Expanding the genetic landscape of moyamoya angiopathy: insights from 74 trios.

In 74 predominantly European sporadic moyamoya angiopathy trios, causative variants were found in 20 probands (27%), including RNF213 and 11 novel candidate genes beyond known loci.

• Why it matters: The genetic architecture of moyamoya angiopathy outside East Asian populations is poorly defined beyond a few syndromic causes, limiting molecular diagnosis and pathway insight.
• What they did: Whole-exome sequencing was performed in 74 sporadic trios, with stringent filtering for de novo and rare inherited variants, gene prioritization using structural modeling and expression, and burden testing versus gnomAD; 200 additional probands were screened for recurrence.
• The result: RNF213 de novo variants in the E3 ligase domain explained 6 severe infant-onset cases, known MMA genes accounted for 14 probands, and SMAD4 p.Arg496Cys recurred in the 200-proband screen, linking MMA to dysregulated TGF-β signaling.

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