Association of De Novo RNF213 Variants With Childhood Onset Moyamoya Disease and Diffuse Occlusive Vasculopathy

Abstract

Objective: To test the hypothesis that de novo genetic variants are responsible for moyamoya disease (MMD) in children with unaffected relatives, we performed exome sequencing of 28 affected children and their unaffected parents.

Methods: Exome sequencing was performed on 28 trios of affected patients with MMD and unaffected parents.

Results: We identified 3 novel rare de novo RNF213 variants, 1 in the RING domain and 2 in a highly conserved region distal to the RING domain (4,114-4,120). These de novo cases of MMD present at a young age with aggressive MMD and uniquely have additional occlusive vascular lesions, including renal artery stenosis. Two previously reported cases had de novo variants in the same limited region and presented young with aggressive MMD, and 1 case had narrowing of the inferior abdominal aorta.

Conclusions: These results indicate a novel syndrome associated with RNF213 rare variants defined by de novo mutations disrupting highly conserved amino acids in the RING domain and a discrete region distal to the RING domain delimited by amino acids 4,114 to 4,120 leading to onset of severe MMD before 3 years of age and occlusion of other arteries, including the abdominal aorta, renal, iliac, and femoral arteries.

Figure 1. Imaging From Patient 1

(A and B) MRI: axial diffusion-weighted image (DWI) and apparent diffusion coefficient (ADC) imaging demonstrating acute right parietal infarct at 8 months of life. (C and D) MRI: axial DWI and ADC imaging demonstrating left frontoparietal infarct at 11 months. (E) Axial T2-weighted MRI at 23 months demonstrating sequelae of prior infarcts. (F) Anteroposterior view of the right common carotid injection during catheter angiogram showing severe right internal carotid stenosis with moyamoya appearance of collaterals (arrow). (G) Anteroposterior view of the left internal carotid injection during catheter angiogram showing stenosis of left internal carotid artery and proximal stenosis of the left anterior, middle, and posterior cerebral arteries with moyamoya appearance of collaterals (arrow).

Figure 2. Location and Conservation of the Rare De Novo Variants in RNF213 Identified in Our Study and in the Literature

(A) Above the protein schematic is the location of the founder variant in the Asian population (p.Arg4810Lys). Orange boxes indicate the 2 AAA+ ATPase domains; blue box shows the RING finger domain. (B) In the close-up, above the protein schematic are the 3 de novo variants identified in our study, and below the protein schematic are the de novo variants reported in the literature. (C) Conservation of the amino acid residues in the RNF213 protein across 11 species (* stands for single fully conserved residue, stands for conservation between groups of strongly similar properties, and . stands for conservation between groups of weakly similar properties). Blue frame delimits the RING finger domain; red frame delimits the novel domain described in this study (isoform NP_001243000.2).

Figure 3. Imaging From Patient 2

(A and B) MRI: axial diffusion-weighted image and apparent diffusion coefficient imaging demonstrating small acute infarct in the left postcentral gyrus. (C) MRI: axial T2 fluid-attenuated inversion recovery imaging demonstrating periventricular white matter hyperintensities, consistent with chronic small vessel disease (arrow). (D) Anteroposterior view of the right internal carotid during catheter angiogram demonstrating severe internal carotid stenosis with moyamoya appearance of collateral vessels (arrow). (E) Anteroposterior view of the left internal carotid during catheter angiogram demonstrating severe internal carotid stenosis with moyamoya appearance of collateral vessels (arrow).