@article {1019, title = {Association of De Novo Variants With Childhood Onset Moyamoya Disease and Diffuse Occlusive Vasculopathy.}, journal = {Neurology}, volume = {96}, year = {2021}, month = {2021 03 30}, pages = {e1783-e1791}, 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 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 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.

}, keywords = {Adenosine Triphosphatases, Adult, Age of Onset, Aortic Diseases, Arterial Occlusive Diseases, Child, Preschool, Female, Femoral Artery, Humans, Iliac Artery, Male, Moyamoya Disease, Mutation, Renal Artery Obstruction, Ubiquitin-Protein Ligases}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000011653}, author = {Pinard, Amelie and Fiander, Maximillian D J and Cecchi, Alana C and Rideout, Andrea L and Azouz, Mohamed and Fraser, Stuart M and McNeely, P Daniel and Walling, Simon and Novara, Sarah C and Hurst, Anna C E and Guo, Dongchuan and Parkash, Sandhya and Bamshad, Michael J and Nickerson, Deborah A and Vandersteen, Anthony M and Milewicz, Dianna M} } @article {219, title = {RNF213 rare variants in an ethnically diverse population with Moyamoya disease.}, journal = {Stroke}, volume = {45}, year = {2014}, month = {2014 Nov}, pages = {3200-7}, 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 = {Adenosine Triphosphatases, Adolescent, Adult, Child, Cohort Studies, Ethnic Groups, Female, Genetic Variation, Humans, Male, Moyamoya Disease, Population Surveillance, Ubiquitin-Protein Ligases, Young Adult}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.114.006244}, author = {Cecchi, Alana C and Guo, Dongchuan and Ren, Zhao and Flynn, Kelly and Santos-Cortez, Regie Lyn P and Leal, Suzanne M and Wang, Gao T and Regalado, Ellen S and Steinberg, Gary K and Shendure, Jay and Bamshad, Michael J and Grotta, James C and Nickerson, Deborah A and Pannu, Hariyadarshi and Milewicz, Dianna M} }