Novel RASA1 mutations in Japanese pedigrees with capillary malformation-arteriovenous malformation

Capillary malformation-arteriovenous malformation (CM-AVM, MIM#608354) is a rare autosomal dominant disorder characterized by multiple cutaneous capillary malformations co-occurring with fast-flow vascular anomalies, such as arteriovenous malformation or fistula. Despite the identification of RASA1 as the first causative gene in Western patients with CM-AVM, there have been no literature reports of Japanese patients with this gene mutation. We herein report two Japanese pedigrees harboring multiple affected members with CM-AVM. Whole-exome sequencing in the two probands identified novel heterozygous mutations in RASA1, which were co-segregated with the disease in each family and were not reported in large-scale sequencing databases. One was a frameshift mutation and the other a splice-site mutation causing aberrant splicing, confirmed by a minigene assay. There were no other genes commonly disrupted among these probands. RASA1 was a major causative gene even in Japanese patients with CM-AVM, although obvious locus heterogeneity was known for this disease.