Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy; Familial Vascular Leukoencephalopathy; Hereditary Multi-Infarct Dementia

CADASIL is characterized by migraine headaches, adult-onset cerebrovascular disease progressing to dementia, and neuroimaging findings of diffuse white matter lesions and subcortical infarcts.

CADASIL is an autosomal dominant disorder caused by mutations in NOTCH3. All confirmed mutations result in loss or gain of a cysteine residue in one of the EFF-like domains of the protein.

1. Confirmation of diagnosis:
   1. In individuals with clinical features suggestive of CADASIL.
2. Prenatal testing (technically feasible but not routinely performed – contact MGL to discuss):
   1. In pregnancies where one member of the couple has CADASIL and a known NOTCH3 mutation.
3. Presymptomatic testing
   1. In adults known to be at risk due to a family history of CADASIL and the mutation is known. Predictive testing will only be performed following genetic counselling by a recognized genetic service.

Select regions, (exons 2 – 6 and 11 and the flanking intronic sequences of these exons) of the NOTCH3 gene are sequenced using Sanger sequencing. Coverage is bidirectional, with the exception of exon 2, which is unidirectional.

NM_000435.2 The ‘A’ within the initiation codon, ATG, is designated as nucleotide number 1.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: 100 μL at 200 ng/μL is optimal (Minimum: 30 μL at 200 ng/μL)

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth and ship to the address below. Samples should be shipped at room temperature with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays). 

Testing is only available to residents of Canada, except in very specific circumstances where testing is urgent or emergent.  Payment is not required when requests are made for individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) AND eligible for testing according to the test utilization guidelines / policy. If the individual undergoing testing is not insured by these providers or does not meet utilization guidelines or policy, please complete a billing form; testing will only commence after receipt of billing informationTest prices can be found here.

Molecular genetic testing is limited by the current understanding of the genome and the genetics of a particular disease, as well as by the method of detection used. This method will not detect all mutations (e.g., large genomic deletions/duplications, promoter mutations, regulatory element mutations).

For carrier/predictive testing due to a family history, it is generally important to first document the gene mutation in an affected or carrier family member. This information should be provided to the laboratory for assessment of whether the assay is appropriate for detection of the familial mutation, and to aid in the interpretation of data.

In some cases, DNA alterations of undetermined or unclear clinical significance may be identified.

Rare single nucleotide variants or polymorphisms could lead to false-negative results. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

A previous bone marrow transplant from an allogenic donor will result in molecular data that reflects the donor genotype rather than the recipient (patient) genotype. Consult the on-service Molecular Geneticist for approach to testing in such individuals.

Transfusions performed with packed red blood cells will generally not affect the outcome of molecular genetic testing. However, if there is no clinical urgency, the cautious approach is to wait one week post packed red cell transfusion before collecting a sample for genetic testing. Consult the on-service Molecular Geneticist as needed.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.