@article{0dcf0393dd0649c9ba2b64a401844a95,
title = "Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures",
abstract = "The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in vitro assays with recombinant proteins in HEK293T cells and ex vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.",
keywords = "ADAR2, RNA editing, epilepsy, intellectual disability, microcephaly, migrating focal seizures",
author = "Tan, {Tiong Yang} and Ji{\v r}{\'i} Sedm{\'i}k and Fitzgerald, {Mark P.} and Halevy, {Rivka Sukenik} and Keegan, {Liam P.} and Ingo Helbig and Lina Basel-Salmon and Lior Cohen and Rachel Straussberg and Chung, {Wendy K.} and Mayada Helal and Reza Maroofian and Henry Houlden and Jane Juusola and Simon Sadedin and Lynn Pais and Howell, {Katherine B.} and White, {Susan M.} and John Christodoulou and O'Connell, {Mary A.}",
note = "Funding Information: We acknowledge the Core Facility Cellular Imaging (CELLIM) of Central European Institute of Technology (CEITEC) supported by the Czech-BioImaging large RI project (LM2015062 funded by the Ministry of Education Youth and Sports Czech Republic (MEYS CR) ), for support with obtaining scientific data presented in this paper. W.K.C. was funded by grants from the Simons Foundation Autism Research Initiative (SFARI) and the JPB Foundation . This work was supported by the European Union{\textquoteright}s Seventh Framework Programme for research, technological development, and demonstration under grant agreement number 621368 to M.A.O. L.P.K. has received funding from Czech Science Foundation project number 19-16963S . The research conducted at the Murdoch Children{\textquoteright}s Research Institute was supported by the Victorian Government{\textquoteright}s Operational Infrastructure Support Program . Sequencing and analysis of individual 1 were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute , the National Eye Institute , and the National Heart, Lung, and Blood Institute under grant UM1 HG008900 to Daniel MacArthur and Heidi Rehm. Funding Information: We acknowledge the Core Facility Cellular Imaging (CELLIM) of Central European Institute of Technology (CEITEC) supported by the Czech-BioImaging large RI project (LM2015062 funded by the Ministry of Education Youth and Sports Czech Republic (MEYS CR)), for support with obtaining scientific data presented in this paper. W.K.C. was funded by grants from the Simons Foundation Autism Research Initiative (SFARI) and the JPB Foundation. This work was supported by the European Union's Seventh Framework Programme for research, technological development, and demonstration under grant agreement number 621368 to M.A.O. L.P.K. has received funding from Czech Science Foundation project number 19-16963S. The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. Sequencing and analysis of individual 1 were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute under grant UM1 HG008900 to Daniel MacArthur and Heidi Rehm. Publisher Copyright: {\textcopyright} 2020 American Society of Human Genetics",
year = "2020",
month = apr,
day = "2",
doi = "10.1016/j.ajhg.2020.02.015",
language = "English",
volume = "106",
pages = "467--483",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "4",
}