Stroke. 2014 Nov;45(11):3200-7. doi: 10.1161/STROKEAHA.114.006244. Epub 2014 Oct 2.

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

Cecchi AC¹, Guo D¹, Ren Z¹, Flynn K¹, Santos-Cortez RL¹, Leal SM¹, Wang GT¹, Regalado ES¹, Steinberg GK¹, Shendure J¹, Bamshad MJ¹; University of Washington Center for Mendelian Genomics, Grotta JC¹, Nickerson DA¹, Pannu H¹, Milewicz DM².

Author information

1: From the Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center, Houston (A.C.C., D.G., Z.R., K.F., E.S.R., H.P., D.M.M.); Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, TX (R.L.P.S.-C., S.M.L., G.T.W.); Department of Genome Sciences (J.S., M.J.B., D.A.N.) and Department of Pediatrics (M.J.B.), University of Washington, Seattle; Department of Neurosurgery, Stanford University, CA (G.K.S.); and Clinical Innovation and Research Institute, Memorial Hermann Hospital, Houston, TX (J.C.G.).
2: From the Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center, Houston (A.C.C., D.G., Z.R., K.F., E.S.R., H.P., D.M.M.); Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, TX (R.L.P.S.-C., S.M.L., G.T.W.); Department of Genome Sciences (J.S., M.J.B., D.A.N.) and Department of Pediatrics (M.J.B.), University of Washington, Seattle; Department of Neurosurgery, Stanford University, CA (G.K.S.); and Clinical Innovation and Research Institute, Memorial Hermann Hospital, Houston, TX (J.C.G.). Dianna.M.Milewicz@uth.tmc.edu.

Abstract

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.