RASA1 somatic mutation and variable expressivity in capillary malformation/arteriovenous malformation (CM/AVM) syndrome

Abstract

Germline mutations in RASA1 are associated with capillary malformation-arteriovenous malformation (CM-AVM) syndrome. CM-AVM syndrome is characterized by multi-focal capillary malformations and arteriovenous malformations. Lymphatic anomalies have been proposed as part of the phenotype. Intrafamilial variability has been reported, suggesting modifiers and somatic events. The objective of the study was to identify somatic RASA1 "second hits" from vascular malformations associated with CM-AVM syndrome, and describe phenotypic variability. Participants were examined and phenotyped. Genomic DNA was extracted from peripheral blood on all participants. Whole-exome sequencing was performed on the proband. Using Sanger sequencing, RASA1 exon 8 was PCR-amplified to track the c.1248T>G, p.Tyr416X germline variant through the family. A skin biopsy of a capillary malformation from the proband's mother was also obtained, and next-generation sequencing was performed on DNA from the affected tissue. A familial germline heterozygous novel pathogenic RASA1 variant, c.1248T>G (p.Tyr416X), was identified in the proband and her mother. The proband had capillary malformations, chylothorax, lymphedema, and overgrowth, while her affected mother had only isolated capillary malformations. Sequence analysis of DNA extracted from a skin biopsy of a capillary malformation of the affected mother showed a second RASA1 somatic mutation (c.2245C>T, p.Arg749X). These results and the extreme variable expressivity support the hypothesis that somatic "second hits" are required for the development of vascular anomalies associated with CM-AVM syndrome. In addition, the phenotypes of the affected individuals further clarify that lymphatic manifestations are also part of the phenotypic spectrum of RASA1-related disorders. © 2016 Wiley Periodicals, Inc.

Genetic tests in lymphatic vascular malformations and lymphedema

“…A patient with capillary malformations and left chylothorax, carrying a truncating heterozygous variant in RASA1 , has been reported 65. An individual carrying a frameshift mutation in RASA1 also showed swelling of the left leg due to lymphatic malformation.…”

RASA1 regulates the function of lymphatic vessel valves in mice

“…It has been proposed that development of vascular lesions in patients with germline RASA1 mutations additionally requires somatic mutation of the inherited normal RASA1 allele, resulting in the complete loss of RASA1 protein in affected cells (2,3). In support of this hypothesis, a RASA1 somatic mutation was recently identified in a CM of a CM-AVM patient with an inherited RASA1 mutation (5).…”

“…Lymphatic vessel (LV) disorders have also been described in some CM-AVM patients. These include chylothorax and chylous ascites (accumulation of lymph in the pleural and peritoneal cavities, respectively), lymphedema, LV malformation, and hyperplasia (2)(3)(4)(5)(6). In 70% of CM-AVM patients, inherited inactivating mutations of the RASA1 gene are responsible for disease development.…”

A novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations

“…Diffuse PAVMs are recorded when PAVMs are involved in every subsegmental artery within at least one lobe [2-3]. Capillary malformations (CM), another kind of vessels disease, can be an isolated clinical disease or associated with syndromic vascular anomalies [4], such as Sturge-Weber, Klippel-Trenaunay, Parkes-Weber, CM-AVMs [5-6], macrocephaly-CM (M-CM), and diffuse CM with overgrowth (DCMO) [3]. Among them, CM-AVMs as capillary level PAVMs, are a newly recognized clinical entity [5-7].…”

“…Capillary malformations (CM), another kind of vessels disease, can be an isolated clinical disease or associated with syndromic vascular anomalies [4], such as Sturge-Weber, Klippel-Trenaunay, Parkes-Weber, CM-AVMs [5-6], macrocephaly-CM (M-CM), and diffuse CM with overgrowth (DCMO) [3]. Among them, CM-AVMs as capillary level PAVMs, are a newly recognized clinical entity [5-7]. So far, only Endoglin ( ENG ), activin A receptor type II-like 1 ( ACVRL1 ), Mothers against decapentapledic homolog 4 ( SMAD4 ), and RAS activator 1 ( RASA1) were reported to be causal genes of PAVMs and CM-AVMs [7-11].…”