , Tony; Medical and Molecular Genetics, School of Medicine
    Purpose ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. Methods An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. Results ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the Drosophila ZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. Conclusion We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability.
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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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    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