What is a RASA1 gene mutations relevance?

Mentioned early this week was the RASA1 gene mutation. Juxtaposed to the pik3ca mutation, this genetic mutation is differentially associated with Parkes Weber, CM-AVM1, CM-AVM2 or HHT. The RASA1 gene mutation is associated with being inherited, a standing a bit clearer when diagnosed with HHT. HHT has long been considered to be inherited. The CM-AVM family of diagnosis does not mean these malformations were necessarily inherited, although it is more probable than not. A Parkes Weber diagnosis when found in conjunction with testing positive for the RASA1 gene mutation is considered to be inherited, although not all Parkes Weber diagnosed test positive for RASA1. This means Parkes Weber can be inherited, but also can be the result of a random cell mutating during gestation, during pregnancy.

Confused yet. The key difference in the biology of the RASA1 mutation, in comparison to the pik3ca mutation spectrum of syndromes and symptoms, is the appearance of artery malformations such as AVMs and ATFs. When artery malformations are involved malformations are classified as High Flow malformations (a lot of blood moving due to the bllod pressure arteries use to move blood). This was the crux for having Parkes Weber Syndrome stand on its own outside of the Klippel-Tranaunay Syndrome classification, the moving away from the use of KTWS to the distinct use of KTS and PWS (meaning Parkes Weber). Also highly likely with the RASA1 mutation is the appearance of Capillary Malformations. Absent the RASA1 gene mutation Capillary Malformations are not typically present in Parkes Weber diagnosed which explains why a conference room of like diagnosed people shows very different phenotypes (looks).

If your sense is that we continue to be diagnosed more by our symptoms, more than our genetics, I share that perspective. There is no definitive test for K-T or PW yet. Is genetic testing worth the money. My answer is yes. For example, Klippel-Trenaunay diagnosed, can look forward to being further diagnosed as a pic3ca variant or not. Parkes Weber diagnosed can look forward to being further diagnosed as a RASA1 variant or not. A pic3ca diagnosis means therapies like Sirolimus may help. A non-RASA1 diagnosis means a future parent has less to worry about as regards inherited anomalies. The RASA1 gene mutation need only appear in one cell of one parent to be passed on. The differences between K-T and PW are real, are consequential. The differences within Syndrome based on genetic profiles are real, are consequential. Given the chance to repeat my childhood I would ask to be genetically tested. And to ring a bell that I often do, I would ask my parents and doctors to have my entire venous system radiologically mapped by experienced Vascular Malformation doctors. The latter in the US is cost prohibitive without Healthcare Insurance companies being compelled to cover these costs. So I lobby my elected representatives to add this requirement to US laws.

Reading Material –

https://www.nature.com/articles/s41431-018-0196-1?WT.feed_name=subjects_diagnosis