Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Genetic Test: Alzheimer's Disease

Description:

Alzheimer disease (AD) is the most common cause of dementia in elderly patients. For late-onset AD, there is a component of risk that runs in families, suggesting the contribution of genetic factors. Early-onset AD is much less common but can occur in non-elderly individuals. Early-onset AD has a stronger component of family risk, with clustering in families, thus suggesting an inherited genetic disease-causing variant.

Alzheimer's disease is commonly associated with a family history. Forty percent of patients with Alzheimer's disease have at least one other afflicted first-degree relative. Numerous genes have been associated with late-onset Alzheimer's disease; while variants in chromosomes 1, 14, and 21 have been associated with early-onset familial Alzheimer's disease (Bird, 2008).

Genetic Variants

Individuals with early-onset familial AD (i.e., before age 65 but as early as 30 years) form a small subset of AD patients. AD within families of these patients may show an autosomal dominant pattern of inheritance. Pathogenic mutations in 3 genes have been identified in affected families: amyloid-beta precursor protein (APP) gene, presenilin 1 (PSEN1) gene, and presenilin 2 (PSEN2) gene. APP and PSEN1 variants have 100% penetrance absent death from other causes, while PSEN2 has 95% penetrance. Variants within these genes has been associated with AD; variants in PSEN1 appear to be the most common. While only 3%–5% of all patients with AD have early-onset disease, pathogenic mutations have been identified in up to 70% or more of these patients. Identifiable genetic mutations are, therefore, rare causes of AD.

Testing for the apolipoprotein E (APOE) epsilon 4 allele among patients with late-onset AD and for APP, PSEN1, or PSEN2 pathogenic variants in the rare patient with early-onset AD have been investigated as an aid in diagnosis in patients presenting with symptoms suggestive of AD, or a technique for risk assessment in asymptomatic patients with a family history of AD. Pathologic variants in PSEN1 and PSEN2 are specific for AD; APP variants are also found is cerebral hemorrhagic amyloidosis of the Dutch type, a disease in which dementia and brain amyloid plaques are uncommon.

The APOE lipoprotein is a carrier of cholesterol produced in the liver and brain glial cells. The APOE gene has 3 alleles-2, 3, and 4-with the 3 allele being the most common. Individuals carry 2 APOE alleles. The presence of at least one, 4 allele is associated with a 1.2- to 3-fold increased risk of AD, depending on the ethnic group. Among those homozygous for 4 (»2% of the population), the risk of AD is higher than for those heterozygous for 4. Mean age of onset of AD is about age 68 years for ε4 homozygotes, about 77 years for heterozygotes, and about 85 years for those with no 4 alleles. About half of patients with sporadic AD carry a 4 allele. However, not all patients with the allele develop AD. The 4 allele represents a risk factor for AD rather than a disease-associated variant. In the absence of APOE testing, first-degree relatives of an individual with sporadic or familial AD are estimated to have a 2- to 4-fold greater risk of developing AD than the general population (Goldman, 2011). There is evidence of possible interactions between 4 alleles, other risk factors for AD (e.g., risk factors for cerebrovascular disease such as smoking, hypertension, hypercholesterolemia, diabetes), and a higher risk of developing AD (Caselli, 2011). However, it is not clear that all risk factors have been taken into account in such studies, including the presence of variants in other genes that may increase the risk of AD.

Studies have also identified rs75932628-T, a rare functional substitution for R47H on the triggering receptor expressed on myeloid cells 2 (TREM2), as a heterozygous risk variant for late-onset AD (Jonsson, 2013; Guerreiro, 2013). On chromosome 6p21.1, at position 47 (R47H), the T allele of rs75932628, encodes a histidine substitute for arginine in the gene that encodes TREM2.

TREM2 is highly expressed in the brain and is known to have a role in regulating inflammation and phagocytosis. TREM2 may serve a protective role in the brain by suppressing inflammation and clearing it of cell debris, amyloids, and toxic products. A decrease in the function of TREM2 would allow inflammation in the brain to increase and may be a factor in the development of AD. The effect size of the TREM2 variant confers a risk of AD that is similar to the APOE epsilon 4 allele, although it occurs less frequently.

Diagnosis of Alzheimer’s Disease

The diagnosis of AD is divided into 3 categories: possible, probable, and definite AD (McKhann, 2011). A diagnosis of definite AD requires postmortem confirmation of AD pathology, documenting the presence of extracellular b-amyloid plaques and intraneuronal neurofibrillary tangles in the cerebral cortex. As a result, a diagnosis of definite AD cannot be made during life, and the diagnosis of probable or possible AD is made on clinical grounds (Hyman, 2012). Probable AD dementia is diagnosed clinically when the patient meets core clinical criteria for dementia and has a typical clinical course for AD. Criteria for diagnosis of probable AD have been developed by the National Institute on Aging and the Alzheimer’s Association (McKhann, 2011). These criteria require evidence of a specific pattern of cognitive impairment, a typical clinical course, and exclusion of other potential etiologies, as follows:

Cognitive impairment

Cognitive impairment established by history from the patient and a knowledgeable informant, plus objective assessment by bedside mental status examination or neuropsychological testing
Cognitive impairment involving a minimum of 2 of the following domains:

Impaired ability to acquire and remember new information
Impaired reasoning and handling of complex tasks, poor judgment
Impaired visuospatial abilities
Impaired language functions
Changes in personality, behavior, or comportment

Initial and most prominent cognitive deficits are 1 of the following:

Amnestic presentation
Nonamnestic presentations, either a language presentation with prominent word-finding deficits; a visuospatial presentation with visual cognitive defects; or a dysexecutive presentation with prominent impairment of reasoning, judgment, and/or problem-solving.

Clinical course

Insidious onset
Clear-cut history of worsening over time
Interference with the ability to function at work or usual activities
Decline from previous level of functioning and performing

Exclusion of other disorders

Cognitive decline not explained by delirium or major psychiatric disorder
No evidence of other active neurologic diseases, including substantial cerebrovascular disease or dementia with Lewy bodies.
Lack of prominent features of variant frontotemporal dementia or primary progressive aphasia.
No medication used with substantial effects on cognition.

A diagnosis of possible AD dementia is made when the patient meets most of the AD criteria but has an atypical course or an etiologically mixed presentation (McKhann, 2011). This may consist of an atypical onset (e.g., sudden onset) or atypical progression. A diagnosis of possible AD is also made when there is another potentially causative systemic or neurologic disorder that is not thought to be the primary etiology of dementia.

Mild cognitive impairment is a precursor of AD in many instances. Mild cognitive impairment may be diagnosed when there is a change in cognition, but insufficient impairment for the diagnosis of dementia (Albert, 2011). Features of mild cognitive impairment are evidence of impairment in 1 or more cognitive domains and preservation of independence in functional abilities. In some patients, mild cognitive impairment may be a predementia phase of AD. Patients with mild cognitive impairment may undergo ancillary testing (e.g., neuroimaging, laboratory studies, neuropsychological assessment) to rule out vascular, traumatic, and medical causes of cognitive decline and to evaluate genetic factors.

Biomarker evidence has been integrated into the diagnostic criteria for probable and possible AD for use in research settings (McKhann, 2011). Other diagnostic tests for AD include cerebrospinal (CSF) fluid levels of Tau protein or amyloid precursor protein, as well as positron emission tomography amyloid imaging. These CSF tests are considered separately in policy No. 2009004. Positron emission tomography amyloid imaging is considered separately in policy No. 2012026.

Regulatory Status

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). Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing.

In November 2017, the 23andMe Personal Genome Service (PGS) Test with Genetic Health Risk Report for Late-onset Alzheimer Disease was granted a de novo classification by the U.S. Food and Drug Administration (class II with general and special controls, FDA product code: PTA). This is a direct-to-consumer test that has been evaluated by the FDA for accuracy, reliability, and consumer comprehension. This test reports whether an individual has variants associated with late-onset AD by detecting the presence of the APOE 4 (rs429353) gene variant.

In June 2021, aducanumab (Aduhelm; Biogen) was approved by the FDA for treatment of AD. This indication was approved under accelerated approval based on reduction in amyloid-beta plaques observed in patients treated with aducanumab. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).

In July 2021, FDA amended the approved label to emphasize the disease stages studied in the clinical trials. The amended label states, "Treatment with aducanumab should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied."

The FDA, under the accelerated approval regulations (21 CFR 601.41), requires that Biogen conduct a randomized, controlled trial to evaluate the efficacy of aducanumab-avwa compared to an appropriate control for the treatment of AD. The trial should be of sufficient duration to observe changes on an acceptable endpoint in the patient population enrolled in the trial. The expected date of trial completion is August 2029 with final report submission to the FDA by February 2030.

Aducanumab is reviewed separately in policy No. 2021042.

Coding

Effective in 2013, there is CPT coding to more specifically report PSEN and APP testing.

CPT code 81405 includes:

PSEN1 (presenilin 1) (e.g., Alzheimer disease), full gene sequence.

CPT code 81406 includes:

APP (amyloid beta [A4] precursor protein) (e.g., Alzheimer disease), full gene sequence, and

PSEN2 (presenilin 2 [Alzheimer disease 4]) (e.g., Alzheimer disease), full gene sequence.

Effective in 2012, there is CPT coding to more specifically report APOE testing.

CPT code 81401 includes:

APOE (apolipoprotein E) (e.g., hyperlipoproteinemia type III, cardiovascular disease, Alzheimer disease), common variants (e.g., *2, *3, *4).

Prior to 2013, the following series of CPT codes were identified by Athena Diagnostics as those used to identify the multiple laboratory steps in testing for apolipoprotein epsilon (APOE) alleles or mutations in the presenilin genes. Some codes would have been used more than once in an individual test.

APOE

83891: Molecular diagnostics; isolation or extraction of highly purified nucleic acid, each nucleic acid type

83892: enzymatic digestion, each enzyme treatment

83894: separation by gel electrophoresis (e.g., agarose, polyacrylamide), each nucleic acid preparation

83898: amplification, target, each nucleic acid sequence

83912: interpretation and report

Mutations of presenilin genes

83891: Molecular diagnostics; isolation or extraction of highly purified nucleic acid, each nucleic acid type

83898: amplification, target, each nucleic acid sequence

83902: reverse transcription

83904: mutation identification by sequencing, single segment, each segment

83912: interpretation and report

Prior to 2013, there was also a CPT genetic testing code modifier that is specific to APOE and should be appended to the above codes for APOE testing – 7A - APOE, commonly called apolipoprotein E (cardiovascular disease or Alzheimer’s disease).

A HCPCS code specific to APOE epsilon 4 allele testing became effective July 1, 2003 –

S3852: DNA analysis for APOE epsilon 4 allele for susceptibility to Alzheimer’s disease.

Effective 1/1/07, there is also a HCPCS code specific to testing for presenilin-1 mutations:

S3855: Genetic testing for detection of mutations in the presenilin-1 gene

Policy/
Coverage:

Effective February 2022

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Genetic testing for the diagnosis or risk assessment of Alzheimer's disease; including but not limited to testing for the apolipoprotein E epsilon 4 allele, presenilin genes, amyloid precursor gene, or TREM2 does not meet 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 the diagnosis or risk assessment of Alzheimer's disease; including but not limited to testing for the apolipoprotein E epsilon 4 allele, presenilin genes, amyloid precursor gene or TREM2 is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Genetic testing to guide initiation or management of a U.S. Food and Drug Administration-approved amyloid-beta targeting therapy (e.g., aducanumab) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For members with contracts without primary coverage criteria, genetic testing to guide initiation or management of a U.S. Food and Drug Administration-approved amyloid-beta targeting therapy (e.g., aducanumab) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective Prior to February 2022

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Effective, July 1998 – August 2013

Genetic testing for the diagnosis or risk assessment of Alzheimer's disease; including but not limited to testing for the apolipoprotein E epsilon 4 allele, presenilin genes or amyloid precursor gene, does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.

For contracts without Primary Coverage Criteria, genetic testing for the diagnosis or risk assessment of Alzheimer's disease; including but not limited to testing for the apolipoprotein E epsilon 4 allele, presenilin genes or amyloid precursor gene is investigational. Investigational services are an exclusion in the member certificate of coverage.

Rationale:

A 1999 TEC Assessment on APOE genotyping offered the following conclusions and observations:

Several consensus statements regarding APOE genotyping have been published, which conclude that APOE genotyping in asymptomatic patients, as a technique of risk assessment, is not recommended. Statements regarding its use as a diagnostic test in symptomatic patients are mixed. In 1998, the American College of Medical Genetics/American Society of Human Genetic Working Group on APOE and Alzheimer’s Disease stated, “Studies to date indicate that the APOE genotype alone does not provide sufficient sensitivity or specificity to allow genotyping to be used as a diagnostic test. In 1997, a national study group supported by the National Institutes of Health (NIH) and composed of AD geneticists, policy experts, and ethicists, stated “The use of APOE genetic testing as a diagnostic adjunct in patients already presenting with dementia may prove useful but it remains under investigation.” In contrast, a report by the Working Group on Molecular and Biochemical Markers of Alzheimer’s Disease stated that APOE genotyping can add “confidence to the clinical diagnosis of AD…” but “...the sensitivity and specificity of the epsilon 4 allele alone are low, indicating that this measure cannot be used as the sole diagnostic test for AD.”
Considering the published data regarding the sensitivity and specificity of APOE genotyping, the TEC Assessment concluded that the addition of APOE genetic testing does not improve the sensitivity of clinical criteria and only marginally improves the specificity of clinical criteria for the diagnosis of AD. In addition, APOE genetic testing would not alter recommended diagnostic testing for other treatable causes of dementia.

Subsequent to the TEC Assessment advances in genetic understanding of AD have been considerable with associations between late-onset AD and more than 20 non-APOE genes suggested (Bertram, 2007). However, relevant literature through November 2008 does not provide evidence supporting clinical utility or benefit from genetic testing for AD.

Tsuang et al prospectively evaluated APOE testing for AD diagnosis in a community-based case series of older patients presenting with memory complaints but no previous diagnosis of dementia. Of 1,028 potential cases, 970 were evaluated; of these, 425 died and 132 were autopsied; of the 132, 71% were confirmed to have AD. The sensitivity and specificity of APOE epsilon 4 alone were poor, yielding positive and negative predictive values of 83% and 41% compared to 81% and 56% for clinical diagnosis alone. Using a criterion of positive clinical diagnosis or APOE epsilon 4 resulted in positive and negative predictive values of 79% and 70%. A criterion of positive clinical diagnosis and APOE epsilon 4 improved positive predictive value to 88% but at the expense of negative predictive value (40%). Eleven individuals had an epsilon 4 allele without neuropathologically confirmed AD. While APOE epsilon 4 increases disease susceptibility, it is associated with only approximately 50% of Alzheimer’s cases.

The effect of APOE genotype on response to AD therapy has also been examined. The USA-1 Study group found APOE genotype did not predict therapeutic response (Raskind et al, 2000). Rigaud et al followed 117 individuals with AD over 36 weeks in an open-label trial of donepezil; 80 subjects completed the trial. They found no statistically significant effect of APOE genotype on change in cognition (assessed by ADAS-Cog). However the study was not designed to examine predictive therapeutic response and there were baseline cognitive differences according to APOE genotype. There is currently insufficient information to make treatment decisions based on APOE subtype.

The REVEAL study was designed to examine consequences of AD risk assessment by APOE genotyping (Chao et al, 2008). Of 289 eligible participants 162 were randomized (mean age, 52.8 years; 73% female; average education, 16.7 years) to either risk assessment based on APOE testing and family history (n=111) or family history alone (n=51). During a 1-year follow-up, those undergoing APOE testing with a high-risk genotype were more likely than low-risk or ungenotyped individuals to take more vitamins change diet or change exercise behaviors. While in this well-educated sample of women there were some behavior changes, none can be considered a meaningful surrogate endpoint.

Genetic testing for PSEN1 detects 30%–60% of familial early-onset AD. A number of mutations have been reported scattered throughout the PSEN1 gene, requiring sequencing of the entire gene when the first affected member of a family with an autosomal dominant pattern of AD inheritance is tested. Mutations in APP and PSEN2 genes account for only a small fraction of cases; it is likely that other causative genes will be discovered.

In 1998, the Alzheimer Disease Working Group of the Stanford Program in Genomics, Ethics, and Society suggested that “predictive or diagnostic genetic testing for highly penetrant mutations (e.g., APP, PSEN1, PSEN2) may be appropriate for individuals from families with a clear autosomal dominant pattern of inheritance, particularly those with a family history of early onset of symptoms.” Such families generally have 3 affected members in 2 generations. In the case of diagnostic testing of clearly symptomatic individuals, testing would do little to change diagnostic confidence; however, it might assist excluding other causes of early-onset dementia, as potentially treatable contributory causes would still require exploring. In cases of early detection of questionably symptomatic individuals (i.e., those with mild cognitive impairment, mutation identification might secure a diagnosis and lead to early treatment. The possibility that earlier diagnosis might lead to improved outcomes, while plausible, is not based on current evidence. Pharmacologic interventions for mild cognitive impairment have not demonstrated benefit in reducing progression to AD (Raschetti et al, 2007).

The nearly complete penetrance of a PSEN1 disease-associated mutation would change the probability of developing AD in an unaffected family member from 50% to either 0% or 100%. Testing for PSEN1 mutations is not useful in predicting age of onset (although it is usually similar to age of onset in affected family members), severity, type of symptoms, or rate of progression in asymptomatic individuals. However, identification of asymptomatic, young adult carriers could allow for reproductive planning. Identification of both symptomatic and asymptomatic carriers could also allow for other types of life planning in advance of incapacitating disease.

It is not uncommon to discover previously unreported PSEN1 mutations in an individual, and without additional family information these may reflect mutations not associated with disease, or new causative mutations restricted to a single family (private mutation). Thus, interpretation of test results of asymptomatic individuals without identification of a mutation in affected family members may be inconclusive in a significant proportion of patients. Should testing be undertaken, affected family members should be tested first or in conjunction with unaffected family members. When no mutation can be identified in affected family members with a clear autosomal dominant pattern of disease inheritance, the family can be referred to a research program for additional study. Any testing should be performed only in the context of adequate pre- and post-test genetic counseling. Finally, it should be noted that pharmacologic therapy for Alzheimer’s disease should be based on the patient’s symptomatology rather than testing results.

Guidelines

American Academy of Neurology

Routine use of APOE genotyping in patients with suspected AD is not recommended at this time (Guideline).
There are no other genetic markers recommended for routine use in the diagnosis of AD (Guideline).

European Federation of Neurological Sciences (EFNS)

Recommendations: genetic testing

Screening for known pathogenic mutations can be undertaken in patients with appropriate phenotype or a family history of an autosomal dominant dementia. This should only be undertaken in specialist centers with appropriate counseling of the patient and family caregivers, and with consent (Good Practice Point*).

Presymptomatic testing may be performed in adults where there is a clear family history, and when there is a known mutation in an affected individual to ensure that a negative result is clinically significant. It is recommended that the Huntington’s disease protocol is followed (Good Practice Point*).

Routine Apo E genotyping is not recommended (Level B*).

*EFNS Evidence Ratings

Level B rating (established as probably useful/predictive or not useful/predictive) requires at least one convincing class II study or overwhelming class III evidence.

Good Practice Point: “…clinical areas for which no high class evidence is available or likely to become available in the near future. In such cases – which should be marked as exceptional – it may be possible to recommend best practice based on the experience of the guideline development group…. ‘good practice points’ should not imply that they are based on more than class IV evidence which implies large clinical uncertainty.’

Third Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD)

Predictive genetic testing for asymptomatic “at risk” individuals with an apparent autosomal dominant inheritance, and a family-specific mutation has been identified:

With appropriate pre-and post-testing counseling, predictive genetic testing (PGT) can be offered to “at risk” individuals (Grade B, Level 2**). Examples:

First-degree relatives of an affected individual with the mutation (e.g., children and siblings);
First cousins of an affected individual if the common ancestors (parents who were siblings) died before the average age of onset of dementia in the family;
Nieces and nephews of affected individuals whose parent (sibling of the affected individual) died well before the average age of onset of dementia in the family;
PGT in minors is not generally offered in Canada, but occasionally may be considered on a case-by-case basis by the relevant medical ethics committee(s);
Individuals who are not “at risk” for the inherited disease do not require testing.

In young persons (60 years or younger) presenting with an early-onset dementia, it is sometimes worthwhile to test for the most common mutations based on the “best estimate” diagnosis (e.g., in early- onset AD, one might test for the most common mutations in PS1, APP). (Grade B, Level 2**) If a mutation is identified, it would have direct implications for offspring of the individual (if a de novo mutation is assumed). Conversely, it would also be important to test other family members such as parents and siblings for possible non-penetrance of a mutation.

Genetic screening with APOE genotype in asymptomatic individuals in the general population is not recommended because of the low specificity and sensitivity. (Grade E, Level 2**)

Genetic testing with APOE genotype is not recommended for the purpose of diagnosing AD because the positive and negative predictive values are low.

(Grade E, Level 2**)

**CCCDTD Evidence Ratings

Grade (B) There is fair evidence to support this maneuver.

Grade (E) There is good evidence to recommend against this procedure.

Level 2: (1) Evidence obtained from well-designed controlled trial without randomization, or (2) Evidence obtained from well-designed cohort or case control analytic studies, preferably from more than one center, or (3) Evidence obtained from comparisons between times or places with or without intervention. Dramatic results in uncontrolled experiments are included in this category.

2010 Update

A MEDLINE search through December 2009 identified no new relevant evidence or guideline statements that would prompt a change in the coverage statement.

Summary

Evidence that testing for AD genetic markers can improve health outcomes is lacking. Guidelines are consistent. Based on this update, the policy statement is unchanged.

2012 Update

A search of the MEDLINE database through August 2012 did not reveal any new information that would prompt a change in the coverage statement.

2013 Update

The policy is being updated with a literature search using the MEDLINE database through August 2013. The following is a summary of the key identified literature.

Susceptibility Testing at the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Gene

Jonsson et al. evaluated 3,550 subjects with AD and found a genome-wide association with only one marker, the T allele of rs75932628 (excluding the ApoE locus and the A673T variant in APP11) (Jonsson, 2013, 2013; Guerreiro, 2013). The frequency of rs75932628 (TREM2) was then tested in a general population of 110,050 Icelanders of all ages and found to confer a risk of AD of 0.63% (odds ratio [OR]: 2.26; 95% confidence interval [CI]: 1.71 to 2.98; p=1.13×10(−8)). In the control population of 8,888 patients 85 years of age or older without a diagnosis of AD, TREM2 frequency was 0.46% (OR: 2.92; 95% CI: 2.09 to 4.09; p=3.42×10(−10)). In 1,236 cognitively intact controls age 85 or older, the frequency of TREM2 decreased even further to 0.31% (OR: 4.66, (95% CI: 2.38 to 9.14; p=7.39×10(−6)). The decrease in TREM2 frequency in elderly patients who are cognitively intact supports the findings associating TREM2 with increasing risk of AD.

Guerriero and colleagues also found a strong association of the R47H TREM2 variant with AD (p=0,001) (Guerriero, 2013). Using 3 imputed data sets of genome-wide association AD studies, a meta-analysis found a significant association with the variant and disease (p=0.002). The authors further reported direct genotyping of R47H in 1,994 AD patients, and 4,062 controls found a highly significant association with AD (OR: 5.05; 95% CI: 2.77 to 9.16; p=9.0×10(−9)).

No clinical trials were identified that address how the use of the TREM2 rs75932628-T variant might be incorporated into clinical practice.

Ongoing Clinical Trials

A search of online site clinicaltrials.gov on August 24, 2013 identified a number of clinical trials on APOE testing and the clinical manifestations of AD among patients with APOE epsilon 4. No studies on TREM2 were identified.

Practice Guidelines and Position Statements

Fourth Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD)

The 2012 Canadian Consensus Conference on Dementia was held in May 2012 to update the third consensus guidelines referenced below. Previous recommendations were endorsed if there weren’t any changes in the literature. Full articles written by the CCCDTD workgroups providing complete background information for the consensus conference are available online at: http://www.healthplexus.net/article/2012-canadian-consensus-conference-dementia.

A summary of consensus recommendations from the CCCDTD4 was published by Gauthier and colleagues in 2012 (Gauthier, 2012). It is noted in the summary that: “Despite a large number of important advances, the CCCDTD4 concluded that fundamental changes in dementia diagnosis and management have not yet arrived.” The 2012 CCCDTD4 summary recommends:

“Testing and longitudinal follow-up of asymptomatic individuals or patients with subjective cognitive impairments not meeting MCI [mild cognitive impairment] criteria, or at-risk individuals (e.g., gene mutation carriers, family history of AD, ApoE epsilon 4) should be restricted to research.”

Summary

Many genes, including APOE and TREM2, have been associated with late-onset Alzheimer’s disease (AD). However, the sensitivity and specificity of these genes is low or unknown for diagnosing AD, and genetic testing has not been shown to add value to the diagnosis of AD made clinically. For individuals with early-onset AD, mutations in the PSEN1 and APP genes are found in a substantial number of patients. However, there is no direct or indirect evidence to establish that clinical outcomes are improved as a result of genetic testing for these mutations.

Therefore, the current evidence does not support genetic testing for AD. The lack of effective methods to prevent the onset of AD or to target AD treatments based on genetic characteristics limits the clinical benefit for such genetic testing. The low sensitivity and specificity of APOE testing for indicating which individuals will progress to AD or as a diagnostic tool, as well as the high likelihood that other genetic findings may affect progression, lend further support to this conclusion. The association of TREM2 and AD has only recently been identified and its clinical utility is unknown.

The coverage statement has been revised to address testing for the TREM2 gene.

2014 Update

A literature search was conducted using the MEDLINE database through August 2014. There was no new literature identified that would prompt a change in the coverage statement.

2015 Update

A literature search conducted using the MEDLINE database through August 2015 did not reveal any new information that would prompt a change in the coverage statement.

2016 Update

A literature search conducted through April 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

Analytic Validity

There is a lack of published evidence on the analytic validity of genetic testing for late-onset familial AD. Analytic validity is expected to be high when current methods of sequencing are performed, ie, Sanger sequencing and/or next-generation sequencing.

Clinical Validity

Naj and colleagues published a genome-wide association study of multiple genetic loci in late-onset AD (Nai, 2014). Genetic data from 9162 white race participants with AD from the Alzheimer Disease Genetics Consortium were assessed for polymorphisms at 10 loci significantly associated with risk of late-onset AD. Analysis confirmed the association of APOE with an earlier age of onset and found significant associations for CR1, BIN1, and PICALM. APOE contributed 3.7% of the variation in age of onset and the other 9 loci combined contributed 2.2% of the variation. Each additional copy of the APOE Ɛ4 allele reduced age of onset by 2.45 years.

Susceptibility testing at the Apolipoprotein E Gene.

The association of the APOE e4 allele with AD is significant; however, APOE genotyping does not have high specificity or sensitivity and is of little value in the predictive testing of asymptomatic individuals(Bird, 2015).

The American College of Medical Genetics and Genomics has concluded that APOE genotyping for AD risk prediction has limited clinical utility and poor predictive value (ACMCG, 2015)

There is a lack of interventions that can delay or mitigate late-onset AD. There is no evidence that early intervention for asymptomatic mutation carriers can delay or mitigate future disease. There are many actions that patients may take following knowledge of a mutation. Changes in lifestyle factors such as diet and exercise, and/or incorporation of “brain training” exercises may occur, but there is no evidence that these types of intervention impact clinical disease.

Reproductive planning may be affected as well, but it is unclear whether outcomes would be improved. Testing for a disease that will not manifest for many decades includes uncertainty about whether treatments for AD will be available at that future time point. This leads to uncertainties about whether reproductive interventions now will reduce the future incidence or severity of disease.

Summary – Genetic Testing for Late Onset Alzheimer’s disease

Both the APOE gene and the triggering receptor gene have shown strong statistical associations with AD, thus demonstrating some degree of clinical validity. However, the clinical sensitivity and specificity of APOE Ɛ4 is poor, and there is a lack of evidence on the clinical sensitivity and specificity of the triggering receptor gene.

No studies were identified that address how the use of the APOE or TREM2 variant might be incorporated into clinical practice. It is not clear how management of asymptomatic patients with these genes would change in a way that improves outcomes. Therefore, clinical utility has not been demonstrated for these tests.

The potential clinical utility of testing is in early identification of asymptomatic patients who are at risk for developing early-onset AD. Genetic testing will in most cases lead to better risk stratification, defining patients who will develop the disease from those who will not. If early identification of patients at risk leads to interventions to delay or mitigate clinical disease, then clinical utility will be established. Identification of asymptomatic, young adult carriers could impact reproductive planning. And clinical utility may be demonstrated if testing leads to informed reproductive planning that improves outcomes. Alternatively, clinical utility could be demonstrated if knowledge of mutation status leads to beneficial changes in psychological outcomes.

There is no evidence that early intervention for asymptomatic mutation carriers can delay or mitigate future disease. There are many actions that patients may take following knowledge of a mutation: changes in lifestyle factors such as diet and exercise, and incorporation of “brain training” exercises may occur, but there is no evidence that these types of intervention impact clinical disease.

Reproductive planning may be affected as well, but it is unclear whether outcomes would be improved. Testing for a disease that will not manifest for more than several decades includes uncertainty about whether treatments for AD will be available. This leads to uncertainties about whether reproductive interventions now will reduce the future incidence or severity of disease.

A substantial percentage of patients with early-onset AD will have a pathogenic mutation, however up to 40% will test negative. Therefore, the clinical sensitivity is suboptimal. The mutations are also found in some individuals who do not have a family history of familial AD, but the false positive rate and clinical specificity is not well-defined.

For those from families with early-onset, familial AD, there are currently no known preventive measures or treatments that can mitigate the effect of the disease. It is not clear how management of asymptomatic patients with these genes would change in a way that improves outcomes. Therefore, clinical utility has not been demonstrated for these tests.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed below:

Ongoing

(NCT00064870) National Cell Repository for Alzheimer’s Disease (NCRAD); planned enrollment 3000; completion date June 2016.

(NCT02198586) Apoe Impact Study on Brain Structure and Function, in a Population 45 to 75 Years Old; planned enrollment 700; completion date December 2016.

(NCT01760005) A Phase II/III Randomized, Double-Blind, Placebo-Controlled Multi-Center Study of 2 Potential Disease Modifying Therapies in Individuals at Risk for and With Dominantly Inherited Alzheimer's Disease; planned enrollment 210; completion date December 2019.

(NCT02564692) Alzheimer’s Prevention Registry GeneMatch Program; planned enrollment 500,000; completion date December 2030.

The American College of Medical Genetics and Genomics

The American College of Medical Genetics and Genomics lists genetic testing for APOE alleles as one of 5 recommendations in the Choosing Wisely initiative (ACMGG, 2015). The recommendation is “Don’t order APOE genetic testing as a predictive test for Alzheimer disease.” The stated rationale is that APOE is a susceptibility gene for later-onset Alzheimer disease (AD), the most common cause of dementia. These recommendations stated that “The presence of Ɛ4 allele is neither necessary nor sufficient to cause AD. The relative risk conferred by the Ɛ4 allele is confounded by the presence of other risk alleles, gender, environment and possibly ethnicity, and the APOE genotyping for AD risk prediction has limited clinical utility and poor predictive value.”

2017 Update

A literature search conducted through August 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

Clinical Validity

Many studies have examined the association between the apolipoprotein ε4 allele (APOE*E4) and AD. The Rotterdam and Framingham studies are both examples of large observational studies demonstrating the association. The Rotterdam Study was a prospective cohort study in the city of Rotterdam, the Netherlands, with main objectives of investigating risk factors of cardiovascular, neurologic, ophthalmologic, and endocrine diseases in the elderly (Slooter, 2011). In a sample of 6852 participants, carriers of a single ε4 allele had a relative risk (RR) of developing AD approximately double that of ε3/ε3 carriers. Carriers of the two ε4 alleles had a relative risk of developing dementia approximately 8 times that of ε3/ε3 carriers. The Framingham Heart Study was a longitudinal cohort study initiated in 1948 in Framingham, Massachusetts, to identify common risk factors for cardiovascular disease (Myers, 1996).

Lambert and colleagues published a large meta-analysis of GWAS of susceptibility loci for late-onset AD in 17,008 AD cases and 37,154 controls of European ancestry (Lambert, 2013). Nineteen loci had genome-wide significance in addition to the APOE locus. The researchers confirmed several genes already reported to be associated with AD (ABCA7, BIN1, CD33, CLU, CR1, CD2AP, EPHA1, MS4A6A–MS4A4E, PICALM). New loci located included HLA-DRB5–HLA-DRB1, PTK2B, SORL1, and SLC24A4-RIN3.

Clinical Utility

The Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) study was designed to examine the consequences of AD risk assessment by APOE genotyping (Chao, 2008). Of 289 eligible participants, 162 were randomized (mean age, 52.8 years; 73% female) to risk assessment based on APOE testing plus family history (n=111) or family history alone (n=51). During a 1-year follow-up, those undergoing APOE testing with a high-risk genotype were more likely than low-risk or untested individuals to take more vitamins (40% vs 24% and 30%), change diet (20% vs 11% and 7%), or change exercise behaviors (8% vs 4% and 5%) , all respectively. There is insufficient evidence to conclude that these short-term behavioral changes would alter clinical outcomes. Green and colleagues examined anxiety, depression, and test-related distress at 6 weeks, 6 months, and 1 year in the 162 participants randomized in REVEAL (Green, 2009). There were no significant differences between the group that received the results of APOE testing and the group that did not in changes in anxiety or depression overall or in the subgroup of participants with the APOE*E4 allele. However, the ɛ4 negative participants had significantly lower test-related distress than ɛ4 positive participants (p=0.01).

Christensen and colleagues examined disclosing associations between APOE genotype and AD risk alone versus AD and coronary artery disease (CAD) risk in an equivalence trial from the REVEAL group (Christensen, 2016). Two hundred ninety participants were randomized to receive AD risk disclosure alone or AD+CAD risk disclosure. The 257 participants who received their genetic information were included in analyses. Mean anxiety, depression, and test-related distress scores were below cutoffs for mood disorders at all time points in both disclosure groups and were similar to baseline levels. At the 12-month follow-up, both anxiety (measured by the Beck Anxiety Index) and depression (measured by the Center for Epidemiologic Studies Depression Scale) fell within the equivalence margin indicating no difference between disclosure groups. Among participants with an ε4 allele, distress (measured by Impact of Event Scale) was lower at 12 months in AD+CAD group than in the AD-only group (difference, -4.8; 95% CI, -8.6 to -1.0; p=0.031). AD+CAD participants also reported more health behavior changes than AD-alone participants, regardless of APOE genotype.

There is a lack of interventions that can delay or mitigate late-onset AD. There is no evidence that early intervention for asymptomatic disease-associated variant carriers can delay or mitigate future disease. There are many actions patients may take following knowledge of a disease-associated variant. Changes in lifestyle factors (eg, diet, exercise) and/or incorporation of “brain training” exercises can be made, but there is no evidence that these interventions impact clinical disease.

Analytic Validity

There is a lack of published evidence on the analytic validity of genetic testing for early-onset familial AD. Analytic validity is expected to be high when current methods of sequencing are performed (ie, Sanger sequencing and/or NGS).

2018 Update

Annual policy review completed with a literature search using the MEDLINE database through September 2018. No new literature was identified that would prompt a change in the coverage statement.

2019 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2019. No new literature was identified that would prompt a change in the coverage statement.

2020 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Genetic yields may vary by population. Giau et al reported on 200 patients with clinically diagnosed early-onset AD from Thailand, Malaysia, the Philippines, and Korea who were genetically screened between 2009 and 2018 (Giau, 2019). Thirty-two (16%) patients carried pathogenic APP (8/32 [25%]), PSEN1 (19/32 [59%]), or PSEN2 (5/32 [16%]) variants. However, this analysis included possible and probable pathogenic variants in addition to those classified as definite. Overall, approximately 84% (p=0.01) of autosomal dominant pedigrees in the tested Asian population were genetically unexplained.

A study by Cochran et al confirmed a high diagnostic yield in early-onset or atypical dementia. Fifty percent (16/32) of patients tested harbored one or more genetic variants capable of explaining symptoms, including variants in APP. Nine of 32 patients (28%) had a variant defined as pathogenic or likely pathogenic whereas 6 had one or more variants with moderate penetrance. The authors noted this supports a potential oligogenic model for early-onset dementia (Cochran, 2019).

2021 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

The APOE epsilon 4 allele is strongly associated with the incidence of and age at onset of AD; many other genes have shown statistical associations with AD incidence and onset, thus demonstrating some degree of clinical validity. However, the clinical sensitivity and specificity of the APOE epsilon 4 allele is poor, and there is a lack of evidence on the clinical sensitivity and specificity of other genes (Elias-Sonnenschein, 2011).

2022 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Exploratory analyses of pooled safety data from 2 phase 3 trials of the FDA-approved amyloid-beta targeting therapy aducanumab indicate that APOE 4 carrier status is associated with a higher incidence of amyloid-related imaging abnormalities (ARIA) (Biogen, 2021; Burkett, 2021). Specifically, the incidence of ARIA-edema was 42% versus 20%, in APOE 4 carriers and non-carriers, respectively. The overall incidence of ARIA was 35% in the treatment arm compared to 3% in placebo. The clinical effects of ARIA range from asymptomatic to severe. Although the majority of patients were asymptomatic or had symptoms such as headache, confusion, or dizziness that resolved with temporary stoppage of the drug, 6.2% of participants receiving the high dose of aducanumab discontinued the drug due to ARIA.

The majority of ARIA-edema radiographic events occurred early in treatment (within the first 8 doses), although ARIA can occur at any time. Among patients treated with a planned dose of aducanumab 10 mg/kg who had ARIA-edema, the maximum radiographic severity was mild in 30%, moderate in 58%, and severe in 13% of patients (refer to prescribing label for classification of severity of ARIA). Resolution occurred in 68% of ARIA-edema patients by 12 weeks, 91% by 20 weeks, and 98% overall after detection. Ten percent of all patients who received aducanumab 10 mg/kg had more than 1 episode of ARIA-edema. Radiographic severity and symptomatic status were similar for APOE 4 carriers and non-carriers.

Aducanumab dosing management decisions in the trials were based on clinical symptom severity and ARIA severity on MRI (Burkett, 2021). After radiographic resolution of ARIA-edema or stabilization of ARIA-hemorrhage and resolution of symptoms (if present), participants could resume dosing at the same dose and titration schedule.

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Exploratory analyses of pooled safety data from 2 phase 3 trials of the FDA-approved amyloid-beta targeting therapy aducanumab indicate that APOE ε4 carrier status is associated with a higher incidence of amyloid-related imaging abnormalities (ARIA) (Biogen, 2022; Burkett, 2021; Salloway, 2022). Specifically, the incidence of ARIA-edema was 43 % versus 20%, in APOE ε4 carriers and non-carriers receiving a 10 mg/kg dose of aducanumab, respectively. The overall incidence of any ARIA ranged from 36-41% in the treatment group compared to 10.3% in the placebo group. The clinical effects of ARIA range from asymptomatic to severe. Although the majority of patients were asymptomatic or had symptoms such as headache, confusion, or dizziness that resolved with temporary stoppage of the drug, 6.2% of participants receiving the high dose of aducanumab discontinued the drug due to ARIA compared to 0.6% in the placebo arm.

CPT/HCPCS:

0289U	Neurology (Alzheimer disease), mRNA, gene expression profiling by RNA sequencing of 24 genes, whole blood, algorithm reported as predictive risk score
0358U	Neurology (mild cognitive impairment), analysis of ß-amyloid 1-42 and 1-40, chemiluminescence enzyme immunoassay, cerebral spinal fluid, reported as positive, likely positive, or negative
81401	Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) ABCC8 (ATP-binding cassette, sub-family C [CFTR/MRP], member 8) (eg, familial hyperinsulinism), common variants (eg, c.3898-9G>A [c.3992-9G>A], F1388del) ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) (eg, acquired imatinib resistance), T315I variant ACADM (acyl-CoA dehydrogenase, C-4 to C-12 straight chain, MCAD) (eg, medium chain acyl dehydrogenase deficiency), commons variants (eg, K304E, Y42H) ADRB2 (adrenergic beta-2 receptor surface) (eg, drug metabolism), common variants (eg, G16R, Q27E) APOB (apolipoprotein B) (eg, familial hypercholesterolemia type B), common variants (eg, R3500Q, R3500W) APOE (apolipoprotein E) (eg, hyperlipoproteinemia type III, cardiovascular disease, Alzheimer disease), common variants (eg, 2, 3, *4) CBFB/MYH11 (inv(16)) (eg, acute myeloid leukemia), qualitative, and quantitative, if performed CBS (cystathionine-beta-synthase) (eg, homocystinuria, cystathionine beta-synthase deficiency), common variants (eg, I278T, G307S) CFH/ARMS2 (complement factor H/age-related maculopathy susceptibility 2) (eg, macular degeneration), common variants (eg, Y402H [CFH], A69S [ARMS2]) DEK/NUP214 (t(6;9)) (eg, acute myeloid leukemia), translocation analysis, qualitative, and quantitative, if performed E2A/PBX1 (t(1;19)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed EML4/ALK (inv(2)) (eg, non-small cell lung cancer), translocation or inversion analysis ETV6/RUNX1 (t(12;21)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed EWSR1/ATF1 (t(12;22)) (eg, clear cell sarcoma), translocation analysis, qualitative, and quantitative, if performed EWSR1/ERG (t(21;22)) (eg, Ewing sarcoma/peripheral neuroectodermal tumor), translocation analysis, qualitative, and quantitative, if performed EWSR1/FLI1 (t(11;22)) (eg, Ewing sarcoma/peripheral neuroectodermal tumor), translocation analysis, qualitative, and quantitative, if performed EWSR1/WT1 (t(11;22)) (eg, desmoplastic small round cell tumor), translocation analysis, qualitative, and quantitative, if performed F11 (coagulation factor XI) (eg, coagulation disorder), common variants (eg, E117X [Type II], F283L [Type III], IVS14del14, and IVS14+1G>A [Type I]) FGFR3 (fibroblast growth factor receptor 3) (eg, achondroplasia, hypochondroplasia), common variants (eg, 1138G>A, 1138G>C, 1620C>A, 1620C>G) FIP1L1/PDGFRA (del[4q12]) (eg, imatinib-sensitive chronic eosinophilic leukemia), qualitative, and quantitative, if performed FLG (filaggrin) (eg, ichthyosis vulgaris), common variants (eg, R501X, 2282del4, R2447X, S3247X, 3702delG) FOXO1/PAX3 (t(2;13)) (eg, alveolar rhabdomyosarcoma), translocation analysis, qualitative, and quantitative, if performed FOXO1/PAX7 (t(1;13)) (eg, alveolar rhabdomyosarcoma), translocation analysis, qualitative, and quantitative, if performed FUS/DDIT3 (t(12;16)) (eg, myxoid liposarcoma), translocation analysis, qualitative, and quantitative, if performed GALC (galactosylceramidase) (eg, Krabbe disease), common variants (eg, c.857G>A, 30-kb deletion) GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), common variants (eg, Q188R, S135L, K285N, T138M, L195P, Y209C, IVS2-2A>G, P171S, del5kb, N314D, L218L/N314D) H19 (imprinted maternally expressed transcript [non-protein coding]) (eg, Beckwith-Wiedemann syndrome), methylation analysis IGH@/BCL2 (t(14;18)) (eg, follicular lymphoma), translocation analysis; single breakpoint (eg, major breakpoint region [MBR] or minor cluster region [mcr]), qualitative or quantitative (When both MBR and mcr breakpoints are performed, use 81278) KCNQ1OT1 (KCNQ1 overlapping transcript 1 [non-protein coding]) (eg, Beckwith-Wiedemann syndrome), methylation analysis LINC00518 (long intergenic non-protein coding RNA 518) (eg, melanoma), expression analysis LRRK2 (leucine-rich repeat kinase 2) (eg, Parkinson disease), common variants (eg, R1441G, G2019S, I2020T) MED12 (mediator complex subunit 12) (eg, FG syndrome type 1, Lujan syndrome), common variants (eg, R961W, N1007S) MEG3/DLK1 (maternally expressed 3 [non-protein coding]/delta-like 1 homolog [Drosophila]) (eg, intrauterine growth retardation), methylation analysis MLL/AFF1 (t(4;11)) (eg, acute lymphoblastic leukemia), translocation analysis, qualitative, and quantitative, if performed MLL/MLLT3 (t(9;11)) (eg, acute myeloid leukemia), translocation analysis, qualitative, and quantitative, if performed MT-ATP6 (mitochondrially encoded ATP synthase 6) (eg, neuropathy with ataxia and retinitis pigmentosa [NARP], Leigh syndrome), common variants (eg, m.8993T>G, m.8993T>C) MT-ND4, MT-ND6 (mitochondrially encoded NADH dehydrogenase 4, mitochondrially encoded NADH dehydrogenase 6) (eg, Leber hereditary optic neuropathy [LHON]), common variants (eg, m.11778G>A, m.3460G>A, m.14484T>C) MT-ND5 (mitochondrially encoded tRNA leucine 1 [UUA/G], mitochondrially encoded NADH dehydrogenase 5) (eg, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes [MELAS]), common variants (eg, m.3243A>G, m.3271T>C, m.3252A>G, m.13513G>A) MT-RNR1 (mitochondrially encoded 12S RNA) (eg, nonsyndromic hearing loss), common variants (eg, m.1555A>G, m.1494C>T) MT-TK (mitochondrially encoded tRNA lysine) (eg, myoclonic epilepsy with ragged-red fibers [MERRF]), common variants (eg, m.8344A>G, m.8356T>C) MT-TL1 (mitochondrially encoded tRNA leucine 1 [UUA/G]) (eg, diabetes and hearing loss), common variants (eg, m.3243A>G, m.14709 T>C) MT-TL1 MT-TS1, MT-RNR1 (mitochondrially encoded tRNA serine 1 [UCN], mitochondrially encoded 12S RNA) (eg, nonsyndromic sensorineural deafness [including aminoglycoside-induced nonsyndromic deafness]), common variants (eg, m.7445A>G, m.1555A>G) MUTYH (mutY homolog [E. coli]) (eg, MYH-associated polyposis), common variants (eg, Y165C, G382D) NOD2 (nucleotide-binding oligomerization domain containing 2) (eg, Crohn's disease, Blau syndrome), common variants (eg, SNP 8, SNP 12, SNP 13) NPM1/ALK (t(2;5)) (eg, anaplastic large cell lymphoma), translocation analysis PAX8/PPARG (t(2;3) (q13;p25)) (eg, follicular thyroid carcinoma), translocation analysis PRAME (preferentially expressed antigen in melanoma) (eg, melanoma), expression analysis PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), common variants (eg, N29I, A16V, R122H) PYGM (phosphorylase, glycogen, muscle) (eg, glycogen storage disease type V, McArdle disease), common variants (eg, R50X, G205S) RUNX1/RUNX1T1 (t(8;21)) (eg, acute myeloid leukemia) translocation analysis, qualitative, and quantitative, if performed SS18/SSX1 (t(X;18)) (eg, synovial sarcoma), translocation analysis, qualitative, and quantitative, if performed SS18/SSX2 (t(X;18)) (eg, synovial sarcoma), translocation analysis, qualitative, and quantitative, if performed VWF (von Willebrand factor) (eg, von Willebrand disease type 2N), common variants (eg, T791M, R816W, R854Q)
81405	Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) Cytogenomic constitutional targeted microarray analysis of chromosome 22q13 by interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities (When performing cytogenomic [genome-wide] analysis, for constitutional chromosomal abnormalities. See 81228, 81229, 81349)
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) ACADVL (acyl-CoA dehydrogenase, very long chain) (eg, very long chain acyl-coenzyme A dehydrogenase deficiency), full gene sequence ACTN4 (actinin, alpha 4) (eg, focal segmental glomerulosclerosis), full gene sequence AFG3L2 (AFG3 ATPase family gene 3-like 2 [S. cerevisiae]) (eg, spinocerebellar ataxia), full gene sequence AIRE (autoimmune regulator) (eg, autoimmune polyendocrinopathy syndrome type 1), full gene sequence ALDH7A1 (aldehyde dehydrogenase 7 family, member A1) (eg, pyridoxine-dependent epilepsy), full gene sequence ANO5 (anoctamin 5) (eg, limb-girdle muscular dystrophy), full gene sequence ANOS1 (anosmin-1) (eg, Kallmann syndrome 1), full gene sequence APP (amyloid beta [A4] precursor protein) (eg, Alzheimer disease), full gene sequence ASS1 (argininosuccinate synthase 1) (eg, citrullinemia type I), full gene sequence ATL1 (atlastin GTPase 1) (eg, spastic paraplegia), full gene sequence ATP1A2 (ATPase, Na+/K+ transporting, alpha 2 polypeptide) (eg, familial hemiplegic migraine), full gene sequence ATP7B (ATPase, Cu++ transporting, beta polypeptide) (eg, Wilson disease), full gene sequence BBS1 (Bardet-Biedl syndrome 1) (eg, Bardet-Biedl syndrome), full gene sequence BBS2 (Bardet-Biedl syndrome 2) (eg, Bardet-Biedl syndrome), full gene sequence BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (eg, maple syrup urine disease, type 1B), full gene sequence BEST1 (bestrophin 1) (eg, vitelliform macular dystrophy), full gene sequence BMPR2 (bone morphogenetic protein receptor, type II [serine/threonine kinase]) (eg, heritable pulmonary arterial hypertension), full gene sequence BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, Noonan syndrome), full gene sequence BSCL2 (Berardinelli-Seip congenital lipodystrophy 2 [seipin]) (eg, Berardinelli-Seip congenital lipodystrophy), full gene sequence BTK (Bruton agammaglobulinemia tyrosine kinase) (eg, X-linked agammaglobulinemia), full gene sequence CACNB2 (calcium channel, voltage-dependent, beta 2 subunit) (eg, Brugada syndrome), full gene sequence CAPN3 (calpain 3) (eg, limb-girdle muscular dystrophy [LGMD] type 2A, calpainopathy), full gene sequence CBS (cystathionine-beta-synthase) (eg, homocystinuria, cystathionine beta-synthase deficiency), full gene sequence CDH1 (cadherin 1, type 1, E-cadherin [epithelial]) (eg, hereditary diffuse gastric cancer), full gene sequence CDKL5 (cyclin-dependent kinase-like 5) (eg, early infantile epileptic encephalopathy), full gene sequence CLCN1 (chloride channel 1, skeletal muscle) (eg, myotonia congenita), full gene sequence CLCNKB (chloride channel, voltage-sensitive Kb) (eg, Bartter syndrome 3 and 4b), full gene sequence CNTNAP2 (contactin-associated protein-like 2) (eg, Pitt-Hopkins-like syndrome 1), full gene sequence COL6A2 (collagen, type VI, alpha 2) (eg, collagen type VI-related disorders), duplication/deletion analysis CPT1A (carnitine palmitoyltransferase 1A [liver]) (eg, carnitine palmitoyltransferase 1A [CPT1A] deficiency), full gene sequence CRB1 (crumbs homolog 1 [Drosophila]) (eg, Leber congenital amaurosis), full gene sequence CREBBP (CREB binding protein) (eg, Rubinstein-Taybi syndrome), duplication/deletion analysis DBT (dihydrolipoamide branched chain transacylase E2) (eg, maple syrup urine disease, type 2), full gene sequence DLAT (dihydrolipoamide S-acetyltransferase) (eg, pyruvate dehydrogenase E2 deficiency), full gene sequence DLD (dihydrolipoamide dehydrogenase) (eg, maple syrup urine disease, type III), full gene sequence DSC2 (desmocollin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 11), full gene sequence DSG2 (desmoglein 2) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 10), full gene sequence DSP (desmoplakin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 8), full gene sequence EFHC1 (EF-hand domain [C-terminal] containing 1) (eg, juvenile myoclonic epilepsy), full gene sequence EIF2B3 (eukaryotic translation initiation factor 2B, subunit 3 gamma, 58kDa) (eg, leukoencephalopathy with vanishing white matter), full gene sequence EIF2B4 (eukaryotic translation initiation factor 2B, subunit 4 delta, 67kDa) (eg, leukoencephalopathy with vanishing white matter), full gene sequence EIF2B5 (eukaryotic translation initiation factor 2B, subunit 5 epsilon, 82kDa) (eg, childhood ataxia with central nervous system hypomyelination/vanishing white matter), full gene sequence ENG (endoglin) (eg, hereditary hemorrhagic telangiectasia, type 1), full gene sequence EYA1 (eyes absent homolog 1 [Drosophila]) (eg, branchio-oto-renal [BOR] spectrum disorders), full gene sequence F8 (coagulation factor VIII) (eg, hemophilia A), duplication/deletion analysis FAH (fumarylacetoacetate hydrolase [fumarylacetoacetase]) (eg, tyrosinemia, type 1), full gene sequence FASTKD2 (FAST kinase domains 2) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence FIG4 (FIG4 homolog, SAC1 lipid phosphatase domain containing [S. cerevisiae]) (eg, Charcot-Marie-Tooth disease), full gene sequence FTSJ1 (FtsJ RNA methyltransferase homolog 1 [E. coli]) (eg, X-linked mental retardation 9), full gene sequence FUS (fused in sarcoma) (eg, amyotrophic lateral sclerosis), full gene sequence GAA (glucosidase, alpha; acid) (eg, glycogen storage disease type II [Pompe disease]), full gene sequence GALC (galactosylceramidase) (eg, Krabbe disease), full gene sequence GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), full gene sequence GARS (glycyl-tRNA synthetase) (eg, Charcot-Marie-Tooth disease), full gene sequence GCDH (glutaryl-CoA dehydrogenase) (eg, glutaricacidemia type 1), full gene sequence GCK (glucokinase [hexokinase 4]) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence GLUD1 (glutamate dehydrogenase 1) (eg, familial hyperinsulinism), full gene sequence GNE (glucosamine [UDP-N-acetyl]-2-epimerase/N-acetylmannosamine kinase) (eg, inclusion body myopathy 2 [IBM2], Nonaka myopathy), full gene sequence GRN (granulin) (eg, frontotemporal dementia), full gene sequence HADHA (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase [trifunctional protein] alpha subunit) (eg, long chain acyl-coenzyme A dehydrogenase deficiency), full gene sequence HADHB (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase [trifunctional protein], beta subunit) (eg, trifunctional protein deficiency), full gene sequence HEXA (hexosaminidase A, alpha polypeptide) (eg, Tay-Sachs disease), full gene sequence HLCS (HLCS holocarboxylase synthetase) (eg, holocarboxylase synthetase deficiency), full gene sequence HMBS (hydroxymethylbilane synthase) (eg, acute intermittent porphyria), full gene sequence HNF4A (hepatocyte nuclear factor 4, alpha) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence IDUA (iduronidase, alpha-L-) (eg, mucopolysaccharidosis type I), full gene sequence INF2 (inverted formin, FH2 and WH2 domain containing) (eg, focal segmental glomerulosclerosis), full gene sequence IVD (isovaleryl-CoA dehydrogenase) (eg, isovaleric acidemia), full gene sequence JAG1 (jagged 1) (eg, Alagille syndrome), duplication/deletion analysis JUP (junction plakoglobin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 11), full gene sequence KCNH2 (potassium voltage-gated channel, subfamily H [eag-related], member 2) (eg, short QT syndrome, long QT syndrome), full gene sequence KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) (eg, short QT syndrome, long QT syndrome), full gene sequence KCNQ2 (potassium voltage-gated channel, KQT-like subfamily, member 2) (eg, epileptic encephalopathy), full gene sequence LDB3 (LIM domain binding 3) (eg, familial dilated cardiomyopathy, myofibrillar myopathy), full gene sequence LDLR (low den
S3852	Dna analysis for apoe epsilon 4 allele for susceptibility to alzheimer's disease

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