Citations 2
Loss‐of‐Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder
Blackburn, Patrick R. , Herkert, Johanna C. , Rinne, Tuula , Thiffault, Isabelle, Rapp, Michele, Alders, Mariel, Maas, Saskia M. , Gérard, Bénédicte, Smol, Thomas , Vincent‐Delorme, Catherine , Isidor, Bertrand , Joset, Pascal , Husson, Thomas , Guerrot, Anne‐Marie , Bacino, Carlos A. , Macmurdo, Colleen, Thompson, Stephanie S., Faivre, Laurence , Deb, Wallid , Vignard, Virginie , Goldenberg, Alice, Lecoquierre, François , Zech, Michael , Necpál, Ján , Winkelmann, Juliane , Koprušáková, Monika Turčanová , Konstantopoulou, Vassiliki , Younce, John R. , Mighton, Chloe, Fung, Charlotte, Morel, Chantal F. , Barth, Magalie , Krapels, Ingrid P.C. , Schoot, Vyne van der , Bußmann, Cornelia, Wortmann, Saskia B. , Ravelli, Claudia , Keren, Boris , Ziegler, Alban , Hasadsri, Linda , Pichurin, Pavel N. , Klee, Eric W. , Grand, Katheryn , Sanchez‐Lara, Pedro A. , Krüger, Elke , Klinkhammer, Hannah , Tartaglia, Marco , Wang, Tianyun , Prokisch, Holger , Shinawi, Marwan , Brunet, Theresa , Tartaglia, Marco , Wang, Tianyun , Lecoquierre, Francois , Faivre, Laurence , Ebstein, Frédéric , Hsieh, Tzung‐Chien , Motta, Marialetizia , Radio, Francesca Clementina , Cogné, Benjamin , Vincent, Marie , Bachmann‐Gagescu, Ruxandra , Rauch, Anita , Ferrero, Giovanni Battista , Ciolfi, Andrea , Rosenfeld, Jill A. , Mau‐Them, Frédéric Tran , Agrawal, Pankaj B. , Madden, Jill A. , Goldenberg, Alice , Jech, Robert , Shinawi, Marwan , Lerner‐Ellis, Jordan P. , DiTroia, Stephanie P. , Bonneau, Dominique , Stegmann, Alexander P.A. , Mignot, Cyril , Zampino, Giuseppe , Mayr, Johannes A , Feichtinger, René G. , Courtin, Thomas , Bezieau, Stéphane , Krawitz, Peter Michael , Eichler, Evan E , Küry, Sébastien
Annals of Neurology | September 20, 2024 | Volume: 97 | Issue: 1 | Pages: 76-89
ObjectiveDe novo variants in cullin‐3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype–phenotype correlation, and investigate the underlying pathogenic mechanism.MethodsGenetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient‐derived T‐cells.ResultsWe assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss‐of‐function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin‐protein conjugates in vitro. Notably, we show that 4E‐BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient‐derived cells.InterpretationOur study further refines the clinical and mutational spectrum of CUL3‐associated NDDs, expands the spectrum of cullin RING E3 ligase‐associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2025;97:76–89
Understanding the Return of Genomic Sequencing Results Process: Content Review of Participant Summary Letters in the eMERGE Research Network
Lynch, John , Sharp, Richard R. , Aufox, Sharon , Bland, Harris T. , Zawatsky, Carrie L. Blout , Buchanan, Adam H. , Halverson, Colin , Harr, Margaret , Hebbring, Scott J. , Hoell, Christin , Holm, Ingrid A. , Jarvik, Gail P. , Kullo, Iftikhar, Kochan, David C., Lazzeri, Amanda L., Leppig, Kathleen A. , Madden, Jill A. , Marasà, Maddalena , Myers, Melanie F. , Peterson, Josh F. , Prows, Cynthia A. , Ralston, James D. , Rasouly, Hila Milo , Scrol, Aaron, Smith, Maureen E. , Stuttgen, Kelsey , Wiesner, Georgia L. , Wynn, Julia , Williams, Janet L. , Lynch, John A , Bland, Sarah T , Holm, Ingrid A , Milo Rasouly, Hila , Smith, Maureen E , Williams, Janet L , Myers, Melanie F , Sharp, Richard R , Jarvik, Gail P , Peterson, Josh F , Marasa, Maddalena , Hoell, Christin , Bowen, Deborah J. , Henrikson, Nora B. , Larson, Eric B. , Rahm, Alanna Kulchak , Sturm, Amy C. , Williams, Marc S
Journal of Personalized Medicine | May 14, 2020 | Volume: 10 | Issue: 2 | Pages: 38
A challenge in returning genomic test results to research participants is how best to communicate complex and clinically nuanced findings to participants in a manner that is scalable to the large numbers of participants enrolled. The purpose of this study was to examine the features of genetic results letters produced at each Electronic Medical Records and Genomics (eMERGE3) Network site to assess their readability and content. Letters were collected from each site, and a qualitative analysis of letter content and a quantitative analysis of readability statistics were performed. Because letters were produced independently at each eMERGE site, significant heterogeneity in readability and content was found. The content of letters varied widely from a baseline of notifying participants that results existed to more detailed information about positive or negative results, as well as materials for sharing with family members. Most letters were significantly above the Centers for Disease Control-suggested reading level for health communication. While continued effort should be applied to make letters easier to understand, the ongoing challenge of explaining complex genomic information, the implications of negative test results, and the uncertainty that comes with some types of test and result makes simplifying letter text challenging.