Genetics of Cavernous Malformation

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Key points

  • CCMs can be sporadic (by chance) or familial (inherited).
  • CCMs form when both copies of a CCM gene in a blood vessel cell are not working (the “two hit model”).
  • People with a founder mutation share the same genetic change from a distant ancestor.
  • Genetic testing can confirm familial CCM, guide care, and help relatives understand their risks.
  • Knowing whether your CCM is sporadic or familial helps doctors plan treatment and include patients in research.

Cavernous malformations (CCMs) are caused by changes in specific genes that help blood vessels stay strong. These genes are called CCM1 (also called KRIT1), CCM2, and CCM3 (also called PDCD10).

The first gene was identified in 1999 and was named CCM1 (for cerebral cavernous malformation 1). CCM2 was identified in 2003, and CCM3 was found in 2005.

  • These genes work together to keep the cells that line blood vessels healthy.
  • Most people are born with two copies of each CCM gene (one from each parent).
  • When a single cell’s CCM genes stop working, a blood vessel may form a CCM.
  • CCMs are fragile and can leak blood, which can cause symptoms like headache, seizures, or stroke.

There are two ways that CCM genes can be changed to cause CCMs:

Inherited (Familial CCM):

  • You are born with a change in a CCM gene from one parent.
  • This is called an autosomal dominant mutation. 
  • Only one parent needs to pass on the change for the child to inherit familial CCM.
  • Children have a 50% chance of inheriting the gene.

Sporadic CCM:

  • The gene change happens by chance in the blood vessels later in life.
  • It is not inherited and cannot be passed on to children.
  • Most people with CCM have this form.

Researchers have found that CCMs develop when both copies of a CCM gene are no longer working in the same blood vessel cell. This is called the “two-hit” model:

  • The first change may in every cell (familial CCM) or by chance in a single cell (sporadic CCM).
  • The second change occurs in a single blood vessel cell.
  • This can trigger the development of a CCM.

Even though the causes differ, the process within the blood vessel is similar in both sporadic and familial CCM.

Sometimes a gene change starts in one person long ago and is passed down for generations. These are called founder mutations.

  • Families with the same founder mutation share a common ancestor.
  • Some well-studied founder mutations exist in the United States, like the CCM1 Common Hispanic Mutation (Q455X) and certain CCM2 variants.
  • Learning about these mutations helps researchers track CCM in families and develop better treatments.

Genetic testing can:

  • Confirm if CCM is familial
  • Help guide medical care and monitoring. People with familial CCM caused by the CCM3 gene tend to have symptoms and CCM hemorrhage (bleeding) at an earlier age.
  • Allow doctors to help group patients correctly for research and clinical trials.

For people with sporadic CCM, genetic testing is usually negative (normal) because the CCM is not inherited.

CCM Genetics and You Webinar

 

Updated 3.14.26.

Links

To find general information on genetics, visit the Medline Plus.

References

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Liquori CL, Berg MJ, Siegel AM, Huang E, Zawistowski JS, Stoffer T, Verlaan D, Balogun F, Hughes L, Leedom TP, Plummer NW, Cannella M, Maglione V, Squitieri F, Johnson EW, Rouleau GA, Ptacek L, Marchuk DA. Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet. 73(6):1459-64, Dec 2003.

Liquori CL, Berg MJ, Squitieri F, Leedom TP, Ptacek L, Johnson EW, Marchuk DA.  Deletions in CCM2 are a common cause of cerebral cavernous malformations.  Am j Hum Genet.  2007 Jan;80(1):69-75.

Pagenstecher A, Stahl S, Sure U, Felbor U.  A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2, or CCM3 in affected endothelial cells.  Hum Mol Genet.  2009 Mar;18(5):911-8.

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Whitehead KJ, Chan AC, Navankasattusas S, Koh W, London NR, Ling J, Mayo AH, Drakos SG, Marchuk DA, Davis GE, Li DY.  The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases.  Nat Med. 2009 Feb; 15(2):177-84.

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