Medical Policy Medical Policy
Policy Num: 11.003.010
Policy Name: Genetic Testing of CADASIL Syndrome
Policy ID: [11.003.010] [Ac / B / M+ / P+] [2.04.75]
Last Review: May 16, 2024
Next Review: May 20, 2025
Related Policies:
| Population Reference No. | Populations | Interventions | Comparators | Outcomes |
| 1 | Individuals: · With suspected CADASIL syndrome | Interventions of interest are: · NOTCH3 genetic testing | Comparators of interest are: · Standard clinical management without genetic testing | Relevant outcomes include: · Overall survival · Test accuracy · Test validity · Changes in reproductive decision making · Change in disease status · Morbid events |
| 2 | Individuals: · Who are asymptomatic with family members who have CADASIL syndrome | Interventions of interest are: · Targeted genetic testing for a known NOTCH3 familial variant | Comparators of interest are: · Standard clinical management without genetic testing | Relevant outcomes include: · Overall survival · Test accuracy · Test validity · Changes in reproductive decision making · Change in disease status · Morbid events |
| 3 | Individuals: · Who are asymptomatic with family members who have CADASIL syndrome whose genetic status is unknown | Interventions of interest are: · NOTCH3 genetic testing | Comparators of interest are: · Standard clinical management without genetic testing | Relevant outcomes include: · Overall survival · Test accuracy · Test validity · Changes in reproductive decision making · Change in disease status · Morbid events |
Variants in the NOTCH3 gene have been causally associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Genetic testing is available to determine if pathogenic variants exist in the NOTCH3 gene for patients with suspected CADASIL and their family members.
For individuals with suspected CADASIL syndrome who receive NOTCH3 genetic testing, the evidence includes case reports, case series, and genotype-phenotype correlation studies evaluating the clinical validity and genetic testing yield for NOTCH3. Relevant outcomes are overall survival, test accuracy and validity, changes in reproductive decision making, change in disease status, and morbid events. The clinical validity studies have demonstrated that a NOTCH3 pathogenic variant 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 derives from testing small numbers of healthy controls, and no false-positive NOTCH3 pathogenic variants have been reported in these populations. The diagnostic yield studies have reported a variable yield, ranging from 10% to 54%. These lower numbers likely reflect testing in heterogeneous populations that include patients with other disorders. No direct evidence was identified demonstrating outcome improvements associated with genetic testing for CADASIL. However, a chain of evidence can be constructed to demonstrate that identification of a NOTCH3 pathogenic variant establishes the diagnosis of CADASIL without the need for a skin biopsy and reduces the need for other diagnostic tests used to exclude other conditions in a differential diagnosis. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who are asymptomatic with family members who have CADASIL syndrome who receive targeted genetic testing for a known NOTCH3 familial variant, the evidence is limited. Relevant outcomes are overall survival, test accuracy and validity, 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 familial variant 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 disease onset. A chain of evidence can be constructed to demonstrate that identification of a NOTCH3 familial variant predicts future development of CADASIL in an asymptomatic individual, eliminates the need for additional diagnostic testing, allows for earlier monitoring for development of systems, aids in reproductive planning, and helps determine the likelihood of an affected offspring. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who are asymptomatic with family members who have CADASIL syndrome whose genetic status is unknown who receive NOTCH3 genetic testing, the evidence is limited. Relevant outcomes are overall survival, test accuracy and validity, changes in reproductive decision making, change in disease status, and morbid events. For asymptomatic family members of an individual with known CADASIL whose genetic status is unknown, knowledge of the presence of a NOTCH3 pathogenic variant 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 disease onset. A chain of evidence can be constructed to demonstrate that identification of a NOTCH3 pathogenic variant predicts future development of CADASIL in an asymptomatic individual, eliminates the need for additional diagnostic testing, allows for earlier monitoring for development of systems, aids in reproductive planning, and helps determine the likelihood of an affected offspring. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
Given the high clinical sensitivity of genetic testing for CADASIL and the severity of the condition but no direct evidence on improvements in outcomes, clinical input was obtained in 2013. Input provided strong consensus that genetic testing for CADASIL syndrome is medically necessary when the diagnosis cannot be made by clinical presentation, magnetic resonance imaging, and skin biopsy results. In these cases, NOTCH3 testing can confirm the diagnosis of CADASIL with a high degree of certainty. Input also provided strong consensus that testing is medically necessary for a first- or a second-degree relative when there is a known pathogenic variant in the family. In these cases, NOTCH3 testing can predict the future development of CADASIL to permit earlier initiation of surveillance for symptoms and determine the likelihood of an affected offspring.
The objective of this evidence review is to determine whether genetic testing improves the net health outcome in individuals with suspected CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) syndrome and in asymptomatic individuals with family members who have CADASIL syndrome.
Genetic testing for a NOTCH3 variant to confirm the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome in a patient 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 the Policy Guidelines section); and
The diagnosis of CADASIL is inconclusive following alternative methods of testing, including magnetic resonance imaging.
For individuals who are asymptomatic with a family member with a diagnosis of CADASIL syndrome:
If there is a family member (first- and second-degree relative) with a known variant, targeted genetic testing of the known NOTCH3 familial variant may be considered medically necessary.
If the family member’s genetic status is unknown, genetic testing of NOTCH3 (see Policy Guidelines section) may be considered medically necessary.
Genetic testing for a NOTCH3 variant to confirm the diagnosis of CADASIL syndrome in all other situations is considered investigational.
Genetic testing for NOTCH3 comprises targeted sequencing of specific exons (eg, exon 4 only, exons 2-6), general sequencing of NOTCH3 exons (eg, exons 2-24 or all 33 exons), or targeted testing for known NOTCH3 pathogenic variants. Skin biopsy should be reserved for patients where NOTCH3 genetic testing is inconclusive (e.g. variants of uncertain significance).
The probability that cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is present in an individualized assessment depends on numerous factors such as family history, symptoms, imaging results, and other specialized testing such as skin biopsy.
Pescini et al (2012) attempted to identify clinical factors that increase the likelihood of a pathogenic variant being present. Table PG1 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, because this score resulted in a high sensitivity (96.7%) and a moderately high specificity (74.2%).
| Features | No. With NOTCH3 Variant | Percent With NOTCH3 Variant | Points |
| Clinical | | | |
| Migraine | 239/463 | 52% | 1 |
| Migraine with aura | 65/85 | 76% | 3 |
| Transient ischemic attack/stroke | 380/526 | 72% | 1 (2 if <50 y) |
| Psychiatric disturbance | 106/380 | 28% | 1 |
| Cognitive decline | 188/434 | 43% | 3 |
| Radiologic | | | |
| LE | 277/277 | 100% | 3 |
| LE extended to temporal pole | 174/235 | 74% | 1 |
| LE extended to external capsule | 228/303 | 75% | 5 |
| Subcortical infarcts | 210/254 | 83% | 2 |
Adapted from Pescini et al (2012).
LE: leukoencephalopathy.
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table PG2). The Society's nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG3 shows the recommended standard terminology-"pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"-to describe variants identified that cause Mendelian disorders.
Table PG2. Nomenclature to Report on Variants Found in DNA
| Previous | Updated | Definition |
| Mutation | Disease-associated variant | Disease-associated change in the DNA sequence |
| | Variant | Change in the DNA sequence |
| | Familial variant | Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives |
Table PG3. ACMG-AMP Standards and Guidelines for Variant Classification
| Variant Classification | Definition |
| Pathogenic | Disease-causing change in the DNA sequence |
| Likely pathogenic | Likely disease-causing change in the DNA sequence |
| Variant of uncertain significance | Change in DNA sequence with uncertain effects on disease |
| Likely benign | Likely benign change in the DNA sequence |
| Benign | Benign change in the DNA sequence |
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Please see the Codes table for details.
Some Plans may have contract or benefit exclusions for genetic testing.
Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an uncommon, autosomal dominant disease, though it is the most common cause of hereditary stroke and hereditary vascular dementia in adults. CADASIL syndrome is an adult-onset, disabling systemic condition, characterized by a 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 differential diagnosis of CADASIL includes the following conditions ( Table 1).
| Acquired Disorders | Inherited Disorders |
| • Sporadic SVD with or without hypertension as the main risk factor • Multiple sclerosis • Primary angiitis of the central nervous system | • Fabry disease • Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy • Familial SVD caused by heterozygous variants in the HTRA1 gene • Some forms of leukodystrophy |
CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; SVD: small vessel disease. Since the clinical presentation of CADASIL varies, the condition 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 findings, are extremely important in diagnosing CADASIL. The clinical features and mode of inheritance (autosomal dominant vs. autosomal recessive) help to distinguish CADASIL from other inherited disorders in a differential diagnosis.
When the differential diagnosis includes CADASIL, various diagnostic tests are available:
Genetic testing, by direct sequencing of select exons or of exons 2 through 24 of the NOTCH3 gene (see the Rationale section). Identification of a NOTCH3 pathogenic variant definitively establishes a diagnosis of CADASIL without the need for additional diagnostic testing (eg, skin biopsy).
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 the NOTCH3 protein in the walls of small blood vessels.2, Lesnick Oberstein et al (2003) estimated the 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 magnetic resonance imaging parameters.3,
Detection of granular osmiophilic material in the same skin biopsy sample by electron microscopy. The major component of granular osmiophilic material is the ectodomain of the NOTCH3 gene product.4, Granular osmiophilic material accumulates directly in vascular smooth muscle cells and, when present, is considered a hallmark of the disease.5, However, granular osmiophilic material 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%.6,7,8,
Examination of brain tissue for the presence of granular osmiophilic material was originally described as limited to brain blood vessels.9, Examination of brain biopsy or autopsy after death was an early criterion standard for diagnosis. In some cases, peripheral staining for granular osmiophilic material has been absent even though positive results were seen in brain blood vessels.
Variants in NOTCH3 have been identified as the underlying cause of CADASIL. In almost all cases, the pathogenic variants lead to loss or gain of a cysteine residue that can lead to increased reactivity of the NOTCH3protein, resulting in ligand-binding and toxic effects.10,
The NOTCH3 gene is found on chromosome 19p13.12 and encodes the third discovered human homologue of the Drosophila melanogaster type I membrane protein NOTCH. The NOTCH3protein 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 (EGF)-like repeats, traverses the membrane once, and has an intracellular domain required for signal transduction.11,
Variants in the NOTCH3 gene have been differentiated into those causative of the CADASIL syndrome (pathogenic variants) and those of uncertain significance. Pathogenic variants affect conserved cysteine residues within 34 EGF-like repeat domains in the extracellular portion of the NOTCH3protein.11,12, More than 150 pathogenic variants have been reported in at least 500 pedigrees. NOTCH3 has 33 exons but all CADASIL variants reported to date have occurred in exons 2 to 24, which encode the 34 EGF-like repeats, with strong clustering in exons 3 and 4, which encode EGF receptors 2 to 5 (>40% of variants in >70% of families occur in these exons).13,A study by Hack et al (2023) identified 3 clinically distinct risk categories (high, medium, and low) of NOTCH3 EGF-like repeats using data from CADASIL and population cohorts (N=4221).14, Some studies have indicated that the clinical variability in CADASIL presentation, particularly about the development of white-matter hyperintensities on magnetic resonance imaging, may be related to genetic modifiers outside the NOTCH3 locus but the specific role of these modifiers is not well-delineated.15,Dupé et al (2023) investigated the phenotypic variability in individuals with CADASIL and found the mutation location in the NOTCH3 gene (n=436) to be strongly related to clinical severity, and found male sex, arterial hypertension, and smoking to be associated with increased disease severity.16,
The probability that CADASIL is present in an individualized assessment depends on numerous factors such as family history, symptoms, imaging results, and other specialized testing (eg, skin biopsy). Pescini et al (2012) attempted to identify clinical factors that increase the likelihood of a pathogenic variant being present, with increasing likelihood with the presence of 1 or several factors, including a migraine, migraine with aura, transient ischemic attack/stroke, psychiatric disturbance, cognitive decline, leukoencephalopathy (with greater risk for leukoencephalopathy extending to the temporal pole or external capsule), and subcortical infarcts.17,
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Genetic testing of NOTCH3 is available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.
This evidence review was created in September 2011 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through February 29, 2024.
Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.
The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.
Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.
The purposes of genetic testing of symptomatic individuals with suspected cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome are to establish the diagnosis of CADASIL without skin biopsy or other invasive testing and to aid in reproductive planning when the diagnosis cannot be made clinically.
The following PICO was used to select literature to inform this review.
The relevant population of interest is individuals with suspected CADASIL.
The test being considered is genetic testing for NOTCH3 variants.
Genetic testing is used to confirm a diagnosis of CADASIL. Referral for genetic counseling is important for the explanation of genetic disease, heritability, genetic risk, test performance, and possible outcomes.
The following practice is currently being used: standard clinical management without genetic testing.
The potential beneficial outcome of primary interest would be changes in management associated with improved outcomes initiated based on confirming a genetic diagnosis of CADASIL. Reductions in skin biopsies or other invasive tests to confirm the diagnosis of CADASIL are also potentially beneficial outcomes.
Potential harmful outcomes are those resulting from a false-positive or false-negative test result. False-positive test results can lead to the inappropriate initiation of treatments or psychological harm after receiving positive test results. False-negative test results can lead to lack of medical or neurologic treatments or surveillance.
The time frame for outcome measures varies from the short-term development of symptoms to long-term changes in disease status and outcomes.
For the evaluation of clinical validity of the tests, studies that met the following eligibility criteria were considered:
Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)
Included a suitable reference standard
Patient/sample clinical characteristics were described
Patient/sample selection criteria were described
Included a validation cohort separate from development cohort
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
Several retrospective and prospective studies have examined the association between NOTCH3 variants and CADASIL, as shown in Table 2. Studies have been divided into 2 categories: Part 1: Diagnostic studies, in which 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 demonstrated that a NOTCH3 pathogenic variant is found in a high percentage of patients with a clinical diagnosis of CADASIL, with studies reporting a clinical sensitivity ranging from 90% to 100%. Limited data on specificity derive from testing small numbers of healthy controls, and no false-positive NOTCH3 variants have been reported in these populations. The diagnostic yield studies have reported a variable yield (range, 10%-54%). These lower numbers likely reflect testing in heterogeneous populations that include patients with other disorders.
Identification of a NOTCH3 pathogenic variant establishes a diagnosis of CADASIL. For individuals suspected of CADASIL:
Perform targeted sequencing and analysis of specific NOTCH3 exons (eg, exon 4 only, exons 2-6) OR
Perform general testing of NOTCH3 exons (eg, exons 2-24 or all 33 exons).
If no NOTCH3 pathogenic variant is identified, a skin biopsy is warranted for immunohistochemical staining for NOTCH3 protein and/or electron microscopy for granular osmiophilic material.
| Study | Patients Evaluated | NOTCH3 Exons Sequenced | Results | ||
| Part 1: Diagnostic studies | Diagnostic Yield | Specificity | |||
| Mosca et al (2011)10, | Patients: 140 with clinical suspicion of CADASIL (Italian, Chinese) Selection: History of premature strokes; migraine with aura; vascular dementia; suggestive MRI findings; consistent family history; or combination of previous criteria | Direct sequencing of exons 2-8, 10, 14, 19-20, 22 | Patients: 14 with pathogenic variants located in 10 exons. 126 patients free of pathogenic variants Family members: Analysis of 15 additional family members identified 11 of the same pathogenic variants | NR | |
| Lee et al (2009)18, | Patients: 39 with suspected CADASIL (Chinese); 100 healthy elderly controls ≥80 y Selection: Suggestive MRI findings and at least 1 of the following: young age at onset, cognitive decline, psychiatric disorders, or consistent family history | Direct sequencing of exons 2-23 | Patients: 9 different SNVs identified in 21/39 patients Family members: No data | 100% No variants in 100 healthy elderly controls | |
| Markus et al (2002)8, | Patients: 83 with suspected CADASIL (U.K.) Selection: Patients were <60 y 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 SNVs identified in 48 families with 116 symptomatic patients, 73% in exon 4, 8% in exon 3, 6% in exons 5 and 6 Family members: No data | NR | |
| Choi et al (2013)9, | Patients: 151 consecutive patients (Korean) Selection: History of acute ischemic stroke, neurologic exam, cranial computed tomography, or MRI | Bidirectional sequencing of exons 3, 4, 6, 11, 18 | Patients: 6 (4%) found with identical NOTCH3 variant (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; history of stroke and dementia higher in patients with variants Family members: No data | NR | |
| Yin et al (2015)19, | Patients: 47 subjects from 34 families (Chinese) diagnosed with suspected CADASIL Diagnosis/selection: MRI abnormalities and presence of >1 typical symptom (eg, migraine, stroke, cognitive deficits, psychiatric symptoms) or presence of atypical symptoms with a positive family history | Testing method per Joutel et al (1997)20,: exons 3 and 4 screened first; if no variants detected, remaining exons analyzed | Patients: 6 known familial variants identified in 8 families and 2 novel pathogenic variants identified in 2 families (exons 3 and 4), and 1 VUS identified in 1 family (exon 2). Overall NOTCH3 pathogenic variant prevalence: 29.4%. | NR | |
| Abramycheva et al (2015)21, | Patients: 30 unrelated patients with suspected CADASIL | Direct sequencing of exons 2-23 via PCR | Patients: 16 SNVs identified in 18 unrelated patients, 12 of which had been previously described and 4 were novel (C194G, V252M, C338F, C484G) | NR | |
| Maksemous et al (2016)22, | Patients: 44 with suspected clinical diagnosis of CADASIL previously screened for standard Sanger sequencing exons (3, 4) and/or (2, 11, 18, 19) and classified as negative for known pathogenic variants | Custom NGS panel | Patients: 6 typical CADASIL pathogenic variants identified in 7/44 patients | NR | |
| Gorukmez et al (2023)23, | Patients: 368 individuals with suspected CADASIL based on radiological and clinical findings | NGS | Patients: 30 variants (17 novel) were detected in 44 individuals from 40 families in exons 2 to 24, 25, 31, and 33 | NR | |
| Part 2: Clinical validity studies | Sensitivity | Specificity | |||
| Peters et al (2005)24, | Patients: 125 unrelated patients diagnosed with CADASIL Diagnosis/selection: Skin biopsy-proven CADASIL patients | Bidirectional sequencing of all exons | Sensitivity: 96% Patients: 54 distinct variants in 120 (96.0%) of 125 patients. In 5 (4.0%) patients, no variants identified. Family members: No data | NR | |
| Tikka et al (2009)25, | Patients: 131 patients from 28 families diagnosed with CADASIL (Finnish, Swedish, French) 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 pathogenic variant-positive Family members: No data; no pathogenic variant reported per family or per unrelated individual | 100% No pathogenic variants in 26 negative controls | |
| Dotti et al (2005)26, | Patients: 28 unrelated, consecutively diagnosed patients with CADASIL (Italian) Diagnosis/selection: Patients diagnosed via clinical and MRI criteria | DHPLC, followed by confirmatory sequencing of identified pathogenic variants | Sensitivity: 100% Patients: All 28 had pathogenic variants | NR | |
| Joutel et al (1997)20, | Patients: 50 unrelated patients with a clinical suspicion of CADASIL and 100 healthy controls Diagnosis/selection: History of recurrent strokes, migraine with aura, vascular dementia, or a combination; brain MRI with suggestive findings; and consistent familial history | SSCP or heteroduplex analysis of all exons, followed by confirmatory sequencing of identified variants | Sensitivity: 90% Patients: 45/50 CADASIL patients had variants | 100% No variants in 100 healthy controls | |
CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; DHPLC: denaturing high-performance liquid chromatography; EM: electron microscope; MRI: magnetic resonance imaging; NGS: next-generation sequencing; NR: not reported; PCR: polymerase chain reaction; SNV: single nucleotide variant; SSCP: single-stranded conformational polymorphism; VUS: variant of uncertain significance. The clinical sensitivity of genetic testing is high given that NOTCH3 is the only gene for which pathogenic variants are known to cause CADASIL. In clinical situations where the diagnosis of CADASIL cannot be confirmed by other methods (clinical presentation, MRI findings), identification of a pathogenic variant in NOTCH3 establishes a diagnosis of CADASIL.
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for individuals managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).
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 an individual 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 individuals 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.
Pescini et al (2012) attempted to identify clinical factors that increase the likelihood of a pathogenic variant being present and therefore might be helpful in selecting individuals for testing.17, The authors first performed a systematic review to determine the frequency with which clinical and radiologic factors are associated with a positive genetic test. Evidence was identified from 15 clinical series of individuals with CADASIL. Table 3 summarizes the pooled frequency of clinical and radiologic features.
| Features | No. With NOTCH3 Variant | Percent With NOTCH3 Variant | Points |
| Clinical | | | |
| Migraine | 239/463 | 52 | 1 |
| Migraine with aura | 65/85 | 76 | 3 |
| Transient ischemic attack/stroke | 380/526 | 72 | 1 (2 if <50 y) |
| Psychiatric disturbance | 106/380 | 28 | 1 |
| Cognitive decline | 188/434 | 43 | 3 |
| Radiologic | | | |
| LE | 277/277 | 100 | 3 |
| LE extended to temporal pole | 174/235 | 74 | 1 |
| LE extended to external capsule | 228/303 | 75 | 5 |
| Subcortical infarcts | 210/254 | 83 | 2 |
Adapted from Pescini et al (2012)17,
LE: leukoencephalopathy.
Using these frequencies, a preliminary scoring system was developed and tested in 61 patients with NOTCH3 pathogenic variants, and in 54 individualswith phenotypic features of CADASIL who were NOTCH3-negative. With the addition of family history and age at onset of transient ischemic attack or stroke, a scoring system was developed, as provided in Table 3. The authors recommended that a total score of 14 be used to select individuals for testing because this score resulted in a high sensitivity (96.7%) and moderately high specificity (74.2%).
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.4,11,
Two randomized, double-blind, placebo-controlled studies evaluated the efficacy and safety of potential treatments for CADASIL. Dichgans et al (2008) showed there was no significant difference between donepezil (n=84) and placebo (n=77) in the primary cognitive endpoint, the cognitive subscale of the Vascular AD Assessment Scale score.27, De Maria et al (2014) found no significant difference between sapropterin (n=32) and placebo (n=29) in change in reactive hyperemia peripheral arterial tonometry response (mean difference, 0.19: 95% confidence interval, -0.18 to 0.56).28,
Two single-arm studies also evaluated the efficacy of potential treatments for CADASIL. Huang et al (2010) found treatment with acetazolamide (N=16) resulted in a significant increase of blood mean flow velocity in the middle cerebral artery (57.68 cm/s) compared with mean flow velocity in the middle cerebral artery at rest before treatment (67.12 cm/s; p=.001).29, During the treatment period, none of the subjects developed new neurologic symptoms, and the original symptoms in these individuals (eg, headaches, dizziness) were relieved. Peters et al (2007), evaluated the use of 3-hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitors (statins) in 24 CADASIL subjects treated with atorvastatin for 8 weeks.30, There was no significant treatment effect on mean flow velocity (p=.5) or cerebral vasoreactivity, as assessed by hypercapnia (p=.5) or intravenous l-arginine (p=.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<.05). Short-term treatment with atorvastatin resulted in no significant improvement of hemodynamic parameters in the overall cohort of CADASIL subjects.
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
Genetic testing of individuals with suspected CADASIL may have clinical utility by:
Establishing a diagnosis of CADASIL in an individual with signs and symptoms of the disease, particularly when other disorders are being considered, without the need for a skin biopsy.
Informing the reproductive decision-making process in preimplantation testing, prenatal (in utero) testing, or altering reproductive planning decisions when a NOTCH3 pathogenic variant is present in a parent. Preimplantation testing is addressed elsewhere (evidence review 4.02.05).
Direct evidence for the clinical utility of genetic testing of individuals with suspected CADASIL is lacking. No specific clinical treatment for CADASIL has established efficacy. However, a chain of evidence for the clinical validity of NOTCH3 pathogenic variants in establishing a diagnosis of CADASIL leading to initiation of supportive care in the form of practical help, emotional support, and counseling may provide a chain of evidence for potential clinical utility.
For individuals with suspected CADASIL syndrome who receive NOTCH3 genetic testing, the evidence includes case reports, case series, and genotype-phenotype correlation studies evaluating the clinical validity and genetic testingyield for NOTCH3. Relevant outcomes are overall survival, test accuracy and validity, changes in reproductive decision making, change in disease status, and morbid events. The clinical validity studies have demonstrated that a NOTCH3 pathogenic variant 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 derives from testing small numbers of healthy controls, and no false-positive NOTCH3 pathogenic variants have been reported in these populations. The diagnostic yield studies have reported a variable yield, ranging from 10% to 54%. These lower numbers likely reflect testing in heterogeneous populations that include patients with other disorders. No direct evidence was identified demonstrating outcome improvements associated with genetic testing for CADASIL. However, a chain of evidence can be constructed to demonstrate that identification of a NOTCH3 pathogenic variant establishes the diagnosis of CADASIL without the need for a skin biopsy and reduces the need for other diagnostic tests used in the exclude other conditions in a differential diagnosis. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
| [X] MedicallyNecessary | [ ] Investigational |
The purposes of targeted familial variant testing of asymptomatic individuals with family members who have CADASIL are to screen at-risk individuals and predict the development of disease, to determine the need for surveillance, and to aid in reproductive planning.
The following PICO was used to select literature to inform this review.
The relevant population of interest is asymptomatic patients with relatives who have CADASIL syndrome.
The following test is currently being used: targeted familial variant testing of NOTCH3.
Asymptomatic individuals with family members with CADASIL may be referred to a medical geneticist for investigation of genetic status for carrying a known familial variant. Referral for genetic counseling is important for the explanation of genetic disease, heritability, genetic risk, test performance, and possible outcomes.
The following practice is currently being used: standard clinical management without genetic testing.
The potential beneficial outcomes of primary interest would be confirming or excluding the need for surveillance or changes in reproductive decision making. A negative genetic test result would eliminate the need for surveillance to detect the development of symptoms and disease. A positive genetic test result would confirm a need for active surveillance and inform the reproductive decision process.
Potential harmful outcomes are those resulting from a false-positive or false-negative test result. False-positive test results can lead to unnecessary medical or neurologic surveillance of asymptomatic individuals. False-negative test results can lead to lack of medical or neurologic surveillance.
The time frame for outcome measures varies from short-term surveillance of asymptomatic individuals for the development of signs or symptoms of CADASIL to long-term development of the disease.
For the evaluation of clinical validity of the tests, studies that met the following eligibility criteria were considered:
Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)
Included a suitable reference standard
Patient/sample clinical characteristics were described
Patient/sample selection criteria were described
Included a validation cohort separate from development cohort
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
See the clinical validity discussion in the Testing Individuals With Suspected CADASIL Syndrome section.
Identification of a NOTCH3 pathogenic variant establishes a diagnosis of CADASIL in both symptomatic and asymptomatic individuals. For testing in asymptomatic individuals with family members who have CADASIL:
When the proband’s NOTCH3 pathogenic variant is known, conduct targeted familial variant testing to determine genetic status.
The testing strategy described is a general approach for targeted genetic testing for a known pathogenic variant previously identified in a family member (familial variant) with CADASIL.
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.
No randomized trials were identified addressing outcomes managed with CADASIL testing.
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
Genetic testing of asymptomatic individuals with family members who have CADASIL may have clinical utility by:
Confirming or excluding the need for surveillance based on the presence or absence of a known familial variant.
Informing the reproductive decision-making process in preimplantation testing, prenatal (in utero) testing, or altering reproductive planning decisions when a known NOTCH3 familial variant is present in a parent. Preimplantation testing is addressed elsewhere (evidence review 4.02.05).
Genetic counseling is recommended to discuss the impact of positive or negative test results, followed by molecular testing if desired.5, At present, for an asymptomatic individual, knowledge of familial variant status will generally not lead to any management changes that can prevent or delay the onset of the disorder. Avoiding tobacco use can be a factor that delays the onset of disease, but this is a general recommendation that is not altered by genetic testing. However, a negative test may preclude the need for surveillance for complications. Genetic testing may also assist reproductive decision making.
A chain of evidence can be constructed to demonstrate that identification of a NOTCH3 pathogenic variant predicts future development of CADASIL in an asymptomatic individual, eliminates the need for additional diagnostic testing, allows for earlier monitoring for development of systems, aids in reproductive planning, and helps determine the likelihood of an affected offspring.
Direct evidence for the clinical utility of genetictesting of asymptomatic relatives of patients with CADASIL is lacking. No specific clinical treatment for CADASIL has established efficacy. However, a chain of evidence can be developed for potential clinical utility, particularly for reproductive decision-making process for preimplantation and/or prenatal testing.
For individuals who are asymptomatic with family members who have CADASIL syndrome who receive targeted genetic testing for a known NOTCH3 familial variant, the evidence is limited. Relevant outcomes are overall survival, test accuracy and validity, 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 familial variant 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 disease onset. A chain of evidence can be constructed to demonstrate that identification of a NOTCH3 familial variant predicts future development of CADASIL in an asymptomatic individual, eliminates the need for additional diagnostic testing, allows for earlier monitoring for development of systems, aids in reproductive planning, and helps determine the likelihood of an affected offspring. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
| [X] MedicallyNecessary | [ ] Investigational |
The purposes of genetic testing of NOTCH3 in asymptomatic individuals with family members with CADASIL whose genetic status is unknown are to screen at-risk individuals and to predict the development of disease, determine the need for surveillance, and aid in reproductive planning.
The following PICO was used to select literature to inform this review.
The relevant population of interest is asymptomatic patients with relatives who have CADASIL and whose genetic status is unknown.
The test being considered is genetic testing of NOTCH3 variants.
Asymptomatic individuals with family members who have CADASIL may be referred to a medical geneticist for investigation of genetic status for carrying a known familial variant. Referral for genetic counseling is important for the explanation of genetic disease, heritability, genetic risk, test performance, and possible outcomes.
The following practice is currently being used: standard clinical management without genetic testing.
The potentially beneficial outcomes of primary interest would be confirming or excluding the need for surveillance or changes in reproductive decision making. A negative genetic test result would eliminate the need for surveillance to detect the development of symptoms and disease. A positive genetic test result would confirm a need for active surveillance and also inform the reproductive decision-making process.
Potential harmful outcomes are those resulting from a false-positive or false-negative test result. False-positive test results can lead to unnecessary medical or neurologic surveillance of asymptomatic individuals. False-negative test results can lead to lack of medical or neurologic surveillance.
The time frame for outcome measures varies from short-term surveillance of asymptomatic individuals for the development of signs or symptoms of CADASIL to long-term development of the disease.
For the evaluation of clinical validity of the tests, studies that met the following eligibility criteria were considered:
Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)
Included a suitable reference standard
Patient/sample clinical characteristics were described
Patient/sample selection criteria were described
Included a validation cohort separate from development cohort
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
See the clinical validity discussion in the Testing Individuals With Suspected CADASIL Syndrome section.
For testing in asymptomatic individuals with family members who have CADASIL whose genetic status is unknown:
Perform targeted sequencing and analysis of specific NOTCH3 exons (eg, exon 4 only, exons 2- 6) OR
Perform general testing of NOTCH3 exons (eg, exons 2-24 or all 33 exons).
This testing strategy to perform sequence analysis of multiple NOTCH3 exons to identify pathogenic variants is a general approach for genetic testing for NOTCH3.
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.
No randomized trials were identified addressing outcomes managed with CADASIL testing.
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
Genetic testing of asymptomatic individuals with family members who have CADASIL may have clinical utility by:
Confirming or excluding the need for surveillance based on the presence or absence of a NOTCH3 pathogenic variant.
Informing the reproductive decision-making process in preimplantation testing, prenatal (in utero) testing, or altering reproductive planning decisions when a known NOTCH3 pathogenic variant is present in a parent. Preimplantation testing is addressed elsewhere (evidence review 4.02.05).
Similar to the case where there is a known family variant associated with CADASIL, direct evidence for the clinical utility of genetictesting of asymptomatic relatives of patients with CADASIL is lacking. However, a chain of evidence can be developed to support the clinical utility of testing, as outlined above.
For individuals who are asymptomatic with family members who have CADASIL syndrome whose genetic status is unknown who receive NOTCH3 genetic testing, the evidence is limited. Relevant outcomes are overall survival, test accuracy and validity, changes in reproductive decision making, change in disease status, and morbid events. For asymptomatic family members of an individual with known CADASIL whose genetic status is unknown, knowledge of the presence of a NOTCH3 pathogenic variant 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 disease onset. A chain of evidence can be constructed to demonstrate that identification of a NOTCH3 pathogenic variant predicts future development of CADASIL in an asymptomatic individual, eliminates the need for additional diagnostic testing, allows for earlier monitoring for development of systems, aids in reproductive planning, and helps determine the likelihood of an affected offspring. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
| [X] MedicallyNecessary | [ ] Investigational |
The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions
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 the statement that genetic testing to confirm the diagnosis of CADASIL was investigational. All reviewers expressed support for testing to confirm the diagnosis in select patients, particularly when the diagnosis of CADASIL is inconclusive, and when the pretest likelihood of CADASIL is moderate to high. In addition to consensus among reviewers, contextual factors in support of medical necessity are present for this indication, ie, there is a highly suggestive 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 pathogenic variant (familial variant) in the family. For this indication, contextual factors in support of medical necessity were not present. High-quality trials are unlikely to be performed.
Clinical consultation was obtained in 2020 indicating that skin biopsy prior to NOTCH3 testing is not necessary; skin biopsy should be reserved for patients where NOTCH3 genetic testing is inconclusive (e.g. variants of uncertain significance).
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.
No guidelines or position statements with US representation or that were informed by a systematic review were identified.
In a 2023 scientific statement, the American Heart Association reviewed the current clinical, genetic, and imaging aspects of CADASIL to provide prevention, management, and therapeutic considerations to support future treatment recommendations.31, In consideration of when to test for NOTCH3 mutations, they state to "[c]onsider gene testing in patients with small vessel stroke before 55 y[ears] of age with a paucity of vascular risk factors (eg, normotensive, nondiabetic, nonsmoker) or positive family history of CADASIL."
Not applicable.
There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.
One currently ongoing trial that might influence this review is listed in Table 4.
| NCT No. | Trial Name | Planned Enrollment | Completion Date |
| Ongoing | |||
| NCT04310098 | Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Registry Study | 1000 | Mar 2049 |
| NCT06148051 | AusCADASIL: An Australian Cohort of CADASIL | 300 | March 2027 |
| NCT05677880 | Unraveling the Early Phases of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) | 500 | Jan 2026 |
| NCT05072483 | Natural History Study of CADASIL | 140 | June 2041 |
| Codes | Number | Description |
|---|---|---|
| CPT | 81406 | Molecular pathology procedure, Level 7 (includes NOTCH3) |
| ICD-10-CM | A81.2 | Progressive multifocal leukoencephalopathy |
| I67.850 | Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy | |
| Z13.79 | Encounter for other screening for genetic and chromosomal anomalies | |
| Z82.41- Z82.49 | Family history of ischemic heart disease and other diseases of the circulatory system | |
| ICD-10-PCS | Not applicable. No ICD procedure codes for laboratory tests. | |
| Type of service | Pathology/Laboratory | |
| Place of service | Laboratory/Reference Laboratory |
As per correct coding guidelines.
| Date | Action | Description |
|---|---|---|
| 05/16/2024 | Annual Review | Policy updated with literature review through February 29, 2024; references added. Policy statements unchanged. |
| 05/08/2023 | Annual Review | Policy updated with literature review through January 16, 2023; no references added. Minor editorial refinement to policy statement; intent unchanged. Paragraph was added for promotion of greater diversity and inclusion in clinical research of historically marginalized groups. |
| 05/12/2022 | Annual Review | Policy updated with literature review through January 17, 2022; no references added. Policy statements unchanged. ICD 10 CM: Z82 Range entended to Z82.41- Z82.49 .ICD 10 CM I67.89 changed to I67.850 . |
| 05/21/2021 | Annual Review | Policy updated with literature review through February 25, 2021; no references added. Policy statements unchanged. |
| 05/18/2020 | Annual Review | Policy updated with literature review through April 2, 2020; European Academy of Neurology consensus recommendations added. Policy statement changed to remove skin biopsy requirement prior to genetic testing. |
| 04/17/2020 | Annual Review | Includes cpt codes 81406 |
| 04/12/2019 | Annual Review | No changes |
| 04/12/2018 | Revision | |
| 12/02/2016 | Revision | |
| 10/15/2015 | Revision | |
| 09/17/2013 | Revision |