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.
- sequence analysis
- nervous system diseases
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RM and JříS contributed equally.
Contributors All authors contributed to the accrual of subjects and/or data. RM, JS, NM and MS contributed to the conception and design of the study and drafted the manuscript. All authors have revised the manuscript for important intellectual content and approved the final version.
Funding This study was funded by The Medical Research Council (MRC) (MR/S01165X/1, MR/S005021/1), The Wellcome Trust (Synaptopathies Strategic Award, WT093205MA, WT104033AIA), The Rosetree Trust, Ataxia UK, The MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK) and Muscular Dystrophy Association (MDA USA). MAO'C has received funding from Czech Science Foundation, project No. 20–11101S.
Competing interests The authors declare that PB and CB are employees of CENTOGENE AG, Rostock, Germany.
Patient consent for publication Parental/guardian consent obtained.
Ethics approval The institutional review boards of University College London approved the study and all participants provided written informed consent.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement The data supporting the findings of this study are available within the article.
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