Aims Vein of Galen arterial malformation (VGAM) is a rare high flow cerebral arteriovenous malformation which most commonly presents with cardiac failure in infancy. VGAM is considered to be a sporadic disorder, with a population incidence of 1 in 100,000. No genetic basis or increased risk of recurrence within affected families has been identified previously. Recently, RASA1 gene mutations have been identified as causative in the autosomal dominant capillary malformation arteriovenous (AV) malformation (CM-AVM) syndrome, a condition presenting with multiple skin AV malformations. A large European study of affected kindreds identified associated non-cutaneous AV malformations and, amongst 140 individuals, identified two cases of VGAM, raising the possibility of a genetic basis for this condition1.The aim of the present study was to assess the frequency and type of RASA1 mutations in a population presenting with VGAM malformation.
Methods A National Centre for VGAM treatment obtained consent for RASA 1 mutation analysis for all cases presented to the service from January 2011. Genomic DNA was obtained from blood samples and the 25 exons of the RASA1 gene were sequenced for each patient.
Results RASA1 analysis has been undertaken for 11 cases and four were positive for mutations: c.2912T > C(missense), c.2125C > T (truncated) and C.2119C > T (missense) (two cases). The two cases with the C.2119C > T mutation were siblings. One case, with the c.2125C > T mutation, developed the typical CM-AVM rash.
Conclusions RASA1 mutations are strongly associated with VGAM and are biologically plausible causative mutations. The autosomal dominant inheritance of this mutation, has a significant implication for counselling affected families.
Revencu N, Boon L, Mulliken J et al ParkesWeber Syndrome, Vein of Galen Aneurysmal Malformation, and Other Fast-Flow Vascular Anomalies Are Caused by RASA1 Mutations. Human Mutation 29(7),959–965,2008