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

Abstract

ObjectiveTo 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.MethodsExome sequencing was performed on 28 trios of affected patients with MMD and unaffected parents.ResultsWe 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.ConclusionsThese 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.

RNF213 and GUCY1A3 in Moyamoya Disease: Key Regulators of Metabolism, Inflammation, and Vascular Stability

“…Importantly, these lesions have common pathological features ( 6 ). In agreement with this finding, the p.R4810K mutation in RNF213 gene was also shown to be associated with coronary artery disease ( 7 , 8 ), pulmonary artery hypertension ( 9 ), and renal artery stenosis ( 10 ). GUCY1A3 mutations were first detected in patients with quasi-MMD (syndromic MMD) with achalasia ( 11 ), but some cases show only moyamoya arteriopathy in the absence of achalasia ( 12 ).…”

Ring Finger Protein 213 in Moyamoya Disease With Pulmonary Arterial Hypertension: A Mini-Review

“…Thus, these results have suggested the importance of RNF213 in MMD with PAH. In addition, several reports documented that RNF213 gene mutations not only increase the risk of MMD but also are associated with intracranial atherosclerosis ( 46 , 47 ) and systemic vascular diseases, such as PPAS ( 15 , 20 ), renal artery stenosis ( 48 ), and coronary artery disease ( 49 , 50 ). Therefore, MMD, PAH, and renal artery stenosis may be the specific manifestations of pathophysiological changes caused by RNF213 mutation, which can be summarized as spectrums of RNF213 vasculopathy ( 51 , 52 ).…”

Stroke alarm—Arterial ischemic stroke as one of the most time-critical emergencies in children and adolescents

“…Mit zunehmender Häufigkeit genetischer Diagnostik wächst auch das Wissen um mögliche prädisponierende genetische Faktoren. Erwähnt seien hier auch die zunehmenden Erkenntnisse zur RNF213 -Mutation und ihrer phänotypischen Bandbreite [ 52 ].…”