Article Category: Technical Report
Published Online: Sep 19, 2018
Page range: 83 - 85
DOI: https://doi.org/10.2478/ebtj-2018-0046
Keywords
© 2018 Yeltay Rakhmanov, Paolo Enrico Maltese, Carla Marinelli, Leonardo D’Agruma, Tommaso Beccari, Munis Dundar, Matteo Bertelli, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
(Other synonyms: Familial cavernous angioma, cavernous angiomatous malformations, hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations)
Cerebral cavernous malformations (CCM, OMIM disease: 116860) are a specific type of vascular malformation of the central nervous system. Their morphological structure consists of well-circumscribed collections of dilated, thin-walled vascular channels lined by simple endothelium and thin fibrous adventitia, containing blood that is usually clotted or in a state of decomposition (1).
The overall prevalence of all CCM has been estimated at 1/200 to 1/1,000 individuals. Familial CCM accounts for about 20% of all CCM cases with an estimated prevalence of 1/5,000 -1/10,000 and is therefore rare, unlike the common sporadic CCM. A strong founder effect has been detected in Hispanic-American families affected by CCM (2).
There are sporadic and familial forms of CCM. Sporadic cases are characterized by a lack of family history of the disease and usually MRI evidence of a single lesion (3, 4), although multiple lesions have been reported (5, 6). In contrast, familial cases mostly exhibit multiple lesions that progress in number and size over time (7).
Diagnostic procedures should be based on identification of symptoms (seizure disorder, focal neurological deficits, nonspecific headaches, cerebral haemorrhage, vascular skin lesions, capillary malformations, hyperkeratotic cutaneous capillary venous malformations, venous malformations, red macules, and/or nodular venous malformations, retinal cavernomas and rare choroidal hemangiomas) with the aid of high-resolution MR imaging using either gradient echo (GRE) or susceptibility-weighting (SWI) and angiography (8), and collecting information on family history.
Differential diagnosis should consider arteriovenous malformations, venous malformations, telangiectases, vascular tumors such as hemangioblastomas (including those seen in Von Hippel-Lindau syndrome) and vascular malformations associated with Sturge-Weber syndrome.
CCM has autosomal dominant inheritance with incomplete penetrance and include:
CCM1 (OMIM disease 116860) -
CCM2 (OMIM disease 603284) -
CCM3 (OMIM disease 603285) -
Somatic mutations in the three genes have been identified in CCM lesions from both sporadic and familial patients (9). Gault et al. found somatic mutations in the
Pathogenic variants may include missense, nonsense, splicing, small insertions, small deletions, small indels, gross insertions and gross deletions.
To determine the gene defect responsible for the disease;
To confirm clinical diagnosis;
To assess the recurrence risk and perform genetic counselling for at-risk/affected individuals.
The test is listed in the Orphanet database and is offered by 9 accredited medical genetic laboratories in the EU, and in the GTR database, offered by 12 accredited medical genetic laboratories in the US.
Guidelines for clinical use of the test are described in Genetics Home Reference (
A multi-gene next generation sequencing panel is used for the detection of nucleotide variations in coding exons and flanking introns of the above genes.
Potentially causative variants and regions with low coverage are Sanger-sequenced. Sanger sequencing is also used for family segregation studies.
Multiplex Ligation Probe Amplification (MLPA) is used to detect insertions and deletions in
To perform molecular diagnosis, a single sample of biological material is normally sufficient. This may be 1 ml peripheral blood in a sterile tube with 0.5 ml K3EDTA or 1 ml saliva in a sterile tube with 0.5 ml ethanol 95%. Sampling rarely has to be repeated.
Gene-disease associations and the interpretation of genetic variants are rapidly developing fields. It is therefore possible that the genes mentioned in this note may change as new scientific data is acquired. It is also possible that genetic variants today defined as of “unknown or uncertain significance” may acquire clinical importance.
Identification of pathogenic variants in the above genes confirms the clinical diagnosis and is an indication for family studies.
A pathogenic variant is known to be causative for a given genetic disorder based on previous reports, or predicted to be causative based on loss of protein function or expected significant damage to proteins or protein/protein interactions. In this way it is possible to obtain a molecular diagnosis in new/other subjects, establish the risk of recurrence in family members and plan preventive and/or therapeutic measures.
Detection of a variant of unknown or uncertain significance (
The absence of variations in the genomic regions investigated does not exclude a clinical diagnosis but suggests the possibility of:
alterations that cannot be identified by sequencing, such as large rearrangements that cause loss (deletion) or gain (duplication) of extended gene fragments;
sequence variations in gene regions not investigated by this test, such as regulatory regions (5’ and 3’ UTR) and deep intronic regions;
variations in other genes not investigated by the present test.
Unexpected results may emerge from the test, for example information regarding consanguinity, absence of family correlation or other genetically-based diseases.
In autosomal dominant transmission, the probability that an affected carrier transmit the variant to his/her children is 50% in any pregnancy, irrespective of the sex of the child conceived.
The test is limited by current scientific knowledge regarding the gene and disease.
NGS Analytical sensitivity >99.99%, with a minimum coverage of 10X; Analytical specificity 99.99%.
SANGER Analytical sensitivity >99.99%; Analytical specificity 99.99%.
MLPA Analytical sensitivity >99.99%; Analytical specificity 99.99%.
Clinical sensitivity: the variations in the aforementioned genes are associated with CCM, but in many cases, these are individual variations (identified in one or few families) and total epidemiological data is therefore not available.
Clinical specificity: Data not available.
The genetic test is appropriate when:
the patient meets the diagnostic criteria for CCM;
the sensitivity of the test is greater than or equal to that of tests described in the literature.
| Clinical management | Utility |
|---|---|
| Confirmation of clinical diagnosis | Yes |
| Differential diagnosis | Yes |
| Couple risk assessment | Yes |
| Availability of clinical trials can be checked on-line at | |