Fig. 1: VOGM-associated variants in RASA1 and EPHB4.
From: Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations
a In the normal anatomy shown on a lateral projection subtracted angiogram of a 4-year-old boy (left), the deep veins drain into the straight sinus (white star). The normal deep venous anatomy involves the internal cerebral veins (white arrow) and the basal vein of Rosenthal (white arrowhead). VOGM is shown on a lateral projection subtracted angiogram of a 3 day-old boy (right), where the falcon sinus (black star) is commonly observed as the draining vein and involves prominent supply from splenial vessels deriving from the anterior cerebral artery (black arrows), as well as posterior choroidal arteries (black arrowhead). The normal drainage of the torcular typically involves the bilateral transverse and sigmoid sinuses (white dashed line). In the abnormal venous anatomy, VOGM typically recruit dilated occipital sinuses (black dashed line). b Quantile-quantile plot of observed versus expected p-values (one-sided Poisson test, not adjusted) for rare damaging (D-mis + LoF) DNVs with MAF ≤ 4 x 10−4 in the Exome Aggregation Consortium database for all genes. The exome-wide significant cutoff was 8.6 × 10−7 (0.05 / (3 × 19,347)). D-mis are missense variants predicted to be deleterious per MetaSVM or MPC ≤ 2. LoF, loss-of-function variants. DNV, de novo variant. MAF, minor allele frequency. c RASA1 and EPHB4 functional domains (green rectangles) with the location of VOGM variants and phylogenetic conservation of wild-type amino acids (red text) at each mutated position. 5 LoF variants were found in RASA1, including 2 DNVs (p. R427X and p. V527Mfs*16), and 3 transmitted variants (p. H743fs*24, p. R709X and p. Y872*). Transmitted damaging variants in EPHB4 including 2 variants in the Fibronectin type III domain (p. E432Gfs*7 and p. A509G), and 3 D-mis variants (p. K650N, p. R838W, p. F867L) in the kinase domain. d Quantile-quantile plots of observed versus expected p-values (one-sided Fisher’s exact test, not adjusted) for rare damaging (D-mis + LoF) variants with MAF ≤ 5 x 10−5 in the Genome Aggregation database (gnomAD) from case-control burden test. The genome-wide significant cutoff was 2.6 × 10−6 (0.05 of 19,347).
