Clinical Policy Title: Genomic tests in neurology

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1 Clinical Policy Title: Genomic tests in neurology Clinical Policy Number: Effective Date: January 1, 2016 Initial Review Date: June 16, 2015 Most Recent Review Date: September 14, 2017 Next Review Date: September 2018 Policy contains: Genomic tests Neurology Alzheimer s disease Glycosphingolipid storage disorders Related policies: CP# CP# CP# CP# CP# Genetic testing for autism spectrum disorders Genetic testing for rare diseases Genomic testing in sensorineural hearing loss Maternal genetic testing Array comparative genomic hybridization testing ABOUT THIS POLICY: Prestige Health Choice has developed clinical policies to assist with making coverage determinations. Prestige Health Choice s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by Prestige Health Choice when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Prestige Health Choice s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. Prestige Health Choice s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Prestige Health Choice will update its clinical policies as necessary. Prestige Health Choice s clinical policies are not guarantees of payment. Coverage policy Prestige Health Choice considers genomic testing for screening for neurologic disease [e.g., Alzheimer s disease (AD) or glycosphingolipid storage disorder (GSD)] to be investigational, and therefore not medically necessary (Polivka 2016, Zayats 2015, Chen 2012, McKahn 2011, Beecham 2009, Hsuing 2004). Limitations: Coverage determinations are subject to benefit limitations and exclusions as delineated by the state Medicaid authority. The Florida Medicaid website can be accessed at 1

2 Alternative covered services: A primary care physician or a medical or surgical specialist, geneticist or other qualified provider may evaluate a patient for AD or GSD with alternative covered services, including routine office consultation and clinical investigation with laboratory, imaging, functional testing and diagnostic procedures. Background AD is a progressive and ultimately fatal dementia that can be familial or idiopathic (no family history). The majority of AD is late-onset, but there is also a less common early-onset form of AD, which appears before age 65 and is associated with a rapid decline of severe neurochemical and neuropathological change. Currently the diagnosis of AD is a clinical diagnosis, focusing on the exclusion of other causes of senile dementia. In 1988 the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA) published clinical criteria for the diagnosis of AD. These organizations defined three categories: possible, probable and definite AD. The only difference between probable and definite AD is that the definite category requires a brain biopsy confirming the presence of characteristic neurofibrillary tangles. GSDs (e.g., Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis and type 2 Gaucher disease) are associated with brain changes that cause nervous system degeneration. The identification of a reliable genomic marker is vital to establish the DNA mutations that are etiologic of these disorders and to identify features of disease that can be used as potential therapeutic strategies in future clinical trials. The GM1 and GM2 gangliosidoses are particularly troubling in this regard. These lysosomal storage disorders primarily affect the brain and are uniformly fatal. No effective therapy for patients with these disorders has yet been demonstrated. Since these disorders are fatal, very little natural history information or disease characterization has been collected. Searches Prestige Health Choice searched PubMed and the databases of: UK National Health Services Center for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). 2

3 We conducted searches on July 26, Search terms were: "neurologic (MeSH)," "genome (MeSH)" and "test (MeSH)." We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings The merits of definitive neurologic genome testing are several. At present much neurologic diagnosis is made by exclusion, a process that proves challenging for physicians and hard for individuals to understand in lay terms. There is advantage also in establishing a family predilection for neurologic disease, both with regard to future screening and for family planning, which has been advanced by the discovery of four genes that are frequently (40 percent of cases) aligned with AD: 1) apolipoprotein E (APOE) gene, 2) amyloid AB precursor gene, 3) presenilin 1 gene and 4) presenilin 2 (PSEN2) gene. For example, the presence of at least one epsilon 4 allele for APOE lipoprotein is associated with an increased risk of AD of 1.2 to 3 fold, depending on the ethnic group. For those homozygous for epsilon 4, the risk of AD is higher. A systematic review (SR) of 2,186 confirmed AD cases and 2,507 healthy controls examined the genomic association of PSEN2 polymorphisms, rs8383 and 5'indel, with the risk of sporadic AD (Chen 2012). The analysis suggested a significant association between SNP rs8383 polymorphism and AD risk with no evidence of between-study heterogeneity or publication bias. Unfortunately the authors did not find any evidence supporting the association between the 5'indel polymorphism and the risk of AD. The stratified analyses of apolipoprotein ε4 status or ethnicity also failed to reveal a statistically significant association between the 5'indel polymorphism of PSEN2 and AD risk. The authors concluded that PSEN2 rs8383 polymorphism is associated with an increased risk of sporadic AD. The authors also acknowledged that larger scale studies are needed to confirm these findings and to define potential gene-gene interactions. 3

4 Revised diagnostic guidelines for AD from the National Institute on Aging and the Alzheimer's Association do not advocate for the routine diagnostic use of biomarkers for AD, calling for more research on the matter. The authors do go on to add, though, that "the use of biomarkers to enhance certainty of AD pathophysiological process may be useful in three circumstances: 1) investigational studies, 2) clinical trials and 3) as optional clinical tools for use where available and when deemed appropriate by the clinician (McKahn 2011)." Basic science studies have validated these results and suggested even further linkages between the genome and AD (Beecham 2009), and the mechanism through which cognitive impairment progresses to frank AD (Hsuing 2004). A current glycosphingolipid protocol aims to study the natural history of the GM1 and GM2 gangliosidoses in affected individuals of all ages, races and genders using genomic, neurologic, and psychologic techniques (among others). Biomarkers of disease will be explored in CSF and blood samples for correlation with disease staging. There are currently no published data suggesting that genetic testing of individuals with possible or probable AD or GSD affects the conventional diagnostic work-up, treatment or clinical outcomes of the condition. There is inadequate data regarding the role of genetic testing in asymptomatic individuals at risk for these conditions, and no data regarding how test results may alter their medical management, treatment or clinical outcomes. Polivka (2016) assessed IDH1/2 mutations and MGMT promoter methylation status for identification of glioblastoma and 1p/19q co-deletion for oligodendroglioma, and suggested that anti-caps antibodies, β amyloid and amyloid precursor protein markers offer promise in earlier detection of AD. The authors also opined that in the future the α-synuclein marker will become integral to diagnosis of Parkinson s disease. With regard to demyelinating diseases, the authors were optimistic that in time biomarkers may help to distinguish GSD patients at high morbidity and mortality risk from those with a potentially benign course of disease. The authors were explicit in stating that further validation is necessary before incorporation of these biomarkers into standard clinical decision-making algorithms. Policy updates: A randomized controlled trial (Zayats 2015) aimed to explore the genetics of ADHD in an ethnically homogeneous Norwegian population by means of a genome-wide association (GWA) analysis followed by examination of candidate loci. At baseline individuals (478 cases and 880 controls) and autosomal SNPs were subjected to GWA analysis. No single polymorphism reached genome-wide significance. The strongest signal was observed at rs in the ENSG gene (OR=1.51, 4

5 95% CI , p=1.38e-06). Pathway analyses of the top SNPs implicated genes involved in the regulation of gene expression, cell adhesion and inflammation. Among previously identified ADHD candidate genes, prominent association signals were observed for SLC9A9 (rs , OR=1.46, 95% CI = , p=9.95e-05) and TPH2 (rs , OR = 1.38, 95% CI = , p=8.31e-04). The authors concluded that the results point to a spectrum of biological mechanisms underlying the symptoms of ADHD, providing targets for further genetic exploration of this complex disorder. Summary of clinical evidence: Citation Polivka (2016) Content, Methods, Recommendations Current status of biomarker research in neurology. Zayats (2015) Genome-wide analysis of attention deficit hyperactivity disorder in Norway. Narrative review on the role of biomarkers and personalized medicine in neurology. Prospective biomarkers could be routinely used in the neurological practice in many distinct settings. Among them are concurrent assessment of IDH1/2 mutations and MGMT promoter methylation status for glioblastoma and 1p/19q co-deletion for oligodendroglioma. The anti-caps antibodies and β amyloid as well as amyloid precursor protein markers are promising in Alzheimer s disease and α-synuclein in Parkinson s disease. In demyelinating diseases, the goal for the future is to implement biomarkers that could help to distinguish patients with high risk of serious course from patients with potentially benign course of disease. Further validation is necessary before incorporation into standard clinical decisionmaking algorithms. Trial aimed to explore genetics of ADHD in an ethnically homogeneous Norwegian population by means of a genome-wide association (GWA) analysis followed by examination of candidate loci. Participants were recruited through Norwegian medical and birth registries as well as the general population. Genotyping was performed using Illumina Human OmniExpress-12v1 microarrays. Statistical analyses were divided into several steps: (1) genome-wide association in the form of logistic regression in PLINK and follow-up pathway analyses performed in DAPPLE and INRICH softwares, (2) SNP-heritability calculated using genome-wide complex trait analysis (GCTA) tool, (3) gene-based association tests carried out in JAG software, and (4) evaluation of previously reported genome-wide signals and candidate genes of ADHD. In total, individuals (478 cases and 880 controls) and autosomal SNPs were subjected to GWA analysis. The strongest signal was observed at rs in the ENSG gene (OR=1.51, 95% CI , p=1.38e-06). Pathway analyses of the top SNPs implicated genes involved in the regulation of gene expression, cell adhesion and inflammation. Among previously identified ADHD candidate genes, prominent association signals were observed for SLC9A9 (rs , OR=1.46, 95% CI = , p=9.95e-05) and TPH2 (rs , OR = 1.38, 95% CI = , p=8.31e-04). This study confirms the complexity and heterogeneity of ADHD etiology. The results point to a spectrum of biological mechanisms underlying the symptoms of ADHD, providing targets for further genetic exploration of this complex disorder. 5

6 Citation Chen (2012) Content, Methods, Recommendations Presenilin-2 polymorphisms and risk of sporadic AD: evidence from a meta-analysis McKahn (2011) The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging- Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease Beecham (2009) Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease Hsuing (2004) Apolipoptrotein E 4 genotype as a risk factor for cognitive decline and dementia SR with meta-analysis to evaluate the association of the two most extensively studied PSEN2 polymorphisms, rs8383 and 5'indel, with the risk of sporadic AD. Included 2,186 confirmed AD cases and 2,507 healthy controls in total. Established an association between single nucleotide polymorphism (SNP) rs8383 and AD. Guidelines for AD from the National Institute on Aging and the Alzheimer's Association do not advocate for the routine diagnostic use of biomarkers for AD, calling for more research on the matter. However, the guidelines go on to say, "the use of biomarkers to enhance certainty of AD pathophysiological process may be useful in three circumstances: 1) investigational studies, 2) clinical trials and 3) as optional clinical tools for use where available and when deemed appropriate by the clinician." APOE polymorphisms have been consistently associated with the risk of late-onset Alzheimer s disease (LOAD). Genome-wide association study (GWAS) confirmed the known APOE association and identified association with a 12q13 locus. The APOE epsilon4 genotype was a significant risk factor for conversion from cognitive impairment, no dementia (CIND) to AD. Demonstrated significant interaction between the APOE epsilon4 genotype and age for AD and for conversion from CIND to AD. Authors concluded that an APOE epsilon4 allele increases the risk of AD developing from CIND. It is also associated with a decrease in the age at onset of AD. References Professional society guidelines/other: American College of Medical Genetics/American Society of Human Genetics. Statement on use of apolipoprotein E testing for Alzheimer disease. American College of Medical Genetics/American Society of Human Genetics Working Group on APOE and Alzheimer s disease. JAMA. 1995; 274(20):

7 McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011; 7(3): National Institute on Aging/Alzheimer's Association. Apolipoprotein E genotyping in Alzheimer's disease. National Institute on Aging/Alzheimer's Association Working Group. Lancet. 1996; 347(9008): Peer-reviewed references: Beecham GW, Martin ER, Li YJ, et al. Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am J Hum Genet. 2009; 84(1): Chen C, Zhou Z, Li M, et al. Presenilin-2 polymorphisms and risk of sporadic AD: evidence from a metaanalysis. Gene. 2012; 503(2): Hsuing GR, Sadovnick AD, Feldman H. Apolipoptrotein E 4 genotype as a risk factor for cognitive decline and dementia. Data from the Canadian Study of Health and Aging. CMAJ. 2004; 171: Lane R, Feldman HH, Meyer J, et al. Synergistic effect of apolipoprotein E epsilon4 and butyrylcholinesterase K-variant on progression from mild cognitive impairment to Alzheimer's disease. Pharmacogenet Genomics. 2008; 18(4): Polivka J, Polivka J, Krakorova K, Peterka M, Topolcan O. Current status of biomarker research in neurology. The EPMA Journal. 2016;7:14. Zayats T, Athanasiu L, Sonderby I, et al. Genome-wide analysis of attention deficit hyperactivity disorder in Norway. PLoS One. 2015;10(4):e CMS National Coverage Determinations (NCDs): No NCDs identified as of the writing of this policy. Local Coverage Determinations (LCDs): No LCDs identified as of the writing of this policy. Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill in accordance with those manuals. 7

8 CPT Code Description 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) Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of exons, regionally targeted cytogenomic array analysis) Molecular pathology procedure, Level 7 (eg, analysis of exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of exons, cytogenomic array analysis for neoplasia) Lactate (Lactic acid) Comment ICD 10 Code Description Comment F03.90-F03.91 Unspecified dementia G30.0-G30.9 Alzheimer's disease G31.1 Senile degeneration of brain, not elsewhere classified E75.00-E75.09 Disorders of sphingolipid metabolism and other lipid storage disorders E75.10-E75.19 Other and unspecified gangliosidosis E75.22 Gaucher disease E Niemann-Pick disease, unspecified E75.6 Lipid storage disorder, unspecified E77.0 Defects in post-translational modification of lysosomal enzymes E77.8 Other disorders of glycoprotein metabolism E77.9 Disorder of glycoprotein metabolism, unspecified R41.0 Disorientation, unspecified R41.3 Other amnesia (memory loss NOS) R41.81 Age-related cognitive decline HCPCS Level II Code G0452 S3852 Description Molecular pathology procedure; physician interpretation and report DNA analysis for APOE epsilon 4 allele for susceptibility to Alzheimer's disease Comment 8