Coverage Policy Manual
Policy #: 2006026
Category: Laboratory
Initiated: July 2006
Last Review: October 2018
  Genetic Test: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts & Leukoencephalopathy (CADASIL) (NOTCH3)

Description:
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), affects small blood vessels, primarily in the brain.  An abnormality in the muscle cells surrounding blood vessels (vascular smooth muscle cells) gradually destroys the blood vessel cells.  This rare, genetically inherited, vascular disease of the brain can cause stroke, subcortical dementia, migraine-like headaches, and psychiatric disturbances.  Symptoms usually surface around the age of 45 years.  The exact incidence of CADASIL in the United States is not known.  There is no specific treatment for CADASIL and therapy usually consists of interventions seen with ischemic strokes.  Most patients with CADASIL do not have the common risk factors for stroke and heart attack though these features may be present in some people.  
 
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 gold 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.
 
The NOTCH3 gene makes a protein called the NOTCH3 receptor protein, which plays a role in the development, function and maintenance of vascular smooth muscle cells.  Mutations in this gene lead to an abnormal version of the Notch3 protein that builds up in vascular smooth muscle cells.  This accumulation is though to cause the degeneration of these muscle cells, leading to the loss of function of blood vessels in the brain and sometimes the heart.
 
Coding
Effective in 2012, there is a Tier 2 Molecular Pathology CPT code to be used for this testing:
 
81406: Molecular pathology procedure, Level 7 (e.g., analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia).
 

Policy/
Coverage:
Effective October 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Genetic testing for a NOTCH3 variant to confirm the diagnosis of CADASIL syndrome meets member benefit certificate of primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes under the following conditions:
 
    • Clinical signs, symptoms, skin biopsy and imaging results are consistent with CADASIL, indicating that the pretest probability of CADASIL is at least in the moderate-to-high range; and
    • The diagnosis of CADASIL is inconclusive following alternative methods of testing, including skin biopsy and magnetic resonance imaging.
 
For asymptomatic individuals with a first- or second-degree relative with a diagnosis of CADASIL syndrome and a known NOTCH3 variant, targeted genetic testing of the known NOTCH3 familial variant meets member benefit certificate of primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genetic testing for a NOTCH3 variant to confirm the diagnosis of CADASIL syndrome in all other situations does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, genetic testing for NOTCH3 variant to confirm the diagnosis of CADASIL syndrome in all other situations is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective October 2017 – October 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Genetic testing for CADASIL meets member benefit certificate of primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes under the following conditions:
 
    • Clinical signs, symptoms, skin biopsy and imaging results are consistent with CADASIL, indicating that the pretest probability of CADASIL is at least in the moderate-to-high range; and
    • The diagnosis of CADASIL is inconclusive following alternative methods of testing, including skin biopsy and magnetic resonance imaging.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genetic testing for CADASIL for any other reason does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes or is considered investigational. Investigational services are exclusions in the member benefit contract.
 
Effective Prior to October 2017
 
Genetic testing for CADASIL does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  The proof of presence of this gene mutation does not lead to specific therapy or improved outcomes for persons having this gene.  
 
For contracts without primary coverage criteria, genetic testing for CADASIL is considered investigational and is not covered. Investigational services are exclusions in the member benefit contract.

Rationale:
Currently, no specific clinical treatment for CADASIL has established efficacy. Supportive care in the form of practical help, emotional support, and counseling are appropriate for affected individuals and their families (Muqtadar, 2012; Lesnik, 1992). Four studies were found that addressed the efficacy of potential treatments for CADASIL (Dichgans, 2008; Huang, 2010; Peters, 2007; De Maria, 2014).
 
Analytic Validity
Limited 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.
 
Fernandez et al described the development of a next-generation sequencing (NGS) protocol for NOTCH3 and HTRA1 genes in 70 patients referred for clinical suspicion of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), all of whom had previously undergone Sanger sequencing of exons 3 and 4 of the NOTCH3 gene (Fernandez, 2015). NOTCH3 mutations were detected in 6 patients on NGS, including 2 mutations previously detected with Sanger sequencing and 4 mutations in exons 6, 11, and 19.
 
Clinical Validity
Several retrospective and prospective studies have examined the association between NOTCH3 genes and CADASIL (Moscal, 2011; Lee, 2009; Markus, 2002; Choi, 2013; Yin, 2015; Abramycheva, 2015; Peters, 2005; Tikka, 2009; Dotti, 2005; Joutel, 1997). 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 are 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.
 
Clinical Utility
 
Confirmation of a CADASIL Diagnosis
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, because 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.
 
Summary of Evidence
The evidence for the use of genetic testing for mutations associated with CADASIL syndrome in individuals with suspected CADASIL syndrome includes retrospective and prospective studies evaluating the clinical validity and yield of NOTCH3 mutation testing. Relevant outcomes are overall survival, test accuracy and validity, other test performance measures, changes in reproductive decision making, change in disease status, and morbid events. 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.
 
There may be potential clinical utility for genetic testing to diagnose CADASIL in patients whose diagnosis cannot be confirmed by other methods (clinical presentation, magnetic resonance imaging [MRI] findings, skin biopsy). However, no direct evidence was identified demonstrating outcome improvements associated with genetic testing for CADASIL. A strong chain of indirect evidence cannot be constructed given the lack of evidence demonstrating the potential for changes in management that might occur following a diagnosis of CADASIL. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
The evidence for the use of genetic testing for mutations associated with CADASIL syndrome in individuals who are asymptomatic with family members with CADASIL syndrome is limited. Relevant outcomes are overall survival, test accuracy and validity, other test performance measures, changes in reproductive decision making, change in disease status, and morbid events. 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 (eg, reproduction, 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. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
2016 Update
A literature search was conducted using the MEDLINE database through September 2016. There was no new information identified that would prompt a change in the coverage statement.
 
2017 Update
A literature search conducted through September 2017 did not reveal any new information that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
Maksemous and colleagues published a study targeting next generation sequencing identifies novel NOTCH3 gene mutations in CADASIL diagnostics patients (Maksemous, 2016). Patients evaluated were 44 patients with suspected clinical diagnosis of CADASIL previously screened for standard sequencing exons (3, 4) and/or (2, 11, 18, 19) by Sanger sequencing and classified as negative for known pathogenic variants. NOTCH3 Exons custom NGS panel. The results were 6 patients typical CADASIL pathogenic variants identified in 7/44 patients and specificity was not reported.
 
ONGOING AND UNPUBLISHED CLINICAL TRIALS
A search of ClinicalTrials.gov in September 2017 did not identify any ongoing or unpublished trials that would likely influence this review.

CPT/HCPCS:
81406MOLECULAR PATHOLOGY PROCEDURE LEVEL 7

References: Abramycheva N, Stepanova M, Kalashnikova L, et al.(2015) New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). J Neurol Sci. Feb 15 2015;349(1-2):196-201. PMID 25623805

Annunen-Rasila J, Finnila S, et al.(2006) Mitochondrial DNA sequence variation and mutation rate in patients with CADASIL. Neurogentics 2006; [Epub ahead print].

Buffon F, Porcher R, et al.(2006) Cognitive profile in CADASIL. J Neurol Neurosurg Psychiatry 2006; 77:175-80.

Charlton RA, Morris RG, et al.(2006) The cognitive profiles of CADASIL and sporadic small vessel disease. Neurology 2006; 66:1523-6.

Cumurciuc R, Henry P, et al.(2006) Electrocardiogram in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy patients without any clinical evidence of coronary artery disease: a case-control study. Stroke 2006; 37:100-2.

De Maria R, Campolo J, Frontali M, et al.(2014) Effects of Sapropterin on Endothelium-Dependent Vasodilation in Patients With CADASIL: A Randomized Controlled Trial. Stroke. Sep 2 2014. PMID 25184356

De Maria R, Campolo J, Frontali M, et al.(2014) Effects of sapropterin on endothelium-dependent vasodilation in patients with CADASIL: a randomized controlled trial. Stroke. Oct 2014;45(10):2959-2966. PMID 25184356

Dichgans M, Markus HS, Salloway S, et al.(2008) 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

Dotti MT, Federico A, Mazzei R, et al.(2005) The spectrum of Notch3 mutations in 28 Italian CADASIL families. J Neurol Neurosurg Psychiatry. May 2005;76(5):736-738. PMID 15834039

Huang L, Yang Q, Zhang L, et al.(2010) Acetazolamide improves cerebral hemodynamics in CADASIL. J Neurol Sci. May 15 2010;292(1-2):77-80. PMID 20227091

Ishiko A, Shimizu A, et al.(2005) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): a hereditary cerebrovascular disease, which can be diagnosed by skin biopsy electron microscopy. Am J Dermatopathol 2005; 27:131-4.

Joutel A, Vahedi K, Corpechot C, et al.(1997) Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. Nov 22 1997;350(9090):1511-1515. PMID 9388399

Lesnik Oberstein SA, van Duinen SG, van den Boom R, et al.(2003) Evaluation of diagnostic NOTCH3 immunostaining in CADASIL. Acta Neuropathol. Aug 2003;106(2):107-111. PMID 12756589

Low WC, Santa Y, et al.(2006) CADASIL-causing mutations do not alter Notch3 receptor processing and activiation. Neuroreport 2006; 17:945-9.

Maksemous N, Smith RA, Haupt LM, et al.(2016) Targeted next generation sequencing identifies novel NOTCH3 gene mutations in CADASIL diagnostics patients. Hum Genomics. Nov 24 2016;10(1):38. PMID 27881154

Markus HS, Alberts MJ.(2006) Update on genetics of stroke and cerebrovascular disease. Stroke 2006; 37:288-90.

Muqtadar H, Testai FD.(2012) 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

Opherk C, Gonik M, Duering M, et al(2014) 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

Opherk C, Peters N, et al.(2004) Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain 2004; 127:2533-9.

Peters N, Freilinger T, Opherk C, et al.(2007) Effects of short term atorvastatin treatment on cerebral hemodynamics in CADASIL. J Neurol Sci. Sep 15 2007;260(1-2):100-105. PMID 17531269

Peters N, Herzog J, et al.(2004) A two-year follow-up study in 80 CADASIL subjects: progression patterns and implications for clinical trials. Stroke 2004; 35:1603-8.

Peters N, Holtmannspotter M, et al.(2006) Brain volume changes in CADASIL: a serial MRI study in pure subcortical ischemic vascular disease. Neurology 2006; 66:1517-22.

Peters N, Opherk C, Bergmann T, et al.(2005) Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol. Jul 2005;62(7):1091-1094. PMID 16009764

Peters N, Opherk C, et al.(2005) Spectrum of mutations in biopsy-proven CADASIL. Arch Neurol 2005; 62:1091-4.

Razve SS, Bone I.(2006) Single gene disorders causing ischemic stroke. J Neurol 2006; 253:685-700.

Tikka S, Mykkanen K, Ruchoux MM, et al.(2009) Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain. Apr 2009;132(Pt 4):933-939. PMID 19174371

Vahedi K, Chabriat H, et al.(2004) Migraine with aura and brain magnetic resonance imaging abnormalities in patients with CADASIL. Arch Neurol 2004; 61:1237-40.

van den Boom R, Lesnick Oberstein SA, et al.(2006) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): a hereditary cerebrovascular disease, which can be diagnosed by skin biopsy electron microscopy. Am J NeuroRad 2006; 27:359-62.

Yin X, Wu D, Wan J, et al.(2015) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: Phenotypic and mutational spectrum in patients from mainland China. Int J Neurosci. Sep 1 2015; 125(8);585-592.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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