RASA1 – Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM)

Capillary malformation-arteriovenous malformation syndrome (CM-AVM; MONDO:0012016) is an autosomal dominant vascular disorder caused by heterozygous mutations in the RASA1 gene (HGNC:9871). Affected individuals develop multifocal cutaneous capillary malformations and have an elevated risk of fast-flow vascular anomalies, including arteriovenous malformations (AVMs), arteriovenous fistulas, aneurysms, and lymphatic vessel abnormalities. Clinical penetrance is high, with variable expressivity ranging from isolated capillary stains to life-threatening intracranial or spinal AVMs.

Genetic evidence supports a definitive CM-AVM association with RASA1. Over 100 unrelated probands spanning more than 50 families have been reported to carry pathogenic RASA1 variants, including frameshift, nonsense, splice-site, missense, and large deletions, with segregation in multiple multi-generation pedigrees (PMID:18446851; PMID:27625812). Segregation analyses in at least 44 families have confirmed autosomal dominant inheritance with high penetrance and occasional de novo events. Targeted sequencing and gene panels now identify RASA1 variants in up to 73% of clinically defined CM-AVM patients, including prenatal and mosaic cases.

The RASA1 variant spectrum is broad: loss-of-function alleles predominate, including c.2422C>T (p.Gln808Ter) and c.2920del (p.Asn976fs) (PMID:23687085). Splice-site mutations and deep intronic changes have been documented, and postzygotic mosaicism accounts for ~25% of mutation-negative cases on blood testing, revealing low-level mosaic RASA1 mutations in affected tissue (PMID:31300548). No common founder alleles have been established, reflecting locus heterogeneity across populations.

Functional studies demonstrate that RASA1 haploinsufficiency perturbs Ras GTPase-activating protein (RasGAP) activity, leading to aberrant Ras-MAPK signaling in endothelial and lymphatic endothelial cells. Inducible RASA1 knockout mice recapitulate lymphatic valve defects, chylothorax, and vessel hyperplasia (PMID:28530642; PMID:22232212). Somatic "second-hit" RASA1 mutations in vascular lesions further support a two-hit model driving focal malformation development.

No studies have refuted the RASA1–CM-AVM link; rather, clinical and molecular findings converge on a haploinsufficiency mechanism with high penetrance. Mosaic and constitutional variants explain intrafamilial variability, and comorbidity with lymphatic anomalies underscores phenotypic breadth. EPHB4 gene mutations account for a CM-AVM2 subtype but do not detract from the established role of RASA1 in CM-AVM1.

Molecular diagnosis of RASA1 mutations informs management: asymptomatic carriers undergo imaging surveillance for fast-flow vascular lesions, while confirmed negative relatives are spared unnecessary investigations. Prenatal and preimplantation testing is available for families with severe presentations. Genetic counseling should address autosomal dominant transmission, variable expressivity, and mosaicism.

Key Take-home: Pathogenic RASA1 variants cause a definitive autosomal dominant CM-AVM1 syndrome with multifocal capillary malformations, fast-flow vascular anomalies, and lymphatic involvement; molecular testing guides surveillance and family planning.

References

• Human Mutation | 2008 | Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. PMID:18446851
• Journal of Pediatric Genetics | 2012 | RASA1 analysis guides management in a family with capillary malformation-arteriovenous malformation. PMID:27625812
• American Journal of Medical Genetics Part A | 2013 | A novel RASA1 mutation causing capillary malformation-arteriovenous malformation (CM-AVM) presenting during pregnancy. PMID:23687085
• The Journal of Clinical Investigation | 2012 | RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice. PMID:22232212
• The Journal of Clinical Investigation | 2017 | RASA1 somatic mutation and variable expressivity in capillary malformation/arteriovenous malformation (CM/AVM) syndrome. PMID:28530642

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