Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders
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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; Bakhtiari, Somayeh; Kruer, Michael C; Salih, Mustafa A; Kuechler, Alma; Muller, Eric A; Blocker, Karli; Kuismin, Outi; Park, Kristen L; Kochhar, Aaina; Brown, Kathleen; Ramanathan, Subhadra; Clark, Robin D; Elgizouli, Magdeldin; Melikishvili, Gia; Tabatadze, Nazhi; Stark, Zornitza; Mirzaa, Ghayda M; Ong, Jinfon; Grasshoff, Ute; Bevot, Andrea; von Wintzingerode, Lydia; Jamra, Rami A; Hennig, Yvonne; Goldenberg, Paula; Al Alam, Chadi; Charif, Majida; Boulouiz, Redouane; Bellaoui, Mohammed; Amrani, Rim; Al Mutairi, Fuad; Tamim, Abdullah M; Abdulwahab, Firdous; Alkuraya, Fowzan S; Khouj, Ebtissal M; Alvi, Javeria R; Sultan, Tipu; Hashemi, Narges; Karimiani, Ehsan G; Ashrafzadeh, Farah; Imannezhad, Shima; Efthymiou, Stephanie; Houlden, Henry; Sticht, Heinrich; Zweier, Christiane.
in: GENET MED, Jahrgang 25, Nr. 8, 08.2023, S. 100885.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders
AU - Langhammer, Franziska
AU - Maroofian, Reza
AU - Badar, Rueda
AU - Gregor, Anne
AU - Rochman, Michelle
AU - Ratliff, Jeffrey B
AU - Koopmans, Marije
AU - Herget, Theresia
AU - Hempel, Maja
AU - Kortüm, Fanny
AU - Heron, Delphine
AU - Mignot, Cyril
AU - Keren, Boris
AU - Brooks, Susan
AU - Botti, Christina
AU - Ben-Zeev, Bruria
AU - Argilli, Emanuela
AU - Sherr, Elliot H
AU - Gowda, Vykuntaraju K
AU - Srinivasan, Varunvenkat M
AU - Bakhtiari, Somayeh
AU - Kruer, Michael C
AU - Salih, Mustafa A
AU - Kuechler, Alma
AU - Muller, Eric A
AU - Blocker, Karli
AU - Kuismin, Outi
AU - Park, Kristen L
AU - Kochhar, Aaina
AU - Brown, Kathleen
AU - Ramanathan, Subhadra
AU - Clark, Robin D
AU - Elgizouli, Magdeldin
AU - Melikishvili, Gia
AU - Tabatadze, Nazhi
AU - Stark, Zornitza
AU - Mirzaa, Ghayda M
AU - Ong, Jinfon
AU - Grasshoff, Ute
AU - Bevot, Andrea
AU - von Wintzingerode, Lydia
AU - Jamra, Rami A
AU - Hennig, Yvonne
AU - Goldenberg, Paula
AU - Al Alam, Chadi
AU - Charif, Majida
AU - Boulouiz, Redouane
AU - Bellaoui, Mohammed
AU - Amrani, Rim
AU - Al Mutairi, Fuad
AU - Tamim, Abdullah M
AU - Abdulwahab, Firdous
AU - Alkuraya, Fowzan S
AU - Khouj, Ebtissal M
AU - Alvi, Javeria R
AU - Sultan, Tipu
AU - Hashemi, Narges
AU - Karimiani, Ehsan G
AU - Ashrafzadeh, Farah
AU - Imannezhad, Shima
AU - Efthymiou, Stephanie
AU - Houlden, Henry
AU - Sticht, Heinrich
AU - Zweier, Christiane
N1 - Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
PY - 2023/8
Y1 - 2023/8
N2 - 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.
AB - 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.
KW - Humans
KW - Neurodevelopmental Disorders/genetics
KW - Epilepsy/genetics
KW - Genetic Association Studies
KW - Intellectual Disability/genetics
KW - Phenotype
KW - GTP Phosphohydrolases/genetics
KW - GTP-Binding Proteins/genetics
KW - Tumor Suppressor Proteins/genetics
U2 - 10.1016/j.gim.2023.100885
DO - 10.1016/j.gim.2023.100885
M3 - SCORING: Journal article
C2 - 37165955
VL - 25
SP - 100885
JO - GENET MED
JF - GENET MED
SN - 1098-3600
IS - 8
ER -