Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders.
Publication/Presentation Date
8-1-2023
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.
Volume
25
Issue
8
First Page
100885
Last Page
100885
ISSN
1530-0366
Published In/Presented At
Langhammer, F., Maroofian, R., Badar, R., Gregor, A., Rochman, M., Ratliff, J. B., Koopmans, M., Herget, T., Hempel, M., Kortüm, F., Heron, D., Mignot, C., Keren, B., Brooks, S., Botti, C., Ben-Zeev, B., Argilli, E., Sherr, E. H., Gowda, V. K., Srinivasan, V. M., … Zweier, C. (2023). Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders. Genetics in medicine : official journal of the American College of Medical Genetics, 25(8), 100885. https://doi.org/10.1016/j.gim.2023.100885
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
37165955
Department(s)
Administration and Leadership
Document Type
Article