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DESCRIPTIONMutations in the NOTCH3 gene have been causally associated with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Genetic testing is available to determine if pathogenic mutations exist in the NOTCH3 gene for patients with suspected CADASIL and their family members.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an uncommon, autosomal dominant disease. It is the most common cause of hereditary stroke and hereditary vascular dementia in adults. The CADASIL syndrome is an adult-onset, disabling systemic condition, characterized by migraine with aura, recurrent lacunar strokes, progressive cognitive impairment, and psychiatric disorders. The overall prevalence of the disease is unknown in the general population.
The clinical presentation of CADASIL is variable, and may be confused with multiple sclerosis, Alzheimer dementia, and Binswanger disease. The specific clinical signs and symptoms, along with family history and brain magnetic resonance imaging (MRI) findings, are extremely important in determining the diagnosis of CADASIL. When the differential diagnosis includes CADASIL, various other tests are available for diagnosis:
Mutations in NOTCH3 have been identified as the underlying cause of CADASIL. In almost all cases, the mutations lead to loss or gain of a cysteine residue that could lead to increased reactivity of the NOTCH3 protein, resulting in ligand-binding and toxic effects.
The NOTCH3 gene is found on chromosome 19p13.2-p13.1 and encodes the third discovered human homologue of the Drosophila melanogaster type I membrane protein NOTCH. The NOTCH3 protein consists of 2,321 amino acids primarily expressed in vascular smooth muscle cells and plays an important role in the control of vascular transduction. It has an extracellular ligand-binding domain of 34 epidermal growth factor-like repeats, traverses the membrane once, and has an intracellular domain required for signal transduction.
Mutations in the NOTCH3 gene have been differentiated into those that are causative of the CADASIL syndrome and those that are of uncertain significance. Causative mutations affect conserved cysteine residues within 34 epidermal growth factor (EGF)-like repeat domains in the extracellular portion of the NOTCH3 protein. (10, 11) More than 150 causative mutations have been reported in at least 500 pedigrees. NOTCH3 has 33 exons, but all CADASIL mutations reported to date have occurred in exons 2–24, which encode the 34 EGF-like repeats, with strong clustering in exons 3 and 4, which encode EGFR 2–5 (>40% of mutations in >70% of families occur in these exons).
There are no manufactured test kits for detecting NOTCH3 gene mutations; therefore, this testing has not been reviewed by the Food and Drug Administration (FDA). Rather, NOTCH3 gene sequencing is a laboratory-developed test (LDT), offered by clinical laboratories licensed under Clinical Laboratory improvement Act (CLIA) for high-complexity testing.
POLICYNOTCH3 testing for the diagnosis of CADASIL is considered investigational.
POLICY GUIDELINESInvestigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY11/17/2011: Approved by Medical Policy Advisory Committee.
11/28/2012: Policy reviewed; no changes.
01/14/2013: Added the following new 2013 CPT code to the Code Reference section: 81479.
10/23/2013: Policy reviewed; no changes.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.04.75
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.