Buchumschlag

De novo variants in RAB11B cause various degrees of lobal developmental delay and intellectual disability in children

Background - RAB11B was described previously once with a severe form of intellectual disability. We aim at validation and delineation of the role of RAB11B in neurodevelopmental disorders. - Methods - We present seven novel individuals with disease-associated variants in RAB11B when compared with th...

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Hauptverfasser: Ahmad, Natalie (VerfasserIn) , Fazeli, Walid (VerfasserIn) , Schließke, Sophia (VerfasserIn) , Lesca, Gaetan (VerfasserIn) , Gokce-Samar, Zeynep (VerfasserIn) , Mekbib, Kedous Y. (VerfasserIn) , Jin, Sheng Chih (VerfasserIn) , Burton, Jennifer (VerfasserIn) , Hoganson, George (VerfasserIn) , Petersen, Andrea (VerfasserIn) , Gracie, Sara (VerfasserIn) , Granger, Leslie (VerfasserIn) , Bartels, Enrika (VerfasserIn) , Oppermann, Henry (VerfasserIn) , Kundishora, Adam (VerfasserIn) , Till, Marianne (VerfasserIn) , Milleret-Pignot, Clara (VerfasserIn) , Dangerfield, Shane (VerfasserIn) , Viskochil, David (VerfasserIn) , Anderson, Katherine J. (VerfasserIn) , Palculict, Timothy Blake (VerfasserIn) , Schnur, Rhonda E. (VerfasserIn) , Wentzensen, Ingrid M. (VerfasserIn) , Tiller, George E. (VerfasserIn) , Kahle, Kristopher T. (VerfasserIn) , Kunz, Wolfram S. (VerfasserIn) , Burkart, Sebastian (VerfasserIn) , Simons, Matias (VerfasserIn) , Sticht, Heinrich (VerfasserIn) , Abou Jamra, Rami (VerfasserIn) , Neuser, Sonja (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: November 2023
In: Pediatric neurology
Year: 2023, Jahrgang: 148, Pages: 164-171
ISSN:1873-5150
DOI:10.1016/j.pediatrneurol.2023.08.023
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.pediatrneurol.2023.08.023
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0887899423002813
Volltext
Verfasserangaben:Natalie Ahmad, Walid Fazeli, Sophia Schließke, Gaetan Lesca, Zeynep Gokce-Samar, Kedous Y. Mekbib, Sheng Chih Jin, Jennifer Burton, George Hoganson, Andrea Petersen, Sara Gracie, Leslie Granger, Enrika Bartels, Henry Oppermann, Adam Kundishora, Marianne Till, Clara Milleret-Pignot, Shane Dangerfield, David Viskochil, Katherine J. Anderson, Timothy Blake Palculict, Rhonda E. Schnur, Ingrid M. Wentzensen, George E. Tiller, Kristopher T. Kahle, Wolfram S. Kunz, Sebastian Burkart, Matias Simons, Heinrich Sticht, Rami Abou Jamra, Sonja Neuser
Beschreibung
Zusammenfassung:Background - RAB11B was described previously once with a severe form of intellectual disability. We aim at validation and delineation of the role of RAB11B in neurodevelopmental disorders. - Methods - We present seven novel individuals with disease-associated variants in RAB11B when compared with the six cases described in the literature. We performed a cross-sectional analysis to identify the clinical spectrum and the core phenotype. Additionally, structural effects of the variants were assessed by molecular modeling. - Results - Seven distinct de novo missense variants were identified, three of them recurrent (p.(Gly21Arg), p.(Val22Met), and p.(Ala68Thr)). Molecular modeling suggests that those variants either affect the nucleotide binding (at amino acid positions 21, 22, 33, 68) or the interaction with effector molecules (at positions 72 and 75). Our data confirmed the main manifestations as neurodevelopmental disorder with intellectual disability (85%), muscular hypotonia (83%), structural brain anomalies (77%), and visual impairment (70%). Combined analysis indicates a genotype-phenotype correlation; variants impacting the nucleotide binding cause a severe phenotype with intellectual disability, and variants outside the binding pocket lead to a milder phenotype with epilepsy. - Conclusions - We confirm that disease-associated missense variants in RAB11B cause a neurodevelopmental disorder and suggest a genotype-phenotype correlation based on the impact on nucleotide binding functionality of RAB11B.
Beschreibung:Gesehen am 22.01.2024
Beschreibung:Online Resource
ISSN:1873-5150
DOI:10.1016/j.pediatrneurol.2023.08.023

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