Medical Policy

 

Subject: Genetic Testing for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Syndrome
Document #: GENE.00042 Publish Date:    08/29/2018
Status: Reviewed Last Review Date:    07/26/2018

Description/Scope

This document addresses genetic testing for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome which is a rare, autosomal dominant, cerebrovascular disease, considered to be the most common cause of hereditary stroke and hereditary vascular dementia in adults. CADASIL syndrome typically presents in adulthood with variable symptoms which may include migraine with aura, recurrent lacunar strokes, progressive cognitive impairment, and psychiatric disorders involving mood disturbances. Genetic testing for pathogenic mutations in the NOTCH3 gene is available for use in the diagnostic workup of individuals with a clinical history and symptoms suspicious for CADASIL syndrome.

Note: For additional information regarding related genetic topics, please see the following:

Position Statement

Investigational and Not Medically Necessary:

Genetic testing for inherited CADASIL syndrome is considered investigational and not medically necessary for all indications, including but not limited to:

Rationale

CADASIL syndrome is considered the most common form of familial vascular dementia and familial brain small vessel arteriopathy. In addition to typical signs and symptoms of CADASIL syndrome, (for example, migraine with aura, stroke, cognitive impairment/dementias, mood disturbances), many individuals with CADASIL also develop leukoencephalopathy, which is characterized by high intensity signal lesions and areas of cystic degeneration of subcortical white matter and basal ganglia, which becomes more visible on MRI as the disease progresses. Clinical symptoms typically progress slowly with the mean onset of symptoms usually seen by age 45. By age 65, most individuals with CADASIL will exhibit cognitive deficits and dementia. There is no known cure for CADASIL syndrome and no treatment with proven efficacy for CADASIL syndrome; medical treatment is directed at relief of the presenting symptoms. Antiplatelet treatment is frequently used, but has not been proven to be effective in CADASIL. Surgery is also utilized in some cases to repair defective blood vessels, due to the degenerative effects of CADASIL, as it progresses. Additional risk factors for stroke, if present, such as hypertension, hyperlipidemia, diabetes, blood clotting disorders, and obstructive sleep apnea, should also be treated. Smoking should be discouraged in individuals at risk for CADASIL syndrome.

A part of the diagnostic workup for suspected CADASIL syndrome includes exclusion of other conditions with similar presentations, including multiple sclerosis, Alzheimer dementia, and Binswanger disease. The diagnosis of CADASIL syndrome has historically been based on specialty evaluation of the individual’s specific clinical presentation, (that is, signs and symptoms), as well as the family history (for autosomal dominant patterns of inheritance) and findings identified with magnetic resonance imaging (MRI) of the brain and specialized testing of skin biopsies. The pathologic hallmark of CADASIL is the presence of electron-dense granules in the media of arterioles that can be identified by electron microscopic evaluation of skin biopsies. These changes are highly specific for CADASIL but the sensitivity of skin biopsy is limited and depends on the quality of the sample and the skills of the pathologist evaluating the biopsy sample (Hervé, 2010; Schultz, 1999).

Genetic molecular testing, which is a method to determine the presence or absence of specific genetic mutations on specific genes, has been proposed as a diagnostic aid in select individuals with moderate to high pretest likelihood of having CADASIL syndrome (based on symptoms), when other conventional diagnostic methods have yielded inconclusive or equivocal results. Genetic testing for CADASIL has also been proposed as part of preconceptional, preimplantation, and prenatal workups to determine carrier status and/or guide reproductive decisions when a pathologic NOTCH3 mutation has been confirmed in a parent or other close relative, (that is, the proband). Mutations in the NOTCH3 gene have been consistently found on chromosome 19p13.2-p13.1 and have been identified as the underlying cause of CADASIL syndrome in more than 90% of confirmed cases. The NOTCH3 protein consists of 2321 amino acids, which are primarily expressed in vascular smooth muscle cells and which have a role in the control of vascular transduction. Over 170 causative NOTCH3 mutations have been reported in the 33 exons of the NOTCH3 protein. All CADASIL-causing mutations have been seen in exons 2 to 24, which encode the 34 epidermal growth factor-like (EGFL) repeats, with strong clustering in exons 3 and 4, which encode EGFL 2 to 5. This means that greater than 40% of NOTCH3 mutations in greater than 70% of confirmed CADASIL cases have occurred in exons 2 to 24. The penetrance of sequence variants in the NOTCH3 gene is believed to be nearly 100%. Genetic testing involves targeted sequence analysis of 1 to 23 exons where known mutations for CADSIL have been identified. Additional mutations found on the NOTCH3 gene are of unknown significance at this time (Chabriat, 2009; Donahue, 2004; Lesnick Oberstein, 2012).

The results of clinical validity studies have demonstrated that NOTCH3 mutations are found in a high percentage of subjects with a clinical diagnosis of CADASIL syndrome. These studies have reported a clinical sensitivity of 90% to 100%, which indicates that a negative test reduces the likelihood that CADASIL is present (Dotti, 2005; Joutel, 1997; Peters, 2005; Tikka, 2009). However, since false-negative tests do occur, a negative test is less definitive in ruling out CADASIL, which depends on the pretest likelihood that CADASIL is present. Currently, there is limited data demonstrating high clinical specificity for genetic testing for CADASIL, which comes from trials with small numbers of healthy controls; however, no false-positive NOTCH3 mutations have been reported in these populations (Lee, 2009). Trials for diagnostic yield have reported variable results ranging from 10% to 54%, which is probably due to the testing of heterogeneous populations that included trial subjects with other disorders.

The clinical utility of genetic testing for CADASIL has been proposed to determine diagnostic confirmation in symptomatic individuals and predictive testing for at-risk individuals with a family history of CADASIL. Additional proposed uses for genetic testing for CADASIL include preimplantation testing and/or prenatal (in utero) testing when a pathologic NOTCH3 mutation has been identified in a parent, but further study is needed to demonstrate the clinical utility of testing in these situations.

According to the American College of Radiology (ACR) Appropriateness Criteria® for Dementia and Movement Disorders, (which was updated in 2014), the following is excerpted regarding current established methods of testing for CADASIL:

Besides familial anamnesis and clinical history, structural MRI changes in these patients help to suggest the diagnosis by showing characteristic hyperintense T2 or fluid-attenuated inversion recovery (FLAIR) lesions which predominate in the frontal, parietal, and anterior temporal cortexes, and in the external capsule. Diagnosis is confirmed by skin biopsy or detection of a pathogenic NOTCH3 mutation on direct sequencing (ACR, 2014).

The European Federation of Neurologic Societies (EFNS) published a guideline on the Molecular Diagnosis of Channelopathies, Epilepsies, Migraine, Stroke and Dementias, in which a Level B recommendation was given for, “Direct sequencing of exons 3 and 4 in the NOTCH3 gene is suggested as a first step if clinical suspicion for CADASIL is high.”  This recommendation is based on evidence from retrospective studies that evaluated a specific mutation in a previously confirmed and clinically diagnosed group of individuals (Burgunder, 2010).

Most affected individuals have an affected parent; de novo mutations appear to be rare. The published evidence has noted that the offspring of an affected person would be at a 50% risk of inheriting the mutation and developing CADASIL over the course of their lifetime. However, the individual clinical course of CADASIL syndrome is highly variable, and further investigation is needed regarding the long-term prognosis and also the causes of death in CADASIL syndrome. The impact of gender and NOTCH3 genotype on disease progression is largely unknown at this time (Lesnick Oberstein, 2012).

Genetic counseling has been recommended to discuss the potential impact of genetic test results in CADASIL syndrome. For an asymptomatic individual, knowledge of mutation status will not generally lead to any management changes that can prevent or delay the onset of the disorder. Genetic testing may assist decision making and reproductive planning, but the impact of these decisions on health outcomes is uncertain (del Rio-Espinola, 2009).

To summarize, currently there is no specific clinical treatment for CADASIL that has established efficacy. Treatment for CADASIL syndrome is directed at symptomatic management. For this reason, confirming a molecular diagnosis of CADASIL by genetic testing does not affect treatment management or clinical outcomes, since no treatment strategy is based on the genetic phenotype. At present, genetic testing has shown clinical utility in confirming the diagnosis for a small subset of individuals with family history and clinical signs and symptoms suggestive of CADASIL when other conventional diagnostic methods have yielded inconclusive results. However, additional study is needed to further define the clinical validity and utility of genetic testing for suspected CADASIL. According to the currently published knowledge base about CADASIL, definitive confirmation of the diagnosis of CADASIL syndrome is usually determined by the presence of electron-dense granules in the media of arterioles (that is, granular osmiophilic material [GOM]) that can be identified by electron microscopic evaluation of skin biopsies (Hervé, 2010). Another diagnostic method that is currently used to evaluate for CADASIL is brain MRI where abnormalities including white matter hyperintensity lesions and/or lacunar infarcts, in addition to positive family history and characteristic symptoms, suggests suspicion for CADASIL syndrome. Genetic testing for CADASIL is considered investigational and not medically necessary for all indications, at this time. This stance is based on insufficient evidence demonstrating the clinical utility of genetic testing for CADASIL, also the current lack of a “Gold standard” with which to confirm the diagnosis and additional unknowns regarding the impact on clinical outcomes, since there are no interventions or treatments for asymptomatic afflicted individuals that are known to delay or prevent the onset of disease.

Background/Overview

The NOTCH3 gene provides instructions for producing the Notch3 receptor protein. This receptor protein is located on the surface of the muscle cells that surround blood vessels (vascular smooth muscle cells). The Notch3 receptor protein is specific to arteries, which are blood vessels that carry blood from the heart to the rest of the body. The protein is not present in veins, which return blood to the heart. When certain molecules attach (bind) to Notch3 receptors, the receptors send signals to the nucleus of the cell. These signals then turn on (activate) particular genes within vascular smooth muscle cells. Notch3 receptors play a key role in the function and survival of vascular smooth muscle cells. These receptors are thought to be essential for the maintenance of healthy muscle cells in the brain's arteries.

To date, there are no genotyping tests for CADASIL that have clearance from the U.S. Food and Drug Administration (FDA). Currently, NOTCH3 gene sequencing is a laboratory-based genetic molecular test, which is performed at clinical laboratories which are licensed under the Clinical Laboratory Improvement Amendments Act (CLIA); the laboratory offering the service must be licensed by CLIA for high complexity testing. At the present time, genetic testing for CADASIL is available in the United States through Athena Diagnostics®, Inc. (Worcester, MA [owned by Quest Diagnostics® Richmond, VA]) and is called the Complete CADASIL Evaluation # 421. According to the manufacturer’s website, this test provides complete sequence analysis of all 23 exons in which variants are known to cause CADASIL syndrome.

Genetic testing for CADASIL is done by sequence analysis/mutation scanning of the targeted NOTCH3 gene with sequencing of the most commonly causative exons within the NOTCH3 gene, followed by complete sequencing of all exons encoding the EGFL repeats, (that is, the domains of neurogenic locus notch homolog protein 3 [Notch3], which is the protein encoded by NOTCH3).

Definitions

Alzheimer Dementia: A slowly progressive disease of the brain that is characterized by impairment of memory and eventually by disturbances in reasoning, planning, language, and perception.

Binswanger Disease: This condition, which is also called subcortical vascular dementia, is a type of dementia caused by widespread, microscopic areas of damage to the deep layers of white matter in the brain. The damage is the result of the thickening and narrowing (atherosclerosis) of arteries that feed the subcortical areas of the brain with resultant impairment of cognitive functions, such as memory, attentiveness, organization, mood and decision making ability.

Deletion/Duplication Analysis: Laboratory testing that identifies the absence of a segment of DNA (deletion) and/or the presence of an extra segment of DNA (duplication).

Exons: Regions in genes that code for proteins.

Molecular Genetic Testing: Testing that involves the analysis of DNA, either through linkage analysis, sequencing or one of several methods of mutation detection.

Multiple Sclerosis: This degenerative, inflammatory disease of the Central Nervous System (CNS) involves destruction of the myelin covering of the nerves with progressive impairment of CNS sensory and motor functions, such as vision, speech, walking and memory.

Mutation Scanning: A process by which a segment of DNA is screened via one of a variety of methods to identify variant gene region(s). Variant regions are further analyzed (by sequence analysis or mutation analysis) to identify the sequence alteration.

Sequence Analysis: Process by which the nucleotide sequence for a particular gene is determined for a segment of DNA.

Subcortical Lacunar Lesions (SLLs): Linearly arranged groups of rounded, circumscribed lesions at the junction of the grey and white matter with a signal intensity that is identical to that of cerebrospinal fluid. SLLs are found in approximately two thirds of affected individuals and may be a specific marker for CADASIL.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
When the code(s) describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT

 

81406

Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia) [when specified as the following]:

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

 

 

ICD-10 Diagnosis

 

F02.80-F02.81

Dementia in other diseases classified elsewhere

G43.001-G43.919

Migraine

G45.9

Transient cerebral ischemic attack, unspecified

G46.0-G46.8

Vascular syndromes of brain in cerebrovascular disease

G93.49

Other encephalopathy [leukoencephalopathy]

I67.3

Progressive vascular leukoencephalopathy

I67.850

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [Note: diagnosis code effective 10/01/2018]

I67.89

Other cerebrovascular disease

I77.89

Other specified disorders of arteries and arterioles

Z82.49

Family history of ischemic heart disease and other diseases of the circulatory system

Z84.81

Family history of carrier of genetic disease

Z86.59

Personal history of other mental and behavioral disorders

Z86.73

Personal history of transient ischemic attack (TIA), and cerebral infarction without residual deficits

References

Peer Reviewed Publications:

  1. Abramycheva N1, Stepanova M1, Kalashnikova L2, et al. New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). J Neurol Sci. 2015; 349(1-2):196-201.
  2. Bentley P1, Wang T, Malik O, et al. CADASIL with cord involvement associated with a novel and atypical NOTCH3 mutation. J Neurol Neurosurg Psychiatry. 2011; 82(8):855-860.
  3. Chabriat H, Joutel A, Dichgans M, et al. Cadasil. Lancet Neurol. 2009; 8(7):643-653.
  4. Choi JC1, Lee KH, Song SK, Lee JS, et al. Screening for NOTCH3 gene mutations among 151 consecutive Korean patients with acute ischemic stroke. J Stroke Cerebrovasc Dis. 2013; 22(5):608-614.
  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. 2009; 9(2):197-210.
  6. Donahue CP, Kosik KS. Distribution pattern of Notch3 mutations suggests a gain-of-function mechanism for CADASIL. Genomics. 2004; 83(1):59-65.
  7. Dotti MT, Federico A, Mazzei R, et al. The spectrum of Notch3 mutations in 28 Italian CADASIL families. J Neurol Neurosurg Psychiatry. 2005; 76(5):736-738.
  8. Hervé D, Chabriat H. CADASIL. J Geriatr Psychiatry Neurol. 2010; 23(4):269-276.
  9. Joutel A, Vahedi K, Corpechot C, et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997; 350(9090):1511-1515.
  10. Kim YE1, Yoon CW, Seo SW, et al. Spectrum of NOTCH3 mutations in Korean patients with clinically suspicious cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Neurobiol Aging. 2014; 35(3):726.e1-6.
  11. Koutroulou I1, Karapanayiotides T1, Grigoriadis N1, Karacostas D1. CADASIL presenting with spontaneous intracerebral hemorrhage: report of a case and description of the first family in Northern Greece. Hippokratia. 2016; 20(1):76-79.
  12. 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. 2009; 256(2):249-255.
  13. Lesnik Oberstein SA, van Duinen SG, van den Boom R, et al. Evaluation of diagnostic NOTCH3 immuno- staining in CADASIL. Acta Neuropathol. 2003; 106(2):107-111.
  14. Liu X1, Zuo Y1, Sun W1, et al. The genetic spectrum and the evaluation of CADASIL screening scale in Chinese patients with NOTCH3 mutations. J Neurol Sci. 2015; 354(1-2):63-69.
  15. Maksemous N, Smith RA, Haupt LM, Griffiths LR. Targeted next generation sequencing identifies novel NOTCH3 gene mutations in CADASIL diagnostics patients. Hum Genomics. 2016; 10(1):38.
  16. Mosca L, Marazzi R, Ciccone A, et al. NOTCH3 gene mutations in subjects clinically suspected of CADASIL. J Neurol Sci. 2011; 307(1-2):144-148.
  17. 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. 2014; 45(4):968-972.
  18. Paraskevas GP1, Bougea A, Synetou M, et al. CADASIL and autoimmunity: coexistence in a family with the R169C mutation at exon 4 of the NOTCH3 gene. Cerebrovasc Dis. 2014; 38(4):302-307.
  19. 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. 2012; 43(11):2871-2876.
  20. Peters N, Opherk C, Bergmann T, et al. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol. 2005; 62(7):1091-1094.
  21. Reyes S, Kurtz A, Hervé D, et al. Presymptomatic genetic testing in CADASIL. J Neurol. 2012; 259(10):2131-2136.
  22. Schultz A, Santoianni R, Hewan-Lowe K. Vasculopathic changes of CADASIL can be focal in skin biopsies. Ultrastruct Pathol. 1999; 23:241-247.
  23. Tikka S, Mykkanen K, Ruchoux MM, et al. Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain. 2009; 132(Pt 4):933-939.
  24. Yin X1, 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. 2015; 125(8):585-592.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American College of Radiology. ACR Appropriateness Criteria®  ACR Appropriateness Criteria® dementia and movement disorders. 2014. Available at: https://www.guideline.gov/content.aspx?id=48285#Section427 . Accessed on June 26, 2018.
  2. Burgunder JM, Finsterer J, Szolnoki Z, et al. European Federation of Neurological Societies (EFNS) Guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias. Eur J Neurol. 2010; 17(5):641-648.
  3. Rutten J, Lesnik Oberstein SA. GeneReviews [website]. CADASIL: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. Last updated July 14, 2016. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1500/. Accessed on June 26, 2018.
  4. Sorbi S, Hort J, Erkinjuntti T, et al. European Federation of Neurological Societies/European Neurological Society (EFNS-ENS) Guidelines on the diagnosis and management of disorders associated with dementia. Eur J Neurol. 2012; 19(9):1159-1179. Available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1468-1331.2012.03784.x/epdf. Accessed on June 26, 2018.
  5. U.S. Food and Drug Administration (FDA). Center for Devices and Radiological Health. CLIA—Clinical Laboratory Improvement Amendments. Updated March 22, 2018. Available at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/IVDRegulatoryAssistance/ucm124105.htm. Accessed on June 26, 2018.
Websites for Additional Information
  1. National Library of Medicine (NLM).Genetics Home Reference. NOTCH3 gene. Updated June 26, 2018. Available at: https://ghr.nlm.nih.gov/gene/NOTCH3#conditions. Accessed on June 26, 2018.
  2. National Society of Genetic Counselors. Position Statement on Genetic Testing of Minors for Adult-onset Disorders. Updated April 12, 2018. Available at: https://www.nsgc.org/p/bl/et/blogaid=860.  Accessed on June 26, 2018.
Index

CADASIL
Complete CADASIL Evaluation #421
Neurogenic locus notch homolog protein 3
NOTCH3
Notch homolog 3 (Drosophila)

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Reviewed

07/26/2018

Medical Policy & Technology Assessment Committee (MPTAC) review. The title was revised to remove the acronym (CADASIL). References were updated.  Updated Coding section with 10/01/2018 ICD-10-CM changes; added I67.850.

 

05/15/2018

The document header wording updated from “Current Effective Date” to “Publish Date.”

Reviewed

08/03/2017

MPTAC review. References were updated.

Reviewed

08/04/2016

MPTAC review. Additional information added to Background/Overview section. References updated. Removed ICD-9 codes from Coding section.

Reviewed

08/06/2015

MPTAC review. References were updated.

New

08/14/2014

MPTAC review. Initial document development.