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MP 2.04.75 Genetic Testing of CADASIL Syndrome

Medical Policy    
Original Policy Date
Last Review Status/Date
Reviewed with literature search/10:2014
  Return to Medical Policy Index


Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


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:

  • Immunohistochemistry assay of a skin biopsy sample, using a monoclonal antibody with reactivity against the extracellular domain of the NOTCH3 receptor. Positive immunostaining reveals the accumulation of NOTCH3 protein in the walls of small blood vessels.(2) Lesnick Oberstein et al (2003) estimated sensitivity and specificity at 85% to 90% and 95% to 100%, respectively, for 2 observers of the test results in a population of patients and controls correlated with clinical, genetic and MRI parameters.(3)
  • Detection of granular osmiophilic material (GOM) in the same skin biopsy sample by electron microscopy. The major component of GOM is the ectodomain of the NOTCH3 gene product.(3) GOM accumulates directly in vascular smooth muscle cells and, when present, is considered a hallmark of the disease.(5) However, GOM may not be present in all biopsy samples. Sensitivity has been reported as low as 45% and 57%, but specificity is generally near or at 100%.(6-8)
  • Genetic testing, by direct sequencing of selected exons or of exons 2-24 of the NOTCH3 gene (see Rationale section).
  • Examination of brain tissue for the presence of GOM. GOM was originally described as limited to brain vessels.(9) Examination of brain biopsy or autopsy after death was an early gold standard for diagnosis. In some cases, peripheral staining for GOM has been absent even though positive results were seen in brain vessels.

NOTCH3 mutations

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.(10)

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 2321 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.(11)

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.(11,12) 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).(13) Some studies indicate that the clinical variability in CADASIL presentation, particularly with regard to the development of white matter hyperintensities on MRI, may be related to genetic modifiers outside the NOTCH3 locus, but the specific role of these modifiers is not well-delineated.(14)

Regulatory Status

As of August 2014, there are no manufactured test kits for detecting NOTCH3 gene mutations; therefore, this testing has not been reviewed by the U.S. Food and Drug Administration. Rather, NOTCH3 gene sequencing is a laboratory-developed test, offered by clinical laboratories licensed under Clinical Laboratory improvement Act for high-complexity testing.


Genetic testing to confirm the diagnosis of CADASIL syndrome may be considered medically necessary under the following conditions:

  • Clinical signs, symptoms, and imaging results are consistent with CADASIL, indicating that the pretest probability of CADASIL is at least in the moderate to high range (see Policy Guidelines section). and
  • The diagnosis of CADASIL is inconclusive following alternate methods of testing, including MRI and skin biopsy.

Genetic testing for CADASIL syndrome in all other situations, including but not limited to testing of asymptomatic patients who have a first- or second-degree relative with CADASIL, is considered investigational.

Policy Guidelines

The probability that CADASIL is present is an individualized assessment, depending on numerous factors such as family history, symptoms, imaging results, and other specialized testing such as skin biopsy.

Pescini et al published a study in 2013 that attempted to identify clinical factors that increase the likelihood of a pathologic mutation being present.(13) The following table summarizes the pooled frequency of clinical and radiologic features, and the points assigned for each finding. The authors recommended that a total score of 14 be used to select patients for testing, as this score resulted in a high sensitivity (96.7%) and a moderately high specificity (74.2%).


Number WithNOTCH3Mutation

Percent WithNOTCH3Mutation


Clinical features

  • Migraine




  • Migraine with aura




  • Transient ischemic stroke/stroke



1 (2 if <50 years old)

  • Psychiatric disturbance




  • Cognitive decline




Radiologic features

  • Leukoencephalopathy (LE)




  • LE extended to temporal pole




  • LE extended to external capsule




  • Subcortical infarcts




LE leukoencephalopathy.

Effective in 2013, there is CPT coding to more specifically report NOTCH3 genetic testing.

Code 81406 includes:

NOTCH3 (notch 3) (eg, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]), targeted sequence analysis (eg, exons 1-23)

Prior to 2013, there was no specific CPT code for this testing. A combination of molecular pathology CPT codes would have been used such as:

83891 Molecular diagnostics; isolation or extraction of highly purified nucleic acid, each nucleic acid type (ie, DNA or RNA)

83898x23 Molecular diagnostics; amplification, target, each nucleic acid sequence

83904x23 Molecular diagnostics; mutation identification by sequencing, single segment, each segment

83909x23 Molecular diagnostics; separation and identification by high resolution technique (e.g., capillary electrophoresis), each nucleic acid preparation

83912 Molecular diagnostics; interpretation and report.

Benefit Application
BlueCard/National Account Issues

No applicable information.


This policy was created in September 2011 and updated periodically with literature review. The most recent update covers the period through September 6, 2014.

Literature that describes the analytic validity, clinical validity, and clinical utility of NOTCH3 testing was sought. No relevant primary data on analytic validity were identified. The test is generally done by gene sequencing analysis, which is expected to have high analytic validity when performed under optimal conditions.

Clinical validity

Several retrospective and prospective studies have examined the association between NOTCH3 genes and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), as shown in the following table. These have been divided into 2 categories: part 1, diagnostic studies, in which the patients enrolled were suspected but not confirmed to have CADASIL; and part 2, clinical validity studies, in which the patients had already been diagnosed with the disease by some method other than genetic testing. The diagnostic studies are more likely to represent the target population in which the test would be used.

The results of the clinical validity studies demonstrate that a NOTCH3 mutation is found in a high percentage of patients with a clinical diagnosis of CADASIL, with studies reporting a clinical sensitivity of 90% to 100%. Limited data on specificity is from testing small numbers of healthy controls, and no false positive NOTCH3 mutations have been reported in these populations. The diagnostic yield studies report a variable diagnostic yield, ranging from 10% to 54%. These lower numbers likely reflect testing in
heterogeneous populations that include patients with other disorders.

Table.Studies of the Association of NOTCH3 With CADASIL Diagnosis; Results of Published Studies SupportingNOTCH3Genotyping Test Claims.


Patients Evaluated

NOTCH3 Exons Evaluated



Part 1 Diagnostic Studies

Diagnostic Yield


Mosca et al (2011)(10)

Patients: 140 patients with clinical suspicion of CADASIL (Italian and Chinese)

Patient Selection: History of premature strokes; migraine with aura; vascular dementia; suggestive MRI findings; a consistent family history; or a combination of the above criteria

Direct sequencing of exons 2-8, 10, 14, 19, 20, and 22

Patients: 14 patients with causative mutations located in 10 different exons. 126 patients free of pathogenic mutations.

Family Members: Analysis of 15 additional family members identified 11 of the same causative mutations


Lee et al (2009)(15)

Patients: 39 patients with suspected CADASIL (China). 100 healthy elderly controls 80 years or older.

Patient Selection: Suggestive MRI findings and at least one of the following: young age at onset, cognitive decline, psychiatric disorders, or consistent family history

Direct sequencing of exons 2-23

Patients: 9 different point mutations identified in 21/39 patients

Family members: No data for additional family members

100%. No mutations found in 100 healthy elderly controls.

Markus et al (2002)(8)

Patients: 83 patients with suspected CADASIL (UK)

Patient Selection: Patients were younger than 60 years of age with recurrent lacunar stroke with leukoaraiosis on neuroimaging. Migraine, psychiatric disorders, or dementia could occur but were not essential.

Direct sequencing of exons 3-4; SSCP of exons 2, 5-23.

Patients:15 different point mutations identified in 48 families with a total of 116 symptomatic patients, 73% in exon 4, 8% in exon 3, and 6% in exons 5 and 6

Family Members: No data for additional family members


Choi et al (2011)(9)

Patients: 151 consecutive Korean patients with acute ischemic stroke

Patient Selection: History of acute ischemic stroke, neurologic exam, cranial computed tomography or MRI

Bidirectional sequencing of exons 3, 4, 6, 11 and 18.

Patients: 6 patients (4%) were found with the identical NOTCH3 mutation (R544C; exon 11). Of these, all had preexisting lacunar infarction, 5 (83.3%) had grade 2-3 white-matter hyperintensity lesions, and a history of hypertension; a history of stroke and dementia was higher in patients with mutations.

Family Members: No data for additional family members


Choi et el (2014)(16) Patients: 47 subjects from 34 families (Chinese) diagnosed with suspected CADASIL
Patient diagnosis/selection: MRI abnormalities and the presence of >1 typical symptom (eg, migraine, stroke, cognitive deficits, psychiatric symptoms) or the presence of atypical symptoms
with a positive family history
Testing method as per Joutel et al(17) ; exons 3 and 4 screened first; if no mutations detected, remaining
exons analyzed
Patients: 6 known mutations were identified in 8 families and 2 novel mutations were identified in 2 families (exons 3 and 4), and 1 VUS was identified in 1 family (exon 2). Overall NOTCH3 mutation prevalence: 29.4%. NR

Part 2 Clinical Validity Studies



Peters et al (2005)(18)

Patients: 125 unrelated patients diagnosed with CADASIL

Patient Diagnosis/Selection: Skin biopsy-proven CADASIL patients referred between 1994 and 2003 (German)

Bidirectional sequencing of all exons

Sensitivity: 96%

Patients: 54 distinct mutations in 120 (96.0%) of the 125 patients. In 5 patients (4.0%), no mutation was identified.

Family Members: No data for additional family patients


Tikka et al (2009)(19)

Patients: 131 patients from 28 families diagnosed with CADASIL (Finnish, Swedish, and French)

Patient Diagnosis/Selection: EM examination of skin biopsy was performed; 26 asymptomatic controls from CADASIL families

Direct sequencing of exons 2-24.

Sensitivity: 100%

Patients: 131 CADASIL patients were mutation-positive

Family Members: No data for additional family patients.

No mutation reporting per family or per unrelated individual.

100%. No mutations were found in the 26 negative controls.

Dotti et al (2005)(20)

Patients: 28 unrelated, consecutively diagnosed patients with CADASIL (Italian)

Patient Diagnosis/Selection: Patients were diagnosed via clinical and MRI

DHPLC, followed by confirmatory sequencing of identified mutations

Sensitivity: 100%

Patients: All 28 patients had mutations


Joutel et al (1997)(17)

Patients: 50 unrelated patients with a clinical suspicion of CADASIL and 100 healthy controls

Patient Diagnosis/Selection: History of recurrent strokes, migraine with aura, vascular dementia, or a combination; brain MRI with suggestive findings; and a consistent familial history

SSCP or heteroduplex analysis of all exons, followed by confirmatory sequencing of identified mutations

Sensitivity: 90%

Patients: 45 of 50 CADASIL patients had mutations

100%. No mutations were found in 100 healthy controls.

DHPLC: denaturing high-performance liquid chromatography; EM: electron microscope; MRI: magnetic resonance imaging; SSCP: single-stranded conformational polymorphism; VUS: variant of uncertain significance. 

The clinical specificity of genetic testing for CADASIL is high, and false-positive results have not been reported in studies of clinical validity. Therefore, a positive genetic test in a patient with clinical signs and symptoms of CADASIL is sufficient to confirm the diagnosis with a high degree of certainty. The clinical sensitivity is also relatively high, in the range of 90% to 100% for patients with a clinical diagnosis of CADASIL. This indicates that a negative test reduces the likelihood that CADASIL is present. However,
since false negative tests do occur, a negative test is less definitive in ruling out CADASIL. Whether a negative test is sufficient to rule out CADASIL depends on the pretest likelihood that CADASIL is present.

Clinical utility

There are several situations in which genetic testing may have clinical utility. The clinical situations addressed in this policy are:

  • Confirmation of a clinical diagnosis of CADASIL in an individual with signs and symptoms of the disease;
  • Predictive testing for at-risk individuals with a family history of CADASIL;

Other situations in which genetic testing may be considered are preimplantation testing and/or prenatal (in utero) testing when a pathologic NOTCH3 mutation is present in a parent. Preimplantation testing is addressed in a separate MPRM policy (MPRM Policy 4.02.05 Preimplantation Genetic Testing).

Confirmation of a CADASIL diagnosis


Pescini et al published a study in 2013 that attempted to identify clinical factors that increase the likelihood of a pathologic mutation being present and therefore might be helpful in selecting patients for testing.(1) The authors first performed a systematic review to determine the frequency with which clinical and radiologic factors were associated with a positive genetic test. Evidence was identified from 15 clinical series of patients with CADASIL. Table 2 summarizes the pooled frequency of clinical and radiologic features.

Table 2: Clinical and Radiologic Features in Patients with NOTCH3 Mutations

Features                                              Number with NOTCH3 Mutation     Percent iwth NOTCH3 Mutation, %
Clinical Features    
Migraine 239/463        52       
Migraine with aura 65/85 76
Transient ischemic attack/stroke 380/526 72
Psychiatric disturbance 106/380 28
Cognitive decline 188/434 43
Radiologic features    
LE 277/277 100
LE extended to temperal pole 174/235 74
LE extended to ecternal capsule 228/303 75
Subcortical infarcts 210/254 83

LE: leukoencephalopathy

Using these frequencies, a preliminary scoring system was developed and tested in 61 patients with NOTCH3 mutations, and in 54 patients with phenotypic features of CADASIL who were NOTCH3- negative. With the addition of family history, and age at onset of transient ischemic attack (TIA)/stroke, a scoring system was developed with the following point values: migraine (1); migraine with aura (3); TIA/stroke (1); TIA/stroke 50 years old or younger (2); psychiatric disturbance (1); cognitive decline (3);
leukoencephalopathy (3); leukoencephalopathy extended to temporal pole (1); leukoencephalopathy extended to external capsule (5); subcortical infarcts (2); family history, 1 generation (1); family history, 2 generations or more (2). The authors recommended that a total score of 14 be used to select patients for testing, as this score resulted in a high sensitivity (96.7%) and a moderately high specificity (74.2%).

Currently, there is no specific clinical treatment for CADASIL that has established efficacy. Supportive care in the form of practical help, emotional support, and counseling are appropriate for affected individuals and their families.(4,11) Four studies were found that addressed the efficacy of potential treatments for CADASIL.

A double-blind, placebo controlled trial that evaluated the efficacy and safety of donepezil hydrochloride (HCl) in individuals with CADASIL was conducted. The study resulted in donepezil HCl having no effect on the primary cognitive end point, the V-ADAS-cog score in patients with CADASIL who had cognitive impairment.(21)

Another study evaluated the efficacy and tolerance of a 24-week treatment with 250 mg/d acetazolamide (ACZ), which could be chronically implemented to improve cerebral hemodynamics in CADASIL patients (n=16). Treatment with ACZ resulted in a significant increase of mean blood flow velocity (MFV) in the middle cerebral artery (MCA) compared with MFV in the MCA at rest before treatment (57.68±12.7 cm/s vs 67.12±9.4 cm/s; p=0.001). During the treatment period, none of the subjects developed new neurologic
symptoms, and the original symptoms in these patients, such as headaches and dizziness, were relieved.(22)

A third study evaluated the use of HMG-CoA-reductase-inhibitors (statins) in 24 CADASIL subjects treated with atorvastatin for 8 weeks. Treatment was started with 40 mg, followed by a dosage increase to 80 mg after 4 weeks. Transcranial Doppler sonography measuring MFV in the MCA was performed at baseline and at the end of the treatment period. There was no significant treatment effect on MFV (p=0.5) or cerebral vasoreactivity, as assessed by hypercapnia (p=0.5) and intravenous L-arginine (p=0.4) in the
overall cohort. However, an inverse correlation was found between vasoreactivity at baseline and changes of both CO2- and L-arginine-induced vasomotor response (both p<0.05). Short-term treatment with atorvastatin resulted in no significant improvement of hemodynamic parameters in the overall cohort of CADASIL subjects.(23)

De Maria et al reported the results of a randomized, double-blinded trial of sapropterin compared with placebo for adults with CADASIL.(24) Sapropterin is a synthetic analog of tetrahydrobiopterin, which is an essential cofactor in nitric oxide synthesis in endothelial cells. Given nitric oxide’s role in cerebrovascular function, the authors hypothesized that sapropterin supplementation would improve cerebral endotheliumdependent vasodilation in CADASIL patients. Endothelial dysfunction was assessed by the reactive hyperemia index by peripheral arterial tonometry (RH-PAT) response, which has previously been demonstrated to be impaired in patients with CADASIL syndrome. Peripheral arterial tonometry (PAT) is a noninvasive, quantitative test that measures changes in digital pulse volume during reactive hyperemia (RH) and evaluates the endothelial function of resistance arteries and nitric oxide-mediated changes in microvascular response. The study randomized 61 subjects from 38 families, 32 to sapropterin and 29 to placebo. In intention-to-treat analysis, there was no significant difference in change in RH-PAT response (mean difference in RH-PAT change, 0.19: 95% confidence interval, -0.18 to 0.56). Both groups demonstrated improvements in RH-PAT values over the course of the study, but after results were adjusted for age, sex, and clinical characteristics, the improvement was not associated with treatment.

Predictive Testing of At-Risk Family Members

It has been suggested that asymptomatic family members follow the guidelines for presymptomatic testing for Huntington disease. Genetic counseling is recommended to discuss the impact of positive or negative test results, followed by molecular testing if desired.(5) For an asymptomatic individual, knowledge of mutation status will generally not lead to any management changes that can prevent or delay the onset of the disorder. Avoiding tobacco use may be 1 factor that delays onset of disease, but this is a general recommendation that is not altered by genetic testing. Genetic testing may assist decision making in such areas as employment choices and reproductive decision making, but the impact of these decisions on health outcomes is uncertain.

Ongoing and Unpublished Clinical Trials
An online search of in August 2014 found no ongoing clinical trials relating to genetic testing for the diagnosis of CADASIL.

Clinical Input Received From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. In response to requests, input was received from 1 physician specialty society and 3 academic medical centers while this policy was under review in 2013.

Most reviewers disagreed with statement that genetic testing was investigational to confirm the diagnosis of CADASIL. All reviewers expressed support for testing to confirm the diagnosis in selected patients, particularly when the diagnosis of CADASIL is inconclusive following other diagnostic testing, and when the pretest likelihood of CADASIL being present is moderate to high. In addition to consensus among the reviewers, contextual factors in support of medical necessity are present for this indication, ie, there is a highly suggestive indirect chain of evidence; high-quality trials are unlikely to be performed, and there is a potential for reducing harms by avoiding additional testing and avoiding anticoagulants and antiplatelet agents when the disease is present.

Reviewers also agreed with the recommendation that testing is medically necessary for a first- or second-degree relative, when there is a known pathologic mutation in the family. For this indication, contextual factors in support of medical necessity were not present. High-quality trials are unlikely to be performed, but other contextual criteria were lacking.

Summary of Evidence

The diagnostic accuracy of genetic testing for NOTCH3 pathologic mutations in patients with suspected CADASIL syndrome cannot be determined with certainty due to the lack of a true criterion standard for diagnosis of CADASIL. However, a high percentage of patients in whom CADASIL is diagnosed by clinical methods will have a pathologic mutation on genetic testing. Conversely, pathologic NOTCH3 mutations are not commonly found in unaffected individuals.

Genetic testing has clinical utility for a subset of patients with clinical signs and symptoms of CADASIL, but in whom the diagnosis cannot be made by other methods. The diagnosis of CADASIL can usually be confirmed by a combination of clinical presentation, magnetic resonance imaging (MRI) findings, and skin biopsy findings. In such cases, NOTCH3 testing is not necessary for diagnosis. In other cases, the diagnosis cannot be made on the basis of clinical presentation, MRI, and skin biopsy results. In these
cases, NOTCH3 testing can confirm the diagnosis of CADASIL with a high degree of certainty. Based on the available evidence and results of clinical vetting, genetic testing may be considered medically necessary to confirm the diagnosis of CADASIL when there is uncertainty in the diagnosis following alternate testing methods, and there is at least a moderate to high likelihood that CADASIL is present based on clinical and imaging results.

For asymptomatic family members of an individual with known CADASIL, knowledge of the presence of a pathologic mutation may lead to changes in lifestyle decisions for the affected individual, for example in the areas of reproduction and employment. However, the impact of these lifestyle decisions on health outcomes is uncertain, and there are no interventions for asymptomatic individuals that are known to delay or prevent the onset of disease. Therefore, genetic testing of asymptomatic relatives is considered investigational.

Practice Guidelines and Position Statements

The European Federation of Neurological Societies 2010 guideline on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias notes that most NOTCH3 mutations occur within exons 3 and 4 and suggests direct sequencing of these 2 exons if clinical suspicion is high.(25)

An updated keyword search in August 2014 on “CADASIL” in the full texts of the American Academy of Neurology guidelines returned no direct guidelines on CADASIL diagnosis or management.

U.S. Preventive Services Task Force Recommendations
No U.S. Preventive Services Task Force recommendations for genetic testing for diagnosis of CADASIL were identified.

Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers. 


  1. Pescini F, Nannucci S, Bertaccini B, et al. The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Scale: a screening tool to select patients for NOTCH3 gene analysis. Stroke. Nov 2012;43(11):2871-2876. PMID 22996955
  2. Joutel A, Favrole P, Labauge P, et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet. Dec 15 2001;358(9298):2049-2051. PMID 11755616
  3. Lesnik Oberstein SA, van Duinen SG, van den Boom R, et al. Evaluation of diagnostic NOTCH3 immunostaining in CADASIL. Acta Neuropathol. Aug 2003;106(2):107-111. PMID 12756589
  4. Muqtadar H, Testai FD. Single gene disorders associated with stroke: a review and update on treatment options. Curr Treat Options Cardiovasc Med. Jun 2012;14(3):288-297. PMID 22528196
  5. del Rio-Espinola A, Mendioroz M, Domingues-Montanari S, et al. CADASIL management or what to do when there is little one can do. Expert Rev Neurother. Feb 2009;9(2):197-210. PMID 19210195
  6. Malandrini A, Gaudiano C, Gambelli S, et al. Diagnostic value of ultrastructural skin biopsy studies in CADASIL. Neurology. Apr 24 2007;68(17):1430-1432. PMID 17452591
  7. Brulin P, Godfraind C, Leteurtre E, et al. Morphometric analysis of ultrastructural vascular changes in CADASIL: analysis of 50 skin biopsy specimens and pathogenic implications. Acta Neuropathol. Sep 2002;104(3):241-248. PMID 12172909
  8. Markus HS, Martin RJ, Simpson MA, et al. Diagnostic strategies in CADASIL. Neurology. Oct 22 2002;59(8):1134-1138. PMID 12395806
  9. Choi JC, Lee KH, Song SK, et al. Screening for NOTCH3 Gene Mutations Among 151 Consecutive Korean Patients With Acute Ischemic Stroke. J Stroke Cerebrovasc Dis. Nov 29 2013;22(5):608-614. PMID 22133740
  10. Mosca L, Marazzi R, Ciccone A, et al. NOTCH3 gene mutations in subjects clinically suspected of CADASIL. J Neurol Sci. Aug 15 2011;307(1-2):144-148. PMID 21616505
  11. Lesnik Oberstein SAJ, Boon EMJ, Dichgans M. CADASIL. In: Pagon RA, Bird TD, Dolan CR, et al., eds. GeneReviews. Seattle WA: University of Washington, Seattle; 1993.
  12. Donahue CP, Kosik KS. Distribution pattern of Notch3 mutations suggests a gain-of-function mechanism for CADASIL. Genomics. Jan 2004;83(1):59-65. PMID 14667809
  13. Chabriat H, Joutel A, Dichgans M, et al. Cadasil. Lancet Neurol. Jul 2009;8(7):643-653. PMID 19539236
  14. Opherk C, Gonik M, Duering M, et al. Genome-wide genotyping demonstrates a polygenic risk score associated with white matter hyperintensity volume in CADASIL. Stroke. Apr 2014;45(4):968-972. PMID 24578207
  15. Lee YC, Liu CS, Chang MH, et al. Population-specific spectrum of NOTCH3 mutations, MRI features and founder effect of CADASIL in Chinese. J Neurol. Feb 2009;256(2):249-255. PMID 19242647
  16. Yin X, Wu D, Wan J, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: Phenotypic and mutational spectrum in patients from mainland China. Int J Neurosci. Sep 1 2014. PMID 25105908
  17. Joutel A, Vahedi K, Corpechot C, et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. Nov 22 1997;350(9090):1511-1515. PMID 9388399
  18. Peters N, Opherk C, Bergmann T, et al. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol. Jul 2005;62(7):1091-1094. PMID 16009764
  19.  Tikka S, Mykkanen K, Ruchoux MM, et al. Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain. Apr 2009;132(Pt 4):933-939. PMID 19174371
  20. Dotti MT, Federico A, Mazzei R, et al. The spectrum of Notch3 mutations in 28 Italian CADASIL families. J Neurol Neurosurg Psychiatry. May 2005;76(5):736-738. PMID 15834039
  21. Dichgans M, Markus HS, Salloway S, et al. Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL. Lancet Neurol. Apr 2008;7(4):310-318. PMID 18296124
  22. Huang L, Yang Q, Zhang L, et al. Acetazolamide improves cerebral hemodynamics in CADASIL. J Neurol Sci. May 15 2010;292(1-2):77-80. PMID 20227091
  23. Peters N, Freilinger T, Opherk C, et al. Effects of short term atorvastatin treatment on cerebral hemodynamics in CADASIL. J Neurol Sci. Sep 15 2007;260(1-2):100-105. PMID 17531269
  24. De Maria R, Campolo J, Frontali M, et al. Effects of Sapropterin on Endothelium-Dependent Vasodilation in Patients With CADASIL: A Randomized Controlled Trial. Stroke. Sep 2 2014. PMID 25184356
  25. Burgunder JM, Finsterer J, Szolnoki Z, et al. EFNS guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias. Eur J Neurol. May 2010;17(5):641-648. PMID 20298421






See Policy Guidelines)

ICD-9-CM diagnosis


Investigational for all diagnoses

ICD-10-CM (effective 10/1/15)   Investigational for all diagnoses
ICD-10-PCS (effective 10/1/15)   Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.


NOTCH3 Testing

Policy History

Date Action Reason
9/01/11 Add to Medicine section, Pathology/Laboratory subsection Policy created with literature search through September 2011, considered investigational.
9/13/12 Replace policy Policy updated with literature review, reference 8 added. Policy statement unchanged
11/8/12 Replace policy- coding update only CPT coding updated
10/10/13 Replace policy Policy updated with literature review through September 2013 and results of clinical vetting. Reference 18 added. Medically necessary statement added for patients with high likelihood of disorder, in whom diagnosis cannot be made by other methods. Title revised to include all genetic testing for CADASIL syndrome and “syndrome” added to title and policy statements.
01/09/14 Replace policy-correction only In first bullet in the first policy statement corrected CADSIL to CADASIL. Code table ICD diagnosis coding entries changed from “Investigational for all diagnoses” to lists of possible codes.
10/09/14 Replace policy Policy updated with literature review through September 6, 2014. References 14, 16, and 24 added. Policy statement unchanged.



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