Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders

Langhammer F, Maroofian R, Badar R, Gregor A, Rochman M, Ratliff JB, Koopmans M, Herget T, Hempel M, Kortüm F, Heron D, Mignot C, Keren B, Brooks S, Botti C, Ben-Zeev B, Argilli E, Sherr EH, Gowda VK, Srinivasan VM, Bakhtiari S, Kruer MC, Salih MA, Kuechler A, Muller EA, Blocker K, Kuismin O, Park KL, Kochhar A, Brown K, Ramanathan S, Clark RD, Elgizouli M, Melikishvili G, Tabatadze N, Stark Z, Mirzaa GM, Ong J, Grasshoff U, Bevot A, von Wintzingerode L, Jamra RA, Hennig Y, Goldenberg P, Al Alam C, Charif M, Boulouiz R, Bellaoui M, Amrani R, Al Mutairi F, Tamim AM, Abdulwahab F, Alkuraya FS, Khouj EM, Alvi JR, Sultan T, Hashemi N, Karimiani EG, Ashrafzadeh F, Imannezhad S, Efthymiou S, Houlden H, Sticht H, Zweier C (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Book Volume: 25

Article Number: 100885

Journal Issue: 8

DOI: 10.1016/j.gim.2023.100885

Abstract

Purpose: Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability. Methods: 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. Results: 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. Conclusion: 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.

Authors with CRIS profile

Involved external institutions

Inselspital, Universitätsspital Bern Switzerland (CH) University College London (UCL) United Kingdom (GB) Thomas Jefferson University United States (USA) (US) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière France (FR) Chaim Sheba Medical Center at Tel HaShomer / המרכז הרפואי עש חיים שיבא – תל השומר‎‎ Israel (IL) University of California San Francisco (UCSF) United States (USA) (US) Indira Gandhi Institute of Child Health India (IN) Phoenix Children's Hospital United States (USA) (US) Universitätsklinikum Essen Germany (DE) The State University of New Jersey (Rutgers) United States (USA) (US) Stanford University United States (USA) (US) Oulu University Hospital Finland (FI) University of Colorado Anschutz Medical Campus United States (USA) (US) Loma Linda University (LLU) United States (USA) (US) MediClubGeorgia Georgia (GE) Murdoch Childrens Research Institute Australia (AU) Center for Integrative Brain Research United States (USA) (US) Child Neurology Consultants of Austin United States (USA) (US) Eberhard Karls Universität Tübingen Germany (DE) Universitätsklinikum Tübingen Germany (DE) Universität Leipzig Germany (DE) Massachusetts General Hospital United States (USA) (US) American Center for Psychiatry and Neurology (ACPN) United Arab Emirates (AE) Mohammed First University / Université Mohammed Premier / جامعة محمد الأول Morocco (MA) ​King Abdulaziz Medical City Saudi Arabia (SA) King Faisal Specialist Hospital & Research Centre Saudi Arabia (SA) Children Hospital Lahore Pakistan (PK) Mashhad University of Medical Sciences (MUMS) Iran, Islamic Republic of (IR) St George's, University of London (SGUL) / St George's Hospital Medical School United Kingdom (GB)

How to cite

APA:

Langhammer, F., Maroofian, R., Badar, R., Gregor, A., Rochman, M., Ratliff, J.B.,... Zweier, C. (2023). Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders. Genetics in Medicine, 25(8). https://dx.doi.org/10.1016/j.gim.2023.100885

MLA:

Langhammer, Franziska, et al. "Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders." Genetics in Medicine 25.8 (2023).

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