Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures

Tiong Yang Tan, Jiří Sedmík, Mark P. Fitzgerald, Rivka Sukenik Halevy, Liam P. Keegan, Ingo Helbig, Lina Basel-Salmon, Lior Cohen, Rachel Straussberg, Wendy K. Chung, Mayada Helal, Reza Maroofian, Henry Houlden, Jane Juusola, Simon Sadedin, Lynn Pais, Katherine B. Howell, Susan M. White, John Christodoulou, Mary A. O'Connell*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)467-483
Number of pages17
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - 2 Apr 2020


FundersFunder number
Core Facility Cellular Imaging
Harvard Center for Mendelian Genomics
Ministry of Education Youth and Sports Czech Republic
National Heart, Lung, and Blood Institute
National Human Genome Research InstituteUM1HG008900
National Eye Institute
JPB Foundation
Seventh Framework Programme621368
Broad Institute
Simons Foundation Autism Research Initiative
Ministerstvo Školství, Mládeže a Tělovýchovy
Grantová Agentura České Republiky19-16963S
State Government of Victoria
Seventh Framework Programme
Central European Institute of TechnologyLM2015062


    • ADAR2
    • RNA editing
    • epilepsy
    • intellectual disability
    • microcephaly
    • migrating focal seizures


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