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De novo variants in RNF213 are associated with a clinical spectrum ranging from Leigh syndrome to early-onset stroke

Lookup NU author(s): Professor Robert Taylor, Professor Bobby McFarlandORCiD, Dr Anita Devlin


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© 2023 American College of Medical Genetics and GenomicsPurpose: RNF213, encoding a giant E3 ubiquitin ligase, has been recognized for its role as a key susceptibility gene for moyamoya disease. Case reports have also implicated specific variants in RNF213 with an early-onset form of moyamoya disease with full penetrance. We aimed to expand the phenotypic spectrum of monogenic RNF213-related disease and to evaluate genotype-phenotype correlations. Methods: Patients were identified through reanalysis of exome sequencing data of an unselected cohort of unsolved pediatric cases and through GeneMatcher or ClinVar. Functional characterization was done by proteomics analysis and oxidative phosphorylation enzyme activities using patient-derived fibroblasts. Results: We identified 14 individuals from 13 unrelated families with (de novo) missense variants in RNF213 clustering within or around the Really Interesting New Gene (RING) domain. Individuals presented either with early-onset stroke (n = 11) or with Leigh syndrome (n = 3). No genotype-phenotype correlation could be established. Proteomics using patient-derived fibroblasts revealed no significant differences between clinical subgroups. 3D modeling revealed a clustering of missense variants in the tertiary structure of RNF213 potentially affecting zinc-binding suggesting a gain-of-function or dominant negative effect. Conclusion: De novo missense variants in RNF213 clustering in the E3 RING or other regions affecting zinc-binding lead to an early-onset syndrome characterized by stroke or Leigh syndrome.

Publication metadata

Author(s): Brunet T, Zott B, Lieftuchter V, Lenz D, Schmidt A, Peters P, Kopajtich R, Zaddach M, Zimmermann H, Huning I, Ballhausen D, Staufner C, Bianzano A, Hughes J, Taylor RW, McFarland R, Devlin A, Mihaljevic M, Barisic N, Rohlfs M, Wilfling S, Sondheimer N, Hewson S, Marinakis NM, Kosma K, Traeger-Synodinos J, Elbracht M, Begemann M, Trepels-Kottek S, Hasan D, Scala M, Capra V, Zara F, van der Ven AT, Driemeyer J, Apitz C, Kramer J, Strong A, Hakonarson H, Watson D, Mayr JA, Prokisch H, Meitinger T, Borggraefe I, Spiegler J, Baric I, Paolini M, Gerstl L, Wagner M

Publication type: Article

Publication status: Published

Journal: Genetics in Medicine

Year: 2024

Volume: 26

Issue: 2

Print publication date: 01/02/2024

Online publication date: 01/11/2023

Acceptance date: 29/10/2023

ISSN (print): 1098-3600

ISSN (electronic): 1530-0366

Publisher: Elsevier B.V.


DOI: 10.1016/j.gim.2023.101013

PubMed id: 37924258


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