Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders.

Langhammer, Franziska; Maroofian, Reza; Badar, Rueda; Gregor, Anne; Rochman, Michelle; Ratliff, Jeffrey B; Koopmans, Marije; Herget, Theresia; Hempel, Maja; Kortüm, Fanny; Heron, Delphine; Mignot, Cyril; Keren, Boris; Brooks, Susan; Botti, Christina; Ben-Zeev, Bruria; Argilli, Emanuela; Sherr, Elliot H; Gowda, Vykuntaraju K; Srinivasan, Varunvenkat M; ... (2023). Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders. Genetics in medicine, 25(8), p. 100885. Springer Nature 10.1016/j.gim.2023.100885

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Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy (DEE) 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 (NDDs). 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 DEE in 16 individuals. We now identified also de novo missense variants in the GTPase domain in six 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 bi-allelic splice-site and truncating variants in nine families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well.


By identifying phenotype-genotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying bi-allelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2 related disorders including both autosomal dominant and recessive NDDs.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Human Genetics
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Humangenetik

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Langhammer, Franziska, Zweier, Christiane Gertrud


600 Technology > 610 Medicine & health




Springer Nature




Pubmed Import

Date Deposited:

11 May 2023 15:55

Last Modified:

04 Jan 2024 11:18

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

RHOBTB2 developmental and epileptic encephalopathy intellectual disability movement disorder neurodevelopmental disorder seizures




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