PT  - JOURNAL ARTICLE
AU  - Yasuhito Ikeuchi
AU  - Jiro Kitayama
AU  - Noriyuki Sahara
AU  - Takuya Okata
AU  - Noriko Miyake
AU  - Naomichi Matsumoto
AU  - Takanari Kitazono
AU  - Tetsuro Ago
TI  - Filamin A Variant as a Possible Second-Hit Gene Promoting Moyamoya Disease–like Vascular Formation Associated With <em>RNF213</em> p.R4810K Variant
AID  - 10.1212/NXG.0000000000200017
DP  - 2022 Oct 01
TA  - Neurology Genetics
PG  - e200017
VI  - 8
IP  - 5
4099  - http://ng.neurology.org/content/8/5/e200017.short
4100  - http://ng.neurology.org/content/8/5/e200017.full
SO  - Neurol Genet2022 Oct 01; 8
AB  - Background and Objective The objective of this case report was to identify a second-hit gene that may promote Moyamoya disease (MMD)–like vascular formation in an individual having the RNF213 p.R4810K variant.Methods We performed magnetic resonance imaging and genetic analyses of RNF213 and FLNA in a 21-year-old woman, who showed Ehlers-Danlos–like symptoms and developed a first-ever unprovoked seizure, and of her healthy parents.Results We identified bilateral periventricular nodular heterotopia (PNH) as the cause of seizures and MMD-like vascular formation in the patient. The patient had the RNF213 p.R4810K variant. Exome analysis identified c.4868delG in the X-linked FLNA gene encoding filamin A p.G1623V fs*41, which could explain PNH and Ehlers-Danlos–like symptoms. Her mother had the same FLNA variant and had asymptomatic bilateral PNH, whereas her father had the RNF213 variant and had normal cerebrovascular structure.Discussion The family study suggested that the FLNA variant promoted MMD-like vascular formation in a patient having the RNF213 variant, while the RNF213 variant amplified the phenotypic changes elicited by the FLNA abnormality. Collectively, we identified a gene abnormality in filamin A, a target of RNF213-mediated proteasomal degradation, that may promote MMD-like vascular formation as a possible second-hit gene in individuals having the RNF213 p.R4810K variant.