Constitutional mosaicism in RASA1‐related capillary malformation‐arteriovenous malformation

Abstract

Capillary malformation‐arteriovenous malformation (CM‐AVM) is caused by germline RASA1 and EPHB4 alterations. RASA1 intralesional second hits have also been reported. Here we report RASA1 constitutional mosaicism, defined here as the presence of a mosaic variant in all cell types of an individual, in two patients with CM‐AVM. High‐throughput sequencing was used to search for RASA1 pathogenic variants in blood samples from two unrelated patients with CM‐AVM. An affected tissue sample from one of the patients was also analyzed. Both patients showed different nonsense RASA1 variants in mosaic, ranging from 7% to 21.5%, in blood samples and in the corresponding affected tissue sample from one of the patients. In conclusion, we report for the first time the presence of RASA1 constitutional mosaicism in CM‐AVM. Constitutional mosaicism has implications for accurate molecular diagnosis and recurrence risk and helps to explain the great phenotypic variability in CM‐AVM.