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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

Harvard

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, 'Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders', GENET MED, Jg. 25, Nr. 8, S. 100885. https://doi.org/10.1016/j.gim.2023.100885

APA

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., ... Zweier, C. (2023). Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders. GENET MED, 25(8), 100885. https://doi.org/10.1016/j.gim.2023.100885

Vancouver

Langhammer F, Maroofian R, Badar R, Gregor A, Rochman M, Ratliff JB et al. Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders. GENET MED. 2023 Aug;25(8):100885. https://doi.org/10.1016/j.gim.2023.100885

Bibtex

@article{e285ef48616b4fe7b54eef0a3c743f7c,
title = "Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders",
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.",
keywords = "Humans, Neurodevelopmental Disorders/genetics, Epilepsy/genetics, Genetic Association Studies, Intellectual Disability/genetics, Phenotype, GTP Phosphohydrolases/genetics, GTP-Binding Proteins/genetics, Tumor Suppressor Proteins/genetics",
author = "Franziska Langhammer and Reza Maroofian and Rueda Badar and Anne Gregor and Michelle Rochman and Ratliff, {Jeffrey B} and Marije Koopmans and Theresia Herget and Maja Hempel and Fanny Kort{\"u}m and Delphine Heron and Cyril Mignot and Boris Keren and Susan Brooks and Christina Botti and Bruria Ben-Zeev and Emanuela Argilli and Sherr, {Elliot H} and Gowda, {Vykuntaraju K} and Srinivasan, {Varunvenkat M} and Somayeh Bakhtiari and Kruer, {Michael C} and Salih, {Mustafa A} and Alma Kuechler and Muller, {Eric A} and Karli Blocker and Outi Kuismin and Park, {Kristen L} and Aaina Kochhar and Kathleen Brown and Subhadra Ramanathan and Clark, {Robin D} and Magdeldin Elgizouli and Gia Melikishvili and Nazhi Tabatadze and Zornitza Stark and Mirzaa, {Ghayda M} and Jinfon Ong and Ute Grasshoff and Andrea Bevot and {von Wintzingerode}, Lydia and Jamra, {Rami A} and Yvonne Hennig and Paula Goldenberg and {Al Alam}, Chadi and Majida Charif and Redouane Boulouiz and Mohammed Bellaoui and Rim Amrani and {Al Mutairi}, Fuad and Tamim, {Abdullah M} and Firdous Abdulwahab and Alkuraya, {Fowzan S} and Khouj, {Ebtissal M} and Alvi, {Javeria R} and Tipu Sultan and Narges Hashemi and Karimiani, {Ehsan G} and Farah Ashrafzadeh and Shima Imannezhad and Stephanie Efthymiou and Henry Houlden and Heinrich Sticht and Christiane Zweier",
note = "Copyright {\textcopyright} 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.",
year = "2023",
month = aug,
doi = "10.1016/j.gim.2023.100885",
language = "English",
volume = "25",
pages = "100885",
journal = "GENET MED",
issn = "1098-3600",
publisher = "Lippincott Williams and Wilkins",
number = "8",

}

RIS

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 -