BACKGROUND: Adenosine-to-inosine RNA editing is a co-transcriptional/post-transcriptional modification of double-stranded RNA, catalysed by one of two active adenosine deaminases acting on RNA (ADARs), ADAR1 and ADAR2. ADARB1 encodes the enzyme ADAR2 that is highly expressed in the brain and essential to modulate the function of glutamate and serotonin receptors. Impaired ADAR2 editing causes early onset progressive epilepsy and premature death in mice. In humans, ADAR2 dysfunction has been very recently linked to a neurodevelopmental disorder with microcephaly and epilepsy in four unrelated subjects. METHODS: We studied three children from two consanguineous families with severe developmental and epileptic encephalopathy (DEE) through detailed physical and instrumental examinations. Exome sequencing (ES) was used to identify ADARB1 mutations as the underlying genetic cause and in vitro assays with transiently transfected cells were performed to ascertain the impact on ADAR2 enzymatic activity and splicing. RESULTS: All patients showed global developmental delay, intractable early infantile-onset seizures, microcephaly, severe-to-profound intellectual disability, axial hypotonia and progressive appendicular spasticity. ES revealed the novel missense c.1889G>A, p.(Arg630Gln) and deletion c.1245_1247+1 del, p.(Leu415PhefsTer14) variants in ADARB1 (NM_015833.4). The p.(Leu415PhefsTer14) variant leads to incorrect splicing resulting in frameshift with a premature stop codon and loss of enzyme function. In vitro RNA editing assays showed that the p.(Arg630Gln) variant resulted in a severe impairment of ADAR2 enzymatic activity. CONCLUSION: In conclusion, these data support the pathogenic role of biallelic ADARB1 variants as the cause of a distinctive form of DEE, reinforcing the importance of RNA editing in brain function and development.

CEITEC Masaryk University Kamenice 735 5 A35 Brno 62500 Czech Republic

CENTOGENE AG Rostock Germany

Clinical Genetics Department Human Genetics and Genome Research Division National Research Centre Cairo Egypt

Department of Genetics Faculty of Science Shahid Chamran University of Ahvaz Ahvaz Iran

Department of Medical Genetics Faculty of Medicine Ahvaz Jundishapur University of Medical Sciences Behbahan Iran

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

Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health Università degli Studi di Genova Genova Italy

Department of Paediatric Neurology Golestan Medical Educational and Research Center Ahvaz Jundishapur University of Medical Sciences Behbahan Iran

Health Research Institute Diabetes Research Center Ahvaz Jundishapur University of medical Sciences Ahvaz Iran

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