Cerebral Cavernous Malformations via the KRIT1/CCM1 Gene, Exon 10

Summary and Pricing

Test Method

Bi-Directional Sanger Sequencing
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
125 KRIT1 81479 81479 $250 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
125KRIT181479 $250 Order Options and Pricing

Pricing Comments

CNV detection may be ordered through Test #600.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

12 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the brain that can cause significant neurological disabilities, including intractable seizures and hemorrhagic stroke. CCMs represent 5-15% of all cerebral vascular malformations and occur in ~0.5% of the general population. CCMs have been reported in infants and children, but the majority of patients present with symptoms between the second and fifth decades. CCMs occur in a sporadic form in which patients usually present with a single lesion and no family history or a familial form characterized by multiple lesions and usually a strong family history. A significant fraction of “sporadic” cases with multiple lesions are members of an undiagnosed affected family. Not all patients with CCMs are clinically symptomatic. Symptomatic lesions may often be removed surgically. For additional information, see Zabramski et al. J Neurosurg 80: 422-432, 1994, Morrison and Akers 2011 GeneReviews (http://www.geneclinics.org/), and Angioma Alliance (http://www.angiomaalliance.org/).

Genetics

Familial cerebral cavernous malformations (CCMs) show autosomal dominant inheritance. Three causative genes for CCMs have been identified: KRIT1 (also called CCM1), encoding a protein that interacts with the Krev-1/rap1a tumor suppressor; CCM2, which is similar to the KRIT1 binding partner ICAP1α; and PDCD10 (or CCM3), the programmed cell death 10 gene. Almost all causative variants (in all three genes) are either nonsense, frameshift, splicing or deletion; missense variants are rare or absent (Denier et al. Ann Neurol 60:550-556, 2006; Plummer et al. Curr Neurol Neurosci Rep 5:391-396, 2005 ; Liquori et al. Am J Hum Genet 80:69-75, 2007). Large, pathogenic deletions in the three CCM genes are relatively common (Liquori et al. 2007; Felbor et al. Neurogenetics 8:149-153, 2007). Penetrance of pathogenic variants in the three CCM genes is incomplete (Morrison and Akers. GeneReviews. 2011). CCMs appear to occur only when there has been a "second hit" somatic variant in the normal allele in an endothelial cell (Akers et al. Hum Mol Genet 18:919-930, 2009; Pagenstecher et al. Hum Mol Genet 18:911-918, 2009).

Clinical Sensitivity - Sanger Sequencing

Test Variants Detected Variant Detection Rate
CCM1/KRIT1 “Common Hispanic” KRIT1 exon 10 (c.1363C>T) ~70% (with American Southwest Hispanic heritage)

Testing Strategy

The identification of the familial Hispanic KRIT1/CCM1 variant entails bidirectional DNA sequencing of the full coding region of KRIT1 exon 10. This test should be ordered first if the patient has Hispanic ancestry. PreventionGenetics also offers sequencing tests for the full KRIT1, CCM2, and PDCD10 genes (Tests #120-123) , a PCR test for the most common CCM2 gene deletion (Test #124), and an aCGH test for all larger copy number variants in the three CCM genes (Test #600).

Indications for Test

Patients who have American Southwest Hispanic heritage and multiple CCMs or a single CCM and family history are candidates for this test. Genetic testing of presymptomatic family members can identify patients who may benefit from more intensive clinical monitoring.

Gene

Official Gene Symbol OMIM ID
KRIT1 604214
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Cerebral Cavernous Malformations 1 AD 116860

Related Tests

Name
Cerebral Cavernous Malformations Panel
Cerebral Cavernous Malformations via the KRIT1/CCM1 Gene

Citations

  • Akers AL, Johnson E, Steinberg GK, Zabramski JM, Marchuk DA. 2009. Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Hum. Mol. Genet. 18: 919–930. PubMed ID: 19088123
  • Denier C, Labauge P, Bergametti F, Marchelli F, Riant F, Arnoult M, Maciazek J, Vicaut E, Brunereau L, Tournier-Lasserve E, Société Française de Neurochirurgie. 2006. Genotype-phenotype correlations in cerebral cavernous malformations patients. Ann. Neurol. 60: 550–556. PubMed ID: 17041941
  • Liquori CL, Berg MJ, Squitieri F, Leedom TP, Ptacek L, Johnson EW, Marchuk DA. 2007. Deletions in CCM2 Are a Common Cause of Cerebral Cavernous Malformations. The American Journal of Human Genetics 80: 69–75. PubMed ID: 17160895
  • Pagenstecher A, Stahl S, Sure U, Felbor U. 2008. A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells. Human Molecular Genetics 18: 911-918. PubMed ID: 19088124
  • Plummer NW, Zawistowski JS, Marchuk DA. 2005. Genetics of cerebral cavernous malformations. Current neurology and neuroscience reports 5: 391–396. PubMed ID: 16131422
  • Zabramski JM, Wascher TM, Spetzler RF, Johnson B, Golfinos J, Drayer BP, Brown B, Rigamonti D, Brown G. 1994. The natural history of familial cavernous malformations: results of an ongoing study. Journal of neurosurgery 80: 422–432. PubMed ID: 8113854

Ordering/Specimens

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