The Invitae Cerebral Cavernous Malformations Panel analyzes three genes that are associated with hereditary vascular cavernous malformations in the brain. These genes were selected based on the available evidence to date to provide appropriate testing for cerebral cavernous malformations (CCM).
Genetic testing of these genes may confirm a diagnosis and help inform treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives.
CCM2 KRIT1 PDCD10
CCM2 KRIT1 PDCD10
Cerebral cavernous malformations (CCMs) are abnormal collections of blood capillaries in the brain and spinal cord. These vascular malformations are characterized by reduced elasticity and thin blood vessels that are susceptible to hemorrhage. CCMs are a small subset of cerebral vascular malformations and can be recognized through neuroimaging. More than half of all individuals with CCMs become symptomatic, most frequently exhibiting seizures, headaches, focal neurological deficits, and cerebral hemorrhages. Vascular lesions in the spinal cord and other tissues are rare. Most affected individuals manifest symptoms after their second decade of life. Many individuals with CCM may never experience symptoms, but those who do often see abrupt onset.
Depending on ethnicity, 10%–50% of individuals with CCM present as familial cases with dominant inheritance and variable penetrance. Some sporadic cases may actually be familial but without symptoms seen in individuals who have pathogenic genetic changes. Familial cases tend to have more brain lesions (observable by neuroimaging) and suffer from hemorrhages more than twice as often as sporadic cases and throughout their adult lives.
Pathogenic variants in three genes explain the etiology in approximately 80% of familial CCM cases, with KRIT1 showing the highest clinical yield (approximately 55%), followed by CCM2 (approximately 15%) and PDCD10 (approximately 10%).
CCM is inherited in an autosomal dominant manner.
The onset of symptoms is age-dependent, with variable penetrance.
Cerebral cavernous malformations show a prevalence of 1 in 200 (0.5%). There is a higher prevalence in the Hispanic population.
The Invitae Cerebral Cavernous Malformations panel may be considered for individuals with cerebral hemorrhages, stroke, abrupt onset of chronic headache, or seizures.
For management recommendations please refer to:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|