Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders.

Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability. By international collaboration, we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders. By western blotting, we investigated the consequences of missense variants in vitro. In accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe developmental and epileptic encephalopathy in 16 individuals. Now, we also identified de novo missense variants in the GTPase domain in 6 individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences. Furthermore, we observed biallelic splice-site and truncating variants in 9 families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well. By identifying genotype-phenotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying biallelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2-related phenotypes, including both autosomal dominant and recessive neurodevelopmental disorders. Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Citation

Franziska Langhammer, Reza Maroofian, Rueda Badar, Anne Gregor, Michelle Rochman, Jeffrey B Ratliff, Marije Koopmans, Theresia Herget, Maja Hempel, Fanny Kortüm, Delphine Heron, Cyril Mignot, Boris Keren, Susan Brooks, Christina Botti, Bruria Ben-Zeev, Emanuela Argilli, Elliot H Sherr, Vykuntaraju K Gowda, Varunvenkat M Srinivasan, Somayeh Bakhtiari, Michael C Kruer, Mustafa A Salih, Alma Kuechler, Eric A Muller, Karli Blocker, Outi Kuismin, Kristen L Park, Aaina Kochhar, Kathleen Brown, Subhadra Ramanathan, Robin D Clark, Magdeldin Elgizouli, Gia Melikishvili, Nazhi Tabatadze, Zornitza Stark, Ghayda M Mirzaa, Jinfon Ong, Ute Grasshoff, Andrea Bevot, Lydia von Wintzingerode, Rami A Jamra, Yvonne Hennig, Paula Goldenberg, Chadi Al Alam, Majida Charif, Redouane Boulouiz, Mohammed Bellaoui, Rim Amrani, Fuad Al Mutairi, Abdullah M Tamim, Firdous Abdulwahab, Fowzan S Alkuraya, Ebtissal M Khouj, Javeria R Alvi, Tipu Sultan, Narges Hashemi, Ehsan G Karimiani, Farah Ashrafzadeh, Shima Imannezhad, Stephanie Efthymiou, Henry Houlden, Heinrich Sticht, Christiane Zweier. Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders. Genetics in medicine : official journal of the American College of Medical Genetics. 2023 Aug;25(8):100885

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PMID: 37165955

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