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

TitleAssociation of De Novo Variants With Childhood Onset Moyamoya Disease and Diffuse Occlusive Vasculopathy.
Publication TypeJournal Article
Year of Publication2021
AuthorsPinard, A, Fiander, MDJ, Cecchi, AC, Rideout, AL, Azouz, M, Fraser, SM, P McNeely, D, Walling, S, Novara, SC, Hurst, ACE, Guo, D, Parkash, S, Bamshad, MJ, Nickerson, DA, Vandersteen, AM, Milewicz, DM
Date Published2021 03 30
KeywordsAdenosine 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

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.

Alternate JournalNeurology
PubMed ID33568546
PubMed Central IDPMC8055312
Grant ListUM1 HG006493 / HG / NHGRI NIH HHS / United States
R01 HL109942 / HL / NHLBI NIH HHS / United States