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
A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants
Borroto, Maria Carla , Michaud, Coralie , Hudon, Chloé, Agrawal, Pankaj B. , Agre, Katherine , Applegate, Carolyn , Beggs, Alan H. , Callewaert, Bert , Chen, Mei-Jan, Curry, Cynthia J. , Devinsky, Orrin , Dudding‐Byth, Tracy , Fagan, K, Finnila, Candice R. , Gavrilova, Ralitza, Hiatt, Susan M. , Hildebrandt, Friedhelm , Wojcik, Monica H. , Kleefstra, Tjitske, Kolvenbach, Caroline M. , Korf, Bruce R. , Kruszka, Paul , Li, Hong , Litwin, Jessica, Marcadier, Julien , Platzer, Konrad , Blackburn, Patrick R. , Reijnders, Margot R.F. , Reutter, Heiko , Schanze, Ina, Shieh, Joseph T.C. , Stevens, Cathy A., Valivullah, Zaheer M. , Boogaard, Marie‐José H. van den , Klee, Eric W. , Campeau, Philippe M. , Applegate, Carolyn D , Callewaert, Bert , Devinsky, Orrin , Wojcik, Monica H , Kruszka, Paul , Platzer, Konrad , Reutter, Heiko , van den Boogaard, Marie-José , Klee, Eric W , Campeau, Philippe M , Beggs, Alan H , Björnsson, Hans T. , Genetti, Casie A. , Kleefstra, Tjitske
Genes | August 6, 2024 | Volume: 15 | Issue: 8 | Pages: 1033
Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in KDM5B, including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in KDM5B. We performed deep phenotyping and collected the clinical information and molecular data of these individuals’ family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive KDM5B variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the KDM5B-related neurodevelopmental disorder and suggests the pathogenicity of certain dominant KDM5B missense variants.