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Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders.

Cali, E; Quirin, T; Rocca, C; Efthymiou, S; Riva, A; Marafi, D; Zaki, MS; Suri, M; Dominguez, R; Elbendary, HM; et al. Cali, E; Quirin, T; Rocca, C; Efthymiou, S; Riva, A; Marafi, D; Zaki, MS; Suri, M; Dominguez, R; Elbendary, HM; Alavi, S; Abdel-Hamid, MS; Morsy, H; Mau-Them, FT; Nizon, M; Tesner, P; Ryba, L; Zafar, F; Rana, N; Saadi, NW; Firoozfar, Z; Gencpinar, P; Unay, B; Ustun, C; Bruel, A-L; Coubes, C; Stefanich, J; Sezer, O; Agolini, E; Novelli, A; Vasco, G; Lettori, D; Milh, M; Villard, L; Zeidler, S; Opperman, H; Strehlow, V; Issa, MY; El Khassab, H; Chand, P; Ibrahim, S; Nejad-Rashidi, A; Miryounesi, M; Larki, P; Morrison, J; Cristian, I; Thiffault, I; Bertsch, NL; Noh, GJ; Pappas, J; Moran, E; Marinakis, NM; Traeger-Synodinos, J; Hosseini, S; Abbaszadegan, MR; Caumes, R; Vissers, LELM; Neshatdoust, M; Montazer, MZ; El Fahime, E; Canavati, C; Kamal, L; Kanaan, M; Askander, O; Voinova, V; Levchenko, O; Haider, S; Halbach, SS; Maia, ER; Mansoor, S; Vivek, J; Tawde, S; Santhosh R Challa, V; Gowda, VK; Srinivasan, VM; Victor, LA; Pinero-Banos, B; Hague, J; Ei-Awady, HA; Maria de Miranda Henriques-Souza, A; Cheema, HA; Anjum, MN; Idkaidak, S; Alqarajeh, F; Atawneh, O; Mor-Shaked, H; Harel, T; Zifarelli, G; Bauer, P; Kok, F; Kitajima, JP; Monteiro, F; Josahkian, J; Lesca, G; Chatron, N; Ville, D; Murphy, D; Neul, JL; Mullegama, SV; Begtrup, A; Herman, I; Mitani, T; Posey, JE; Tay, CG; Javed, I; Carr, L; Kanani, F; Beecroft, F; Hane, L; Abdelkreem, E; Macek, M; Bispo, L; Elmaksoud, MA; Hashemi-Gorji, F; Pehlivan, D; Amor, DJ; Jamra, RA; Chung, WK; Ghayoor, EK; Campeau, P; Alkuraya, FS; Pagnamenta, AT; Gleeson, J; Lupski, JR; Striano, P; Moreno-De-Luca, A; Lafontaine, DLJ; Houlden, H; Maroofian, R (2024) Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders. Genet Med. p. 101251. ISSN 1530-0366 https://doi.org/10.1016/j.gim.2024.101251
SGUL Authors: Mansour, Sahar

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Abstract

PURPOSE: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear. METHODS: We identified 105 affected individuals, including 39 previously reported cases, and systematically analysed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis. RESULTS: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability (GDD/ID), infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe GDD/ID, absent speech, and autistic features, while seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, in particular in pre-rRNA processing. CONCLUSION: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of 'ribosomopathies'.

Item Type: Article
Additional Information: © 2024 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. Under a Creative Commons license (http://creativecommons.org/licenses/by/4.0/)
Keywords: ACTL6B, BAFopathies, autism, epileptic-dyskinetic encephalopathy, ribosomopathies, 0604 Genetics, 1103 Clinical Sciences, Genetics & Heredity
SGUL Research Institute / Research Centre: Academic Structure > Cardiovascular & Genomics Research Institute
Academic Structure > Cardiovascular & Genomics Research Institute > Genomics
Journal or Publication Title: Genet Med
ISSN: 1530-0366
Language: eng
Dates:
DateEvent
17 September 2024Published Online
5 September 2024Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
WT093205MAWellcome Trusthttp://dx.doi.org/10.13039/100004440
WT104033AIAWellcome Trusthttp://dx.doi.org/10.13039/100004440
2012-305121Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
R35NS105078National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
UM1 HG011758National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
512848Muscular Dystrophy Associationhttp://dx.doi.org/10.13039/100005202
T32 GM007526-42National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
#3701International Rett Syndrome Foundationhttp://dx.doi.org/10.13039/100001819
K08 HG008986National Human Genome Research Institutehttps://doi.org/10.13039/100000051
PNRR-MUR-M4C2 PE0000006 Research Program “MNESYS”UNSPECIFIEDUNSPECIFIED
R01 GM073791National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
PubMed ID: 39275948
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/117128
Publisher's version: https://doi.org/10.1016/j.gim.2024.101251

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