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.

Broad Center for Mendelian Genomics Broad Institute of MIT and Harvard Cambridge MA 02142 USA

Central European Institute of Technology Masaryk University Kamenice 735 5 A35 Brno 62500 Czech Republic

Department of Neuromuscular Disorders University College London Queen Square Institute of Neurology London WC1N 3BG UK

Department of Pediatrics Columbia University Medical Center New York NY 10032 USA

Division of Neurology Departments of Neurology and Pediatrics The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania Philadelphia PA 19104 USA; The Epilepsy NeuroGenetics Initiative Children's Hospital of Philadelphia Philadelphia PA 19104 USA

GeneDx Gaithersburg MD 20877 USA

Murdoch Children's Research Institute Melbourne 3052 Australia; Department of Pediatrics University of Melbourne Melbourne 3052 Australia; Department of Neurology Royal Children's Hospital Parkville 3052 Australia

Pediatric Genetics Unit Schneider Children's Medical Center of Israel Petah Tikva 49100 Israel

Raphael Recanati Genetic Institute Rabin Medical Center Beilinson Hospital Petah Tikva 49100 Israel; Sackler Faculty of Medicine Tel Aviv University Tel Aviv 6997801 Israel

Raphael Recanati Genetic Institute Rabin Medical Center Beilinson Hospital Petah Tikva 49100 Israel; Sackler Faculty of Medicine Tel Aviv University Tel Aviv 6997801 Israel; Felsenstein Medical Research Center Petah Tikva 49100 Israel

Sackler Faculty of Medicine Tel Aviv University Tel Aviv 6997801 Israel; Pediatric Neurology Unit Schneider Children's Medical Center of Israel Petah Tikva 49100 Israel

Victorian Clinical Genetics Services Melbourne 3052 Australia; Murdoch Children's Research Institute Melbourne 3052 Australia

Victorian Clinical Genetics Services Melbourne 3052 Australia; Murdoch Children's Research Institute Melbourne 3052 Australia; Department of Pediatrics University of Melbourne Melbourne 3052 Australia

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Adenosine Deaminase Acting on RNA (ADAR) Enzymes: A Journey from Weird to Wondrous

ADAR2 enzymes: efficient site-specific RNA editors with gene therapy aspirations

Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy