RNF213 rare variants in an ethnically diverse population with Moyamoya disease.

TitleRNF213 rare variants in an ethnically diverse population with Moyamoya disease.
Publication TypeJournal Article
Year of Publication2014
AuthorsCecchi, AC, Guo, D, Ren, Z, Flynn, K, Santos-Cortez, RLyn P, Leal, SM, Wang, GT, Regalado, ES, Steinberg, GK, Shendure, J, Bamshad, MJ, Grotta, JC, Nickerson, DA, Pannu, H, Milewicz, DM
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics
Date Published2014 Nov
KeywordsAdenosine Triphosphatases, Adolescent, Adult, Child, Cohort Studies, Ethnic Groups, Female, Genetic Variation, Humans, Male, Moyamoya Disease, Population Surveillance, Ubiquitin-Protein Ligases, Young Adult

BACKGROUND AND PURPOSE: Moyamoya disease (MMD) is a rare, genetically heterogeneous cerebrovascular disease resulting from occlusion of the distal internal carotid arteries. A variant in the Ring Finger 213 gene (RNF213), altering arginine at position 4810 (p.R4810K), is associated with MMD in Asian populations. However, there are a lack of data on the role of RNF213 in patients with MMD of additional ethnicities and diasporic Asian populations. We investigate the contribution of RNF213 alterations to MMD in an ethnically diverse population based in the United States.

METHODS: We initially sequenced RNF213 exons 43, 44, and 45 (encoding the eponymous RING finger domain) and exon 60 (encoding p.R4810K) in 86 ethnically diverse patients with MMD. Comprehensive exome sequencing data from 24 additional patients with MMD was then analyzed to identify RNF213 variants globally. Segregation of variants with MMD and other vascular diseases was assessed in families.

RESULTS: RNF213 p.R4810K was identified in 56% (9/16) of patients with MMD of Asian descent and not in 94 patients of non-Asian descent. 3.6% (4/110) of patients had variants in the exons encoding the RING finger domain. Seven additional variants were identified in 29% (7/24) of patients with MMD who underwent exome sequencing. Segregation analysis supported an association with MMD for 2 variants and a lack of association with disease for 1 variant.

CONCLUSIONS: These results confirm that alterations in RNF213 predispose patients of diverse ethnicities to MMD, and that the p.R4810K variant predisposes individuals of Asian descent in the United States to MMD.

Alternate JournalStroke
PubMed ID25278557
PubMed Central IDPMC4420622
Grant ListU54 HG006493 / HG / NHGRI NIH HHS / United States
R01 HL062594 / HL / NHLBI NIH HHS / United States
UL1 RR024148 / RR / NCRR NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
R01 HL62594 / HL / NHLBI NIH HHS / United States
1U54HG006493 / HG / NHGRI NIH HHS / United States
R01 HL109942 / HL / NHLBI NIH HHS / United States