First Report: Rare RNF213 Variant Associated with Familial Moyamoya Disease in an African American Family

• Published in: Journal of stroke and cerebrovascular diseases Vol. 30; no. 12; p. 106123
• Main Authors: Sunmonu, N. Abimbola, Ambati, Naveen Kumar, Thomas, Matthew J., Ulep, Robin D., Worrall, Bradford
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2021
• Subjects: Adenosine Triphosphatases - genetics; African Americans - genetics; Cerebrovascular; Genetic Predisposition to Disease; Genetic Variation; Humans; Male; Moyamoya; Moyamoya Disease - ethnology; Moyamoya Disease - genetics; Neuroimaging; Paediatric stroke; RNF213; Stroke; Stroke genetics; Ubiquitin-Protein Ligases - genetics; Neuroimaging; Stroke; RNF213; Moyamoya; Cerebrovascular; Stroke genetics; Paediatric stroke
• ISSN: 1052-3057; 1532-8511
• DOI: 10.1016/j.jstrokecerebrovasdis.2021.106123

•1st report of heritable moyamoya disease in Black family.•1st Black people and 5th family worldwide with rare R4131C variant of RNF213 gene.•R4131C is likely pathogenic.•Wide phenotype: asymptomatic carrier to fulminant stroke & cerebrovascular disease.•Racial and ethnic diversity among participants of biomedical research is critical. To investigate potential genetic susceptibility for moyamoya disease (MMD) in an African American family. Neurovascular imaging and analyses of MMD susceptibility genes RNF213 and/or ACTA2 in a young proband with MMD and two first-degree relatives. The proband presented with pseudobulbar affect and chorea, then had a right hemispheric ischaemic stroke and rapidly fatal course. One relative had a mild haemorrhagic thalamic stroke and clinically silent ischaemic infarct. Despite evidence of slowly progressive disease, he remained clinically stable. Another relative was neurologically intact with normal cerebrovascular imaging to date. All three have the rare R4131C (p.Arg4131Cys or p.R4131C, c.12391C>T) variant of the RNF213 gene. They are the first Black people and only the 5th family worldwide known to harbour this variant. MMD was confirmed in both of the patients with neurological events. Our report provides compelling evidence that MMD is a clinically complex, heritable genetic disease. It supports the probable pathogenicity of R4131C. Furthermore, it illustrates the wide phenotypic spectrum of R4131C, from asymptomatic carrier to late presenting, mild disease to catastrophic, rapidly fatal childhood disease. To our knowledge, this is also the first report of heritable MMD in a Black family. Finally, this study highlights the importance of racially and ethnically diverse participants in biomedical research.