RNF213 rare variants in an ethnically diverse population with Moyamoya disease

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.

Keywords: RNF213 protein, human; moyamoya disease; stroke.

Figure 1. RNF213 Alterations in MMD patients

The 12 alterations identified in MMD patients in this study are shown in black above the schematic clustering at the C-terminus of RNF213 protein, with one alteration at the N-terminus. Three alterations identified in probands with familial TAAD are shown in grey above the schematic at the N-terminus of RNF213 protein. Alterations reported by other groups are shown in gray below the protein.^, Known protein domains are indicated in black.

Figure 2. Segregation of RNF213 alterations with MMD and other vascular diseases in MMD families

A. Pedigrees of 9 families of various Asian ethnicities with the RNF213 p.R4810K variant. The variant segregates with MMD in 2 families (MM121 and MM056). Reduced penetrance for MMD in individuals with the RNF213 p.R4810K is also demonstrated. B. Pedigrees of 11 families with other RNF213 rare variants. The p.D4013N alteration segregates with MMD, premature CAD, stroke and presentation with subarachnoid hemorrhage (SAH) in a large European American family (MM096). The p.R3922Q variant does not segregate with MMD in MM006. Disease and mutation status are indicated in the figure key. Circles represent females, squares represent males, and arrowheads indicate the proband in the family. A diagonal line through a circle or square indicates that the individual is deceased, with their age of death shown below. Age at onset of the vascular disease (dx) is shown below each individual when applicable; each disease is coded and correlates with the figure key. Ethnicities are indicated above each pedigree. The superscript X (^X) indicates families in which RNF213 variants were identified through exome sequencing.