Abstract P588: A Rare RNF213 Variant is Associated With Moyamoya Disease in an African American Family

Objective: To investigate potential genetic susceptibility for moyamoya disease (MMD) in an African American family. Methods: A young girl with MMD (proband), her father and paternal half-brother underwent cerebrovascular imaging with MRI and MRA. Cerebral angiography was also performed on the girl and her father. Genetic analysis of the MMD susceptibility gene RNF213 was conducted on all three relatives, while ACTA2 gene was analysed in the proband only. Results: The proband presented with pseudobulbar affect and chorea, then subsequently had a right hemispheric ischaemic stroke and rapid, ultimately fatal clinical decline. Detailed family history raised suspicion for familial MMD and investigation of her relatives. Her father had a small haemorrhagic thalamic stroke without residual neurologic deficits; a clinically silent ischaemic infarct was incidentally discovered on neuroimaging. He remains clinically stable despite slowly progressive disease on imaging. Her brother is neurologically intact and has normal cerebrovascular imaging to date. They are all heterozygous for the rare Arg4131Cys variant in RNF213. They are the first Black people and only the 3rd, 4th and 5th people in the world known to harbour this variant. MMD was confirmed in the girl and her father with cerebral angiogram. Conclusions: This study illuminates the clinical and genetic complexity of familial MMD. It underscores the importance of genetic testing and surveillance cerebrovascular imaging even in asymptomatic relatives of probands with MMD. Although the clinical significance of Arg4131Cys remains unclear, modest variant-disease segregation in this family is consistent with a growing body of evidence supporting its probable pathogenicity. Furthermore, our study illustrates its wide phenotypic spectrum, from asymptomatic carrier to late presenting, mild disease to fulminant, rapidly fatal childhood disease. To our knowledge, this is also the first report of heritable MMD in a Black family. We demonstrate the value of considering diseases more predominant in one specific ancestry when evaluating patients from other ethnic backgrounds. Finally, we highlight the importance of racially and ethnically diverse participants in biomedical research.