Analysis of Whole Genome Sequencing in a Cohort of Individuals with PHACE Syndrome Suggests Dysregulation of RAS/PI3K Signaling

The acronym PHACE stands for the co-occurrence of posterior brain fossa malformations, hemangiomas, arterial anomalies, cardiac defects, and eye abnormalities. The majority of patients have a segmental hemangioma and at least one developmental structural anomaly. The etiology and pathogenesis are unknown. Here we discuss the candidate causative genes identified in a de novo analysis of whole genome sequencing of germline samples from 98 unrelated trios in which the probands had PHACE, all sequenced as part of the Gabriella Miller Kids First Pediatric Research Program. A g:Profiler pathway analysis of the genes with rare, de novo variants suggested dysregulation of the RAS/MAPK and PI3K/AKT pathways that regulate cell growth, migration, and angiogenesis. These findings, along with the developmental anomalies and the vascular birthmark, support including PHACE within the RASopathy family of syndromes.