Rare variant enrichment analysis in pediatric European Moyamoya Angiopathy patients unveils novel candidate susceptibility genes

Abstract Moyamoya angiopathy (MMA) is a rare steno-occlusive condition resulting in transient ischemic attacks and strokes in children and adults. Previous studies, mainly in adult patients, suggested RNF213 as the most prevalent susceptibility gene due to an Asian founder variant. Nevertheless, the genetic landscape in early-onset European MMA patients requires further elucidation. Exome-sequencing was performed in 104 pediatric MMA patients, including three with Down syndrome, and 520 healthy controls. Rare-variant enrichment testing was performed using the R-package SKAT on the whole cohort as well as in a 100% European subset, revealing a total of 28 enriched genes. Both tests showed the most common known MMA genes ( RNF213 and NF1) among the top three enriched genes, underlining the validity of our approach. Seven of the concordantly enriched genes are novel MMA candidates (ATAD2, COL18A1, NAV1, ALOX12B, KRTAP4-7, KCNJ12 , and KBTBD13) . De novo variants were found in NF1, RNF213 , COL18A1, ECI1 , and YIPF1 . In summary, our study confirms RNF213 and NF1 as major susceptibility genes and suggests seven novel early-onset MMA susceptibility genes. Of special interest is the novel candidate gene COL18A1 , which is involved in angiogenesis and endothelial cell proliferation, due to its potential additional role as a modifier of MMA in trisomy 21.