Genetic Testing for Non-Cancerous Inheritable Diseases
Policy Number: Original Effective Date: MM.02.009 03/01/2010 Line(s) of Business: Current Effective Date: HMO; PPO; QUEST Integration 03/01/2019 Section: Medicine Place(s) of Service: Outpatient
I. Description A genetic test is the analysis of human DNA, RNA, chromosomes, proteins, or certain metabolites in order to detect alterations related to an inheritable disorder. This can be accomplished by directly examining the DNA or RNA that makes up a gene (direct testing), looking at markers co-inherited with a disease-causing gene (linkage testing), assaying certain metabolites (biochemical testing), or examining the chromosomes (cytogenetic testing). Genetic tests are conducted for a number of purposes, including predicting disease risk, newborn screening, determining clinical management, identifying carriers, and establishing prenatal or clinical diagnoses or prognoses in individuals, families, or populations. Expanded Carrier Screening The American College of Medical Genetics (ACMG) defines expanded panels as those that use next- generation sequencing to screen for mutations in many genes, as opposed to gene-by-gene screening (e.g., ethnic-specific screening or panethnic testing for cystic fibrosis). An ACMG position statement states that although commercial laboratories offer expanded carrier screening panels, there has been no professional guidance as to which disease genes and mutations to include. Recurrent pregnancy loss also referred to as recurrent spontaneous abortion (RSA) or recurrent miscarriage had been defined as two, three, or more consecutive pregnancy losses by the American College of Obstetricians and Gynecologists (ACOG). The American Society for Reproductive Medicine (ASRM) defines recurrent pregnancy loss as two or more failed pregnancies.
This policy does not address oncology-related genetic testing.
II. Criteria/Guidelines For familial assessments, unless otherwise specified, family will be considered: first-, second- and third degree relatives on the same side of the family. The maternal and paternal sides should be considered independently. First-degree relatives refer to parents, full siblings, and offspring. Second- degree relatives are defined as grandparents, grandchildren, aunts, uncles, nephews, nieces, half- siblings and third-degree relatives are defined as great-grandparents, great-aunts, great-uncles, first cousins. Genetic Testing for Non-Cancerous Inheritable Diseases 2
A. Genetic testing for all the inheritable diseases listed below must meet the following factors (in addition to any specific criteria) in order to be covered: 1. There must be a reasonable expectation based on family history, pedigree analysis, risk factors, and/or symptomatology that a genetically inherited condition exists. 2. The genotypes to be detected by a genetic test must be shown by scientifically valid methods to be associated with the occurrence of the disease. 3. The analytical and clinical utility validity of the test must be established (e.g., test results will influence decisions concerning disease treatment or prevention). B. Genetic testing for the conditions listed below is covered (subject to Limitations and Administrative Guidelines) if after history, physical exam, pedigree analysis, and completion of conventional diagnostic studies, a definitive diagnosis remain uncertain. These include but are not limited to: • Achrondroplasia • Amino acid metabolic disturbances • Charcot-Marie Tooth disease • Classical lissencephaly • Congenital hydrocephalus • Cri-du-chat • Cystic kidney disease (including polycystic kidney, autosomal dominant) • Dwarfism • Fabry disease • Factor XIII deficiency, congenital (Factor XIII beta globulin) • Friedreich's ataxia • Gonadal dysgenesis (Turner's, XO syndrome) • Hereditary progressive muscular dystrophy (Duchene[dystrophin]-Becker's type(limb girdle muscular dystrophy Oculopharyngeal muscular dystrophy • Neurofibromatosis type 2 • Osteogenesis imperfecta • Phenylketonuria • Prader-Willi-Angelman syndrome • Peutz-jeghers • Thanatophoric dysplasia • Tuberous sclerosis • Turners syndrome • Velo cardio facial syndrome • Von Hippel-Lindau syndrome • Von Willebrand's disease C. Genetic testing for cystic fibrosis is covered (subject to Limitations and of Administrative Guidelines) using the ACMG mutation core panel (ACMG 23) for preconception or prenatal carrier testing of an individual who is pregnant or a prospective biologic parent with the capacity and desire to reproduce. Genetic Testing for Non-Cancerous Inheritable Diseases 3
D. The following genetic tests are covered (subject to Limitations and Administrative Guidelines) with precertification: 1. Complete analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is covered (subject to Limitations/Exclusions and Administrative Guidelines) in the following: a. For patients with cystic fibrosis b. Patients with a family history of cystic fibrosis c. Males with congenital bilateral absence of the vas deferens d. Newborns with a positive newborn screening result when mutation testing, using the standard 23-mutation panel, has a negative result e. Cystic Fibrosis testing for Carrier status, not meeting above criteria is covered in the HMSA Prenatal Carrier Testing policy. 2. Chromosomal microarray analysis as first line testing in initial postnatal evaluation of individuals with any of the following: a. Apparent nonsyndromic developmental delay/intellectual disability b. Autism spectrum disorder (Please also refer to the Genetic Testing, Including Chromosomal Microarray Analysis and Next-Generation Sequencing Panels, for the Evaluation of Developmental Delay/Intellectual Disability, Autism Spectrum Disorder, and/or Congenital Anomalies policy) c. Multiple congenital anomalies not specific to a well-delineated genetic syndrome 3. Genetic testing for carrier status of spinal muscular atrophy (SMA in high-risk individuals when ordered by a geneticist or pediatric neurologist meeting any of the following criteria: a. Individuals with a positive family history of SMA, limited to first- or second-degree relatives b. Reproductive partner of an individual with SMA or is a known SMA carrier c. Individuals with a first-degree relative identified as a SMA carrier 4. Genetic testing for FMR1 mutations (including fragile X syndrome) for individuals in any of the following risk categories where the results of the test will affect clinical management or reproductive decisions (For genetic testing for developmental delay, intellectual disability, autism spectrum disorder and congenital anomalies, see HMSA policy for Genetic Testing for Developmental Delay/Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies): a. Genetic testing of an affected individual with intellectual disability, developmental delay or autism spectrum disorder for FMR1 variants is covered. b. Genetic testing of an affected individual or their relatives with a positive cytogenetic fragile X test result related to the risk of carrier status is covered. See HMSA Carrier Testing Policy c. Genetic testing an affected woman with primary ovarian failure under the age of 40 in whom fragile x-associated ovarian failure is suspected is covered. d. Genetic testing of an affected individual with neurologic symptoms consistent with fragile X-associated tremor/ataxia syndrome is covered. e. Fetuses of known carrier mothers. Prenatal testing of a fetus is indicated following a positive Fragile X carrier test in the mother. 5. Carrier screening for Ashkenazi Jewish individuals for (see HMSA Prenatal Carrier Testing policy): Genetic Testing for Non-Cancerous Inheritable Diseases 4
a. Tay-Sachs disease b. Canavan disease c. Familial Dysautomia d. Fanconi anemia e. Niemann-Pick (type A) f. Bloom syndrome g. Gaucher disease h. Mucolipidosis IV
6. Genetic testing for HFE gene mutations related to hereditary hemochromatosis (HH): Genetic testing is available to assess variants in the HFE gene, which are responsible for the majority of clinically significant cases of hereditary hemochromatosis. The majority of patients with HH have variants in the HFE gene, which is on the short arm of chromosome. Known mutations associated with this gene are: C2827, H63D, S65C. a. Patients who meet at least one of the following criteria: 1. Transferrin iron saturation is greater than or equal to 45%, in the absence of confounding causes of hyperferritinemia, including but not limited to alcohol abuse, metabolic syndrome, Inflammatory states or acute and chronic hepatitis. 2. In individuals with a family history of hemochromatosis in a first degree relative. 3. HFE gene mutation testing in patients with unexplained abnormal serum iron indices even in the absence of symptoms. 4. A parental whole HFE gene variant status is unknown when one parent has known hereditary hemochromatosis and testing is to inform homozygosity or heterozygosity status in a child. b. Genetic testing for HFE pathogenic variants is not covered in children with at least one parent with normal HFE gene status. c. Genetic testing for hereditary hemochromatosis in screening of the general population is not covered because it is not known to improve health outcomes.
7. Genetic testing for predisposition to hypertrophic cardiomyopathy (HCM) is: a. Covered for individuals having one first-degree relative with established HCM when there is a known pathogenic gene mutation present in that affective relative. b. Not covered for at-risk individuals without a known variant in the family because testing is not known to improve health outcomes. 8. Genetic testing for suspected congenital Long QT Syndrome (LQTS) for individuals who do not meet the clinical criteria for LQTS but have one of the following: a. A first- or second- degree relative with a known LQTS mutation b. A first- or second- degree relative diagnosed with LQTS by clinical means whose genetic status is unavailable c. Signs and/or symptoms indicating a moderate to high pretest probability of LQTS, defined as a Schwartz score of 2-3. (See Appendix I) 9. Genetic testing for Factor V Leiden and/or prothrombin G20210A mutations when any of the following criteria are met: Genetic Testing for Non-Cancerous Inheritable Diseases 5
a. Age 50 or less , any venous thrombosis b. Age 50 or less , in patients who develop acute arterial thrombosis in the absence of other risk factors for atherosclerotic arterial occlusive disease c. Venous thrombosis in unusual sites (such as portal hepatic, mesenteric and cerebral veins) d. Recurrent venous thrombosis e. Relatives of individuals with venous thrombosis under age 50 f. Venous thrombosis with a first-or second- degree relative with thrombotic disease g. Venous thrombosis in pregnant women or women taking oral contraceptives h. Women with recurrent pregnancy loss or unexplained severe preeclampsia, placental abruption, intrauterine fetal growth retardation or stillbirth i. Myocardial infarction in female smokers under age 50 10. One-time genotypic or phenotypic analysis of the enzyme Thiopurine Methyltransferase (TPMT) is covered in: a. Patients beginning therapy with azathioprine (AZA),mercaptopurine (6-MP) or thioguanine (6- TG) b. Patients on thiopurine therapy with abnormal complete blood count results that do not respond to dose reduction. c. Analysis of the metabolite markers of azathioprine and mercaptopurine, including 6 –methyl- mercaptopureine ribonucleatides and 6- thioguanine nucleotides, is not covered because it is not known to be effective in improving health outcomes.
11. Genetic testing for hemoglobinopathies (i.e., thalassemias and sickle cell disease) is covered when one of the following criteria is met: a. For confirmation of a diagnosis in either of the following situations: i. For individuals with clinical features suggestive of a hemoglobinopathy when test results from conventional studies (e.g., iron deficiency test and serum electrophoresis) are inconclusive and patients have failed a trial of iron therapy, when indicated. ii. Infants who are diagnosed on newborn screening as having a hemoglobinopathy. b. For carrier testing of hemoglobinopathies, please refer to HMSA Carrier Testing policy.
12. Evaluation of members with recurrent pregnancy loss defined as two or more consecutive spontaneous abortions when one of the following criteria is met: a. Karyotype (cytogenetic analysis) of parents to detect balance chromosomal anomalies; b. Prenatal genetic diagnosis for all couples in which one partner has been found to have a balanced translocation or inversion; c. Karyotype of abortus tissue when a couple with recurrent pregnancy loss experiences a subsequent spontaneous abortion. 13. Hereditary pancreatitis (PRSS1): Genetic testing for hereditary pancreatitis (PRSS1 mutation) is covered in symptomatic persons with any of the following indications: 1. A family history of pancreatitis in a 1st-degree (parent, sibling, child) or 2nd-degree (aunt, uncle, grandparent) relative; or Genetic Testing for Non-Cancerous Inheritable Diseases 6
2. An unexplained episode of documented pancreatitis occurring in a child that has required hospitalization, and where there is significant concern that hereditary pancreatitis should be excluded; or 3. Recurrent (2 or more separate, documented episodes with hyper-amylasemia) attacks of acute pancreatitis for which there is no explanation (anatomical anomalies, ampullary or main pancreatic strictures, trauma, viral infection, gallstones, alcohol, drugs, hyperlipidemia, etc.); or 4. Unexplained (idiopathic) chronic pancreatitis.
This policy is based upon guidelines from the Consensus Committees of the European Registry of Hereditary Pancreatic Diseases, the Midwest Multi-Center Pancreatic Study Group and the International Association of Pancreatology (Ellis et al, 2001).
Because of the rapidly evolving field of genetic testing, this policy does not address every genetic test available. All other genetic tests not mentioned in this policy will be reviewed based on medical necessity and the policy criteria (II.A. 1-3).
III. Limitations A. The following genetic tests are not covered because they have not been shown to improve long- term health outcomes: 1. Genetic testing to determine preterm labor 2. Genetic testing to determine warfarin sensitivity (see HMSA Cytochrome 450 policy) 3. Genetic testing for the diagnosis or risk assessment of Alzheimer's disease including but not limited to testing for, apolipoprotein E epsilon 4 allele, presenilin genes or amyloid precursor gene 4. Genetic testing for helicobacter pylori treatment 5. MTHFR polymorphism testing B. Genetic testing is not covered in the following circumstances: 1. Family members of subscribers, who themselves are not subscribers or dependents 2. Members if the results of the genetic testing are for the benefit of relatives who are not subscribers or dependents C. If a patient has been screened previously, CF screening results should be documented and the test should not be repeated. D. Complete analysis of the CFTR gene by DNA sequencing is not appropriate for routine carrier screening (see HMSA Carrier Testing policy). E. Except as referenced in Criteria/Guidelines, genetic screening of individuals is not covered in the absence of associated signs, symptoms or complaints. General population screening for genetic disorders is not covered except where mandated by State and Federal law. F. Laboratories that conduct genetic testing must be CLIA certified. G. Genetic counseling is not a covered benefit. H. Genetic tests for a specific inherited disease will be covered once per lifetime, unless new techniques that increase sensitivity are utilized. I. Home genetic testing is not a covered benefit. Genetic Testing for Non-Cancerous Inheritable Diseases 7
J. For a known deleterious mutation, HMSA will only cover a targeted single site analysis genetic test not a full analysis (i.e., testing for the mutation that has been identified in the family). K. The following expanded prenatal panel tests are not covered because the clinical utility has not been established: (This is not an all-inclusive list) Please refer to HMSA Carrier Testing Policy 1. Counsyl 2. GoodStart Select 3. Inherigen 4. Inheritest 5. Natera One Disease Panel 6. Progenity CFnxt L. Genetic testing for hereditary pancreatitis is not covered for all other indications not mentioned above because it is not known to be effective for indications other than the ones listed above.
IV. Administrative Guidelines A. For the genetic tests requiring precertification complete HMSA's Precertification Request and fax or mail the form as indicated with the following information: 1. Specify the condition for which the genetic test is being performed and if there are any known first- or second- degree relatives with the condition 2. Other types of biochemical testing apart from molecular genetic testing (enzyme activity assays, hemoglobin electrophoresis, blood chemistries, etc.), phenotypic findings and relevant clinical history and exam details 3. Specify how the results of the genetic test will impact the clinical management of the patient in terms of improving health outcomes B. If precertification is not sought, the member will not be held responsible for payment of denied services unless an Agreement of Financial Responsibility is completed and signed. C. Applicable codes requiring precertification:
CPT Codes Description 81221 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis ;known familial variants 81222 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis; duplication/deletion variants 81223 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis; full gene sequence 81224 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis; intron 8 poly-T analysis 81228 Cytogenetic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants, (e.g., Bacterial Artificial Chromosome [BAC] or oligo-based comparative genomic hybridization [CGH] microarray analysis) 81229 Cytogenomic constitutional (genome-wide) microarray analysis; Genetic Testing for Non-Cancerous Inheritable Diseases 8
interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities 81240 F2 (prothrombin, coagulation factor II) (e.g. hereditary hypercoagulability) gene analysis, 20210G>A variant 81241 F5 (coagulation factor V) (e.g. hereditary hypercoagulability) gene analysis, Leiden variant 81243 FMR1 (fragile X mental retardation 1) (e.g. fragile X mental retardation) gene analysis; evaluation to detect abnormal alleles 81244 FMR1 (fragile X mental retardation 1) (e.g. fragile X mental retardation) gene analysis; characterization of alleles 81251 GBA (glucosidase, beta, acid) (e.g., Gaucher disease) gene analysis, common variants (e.g., N370S, 84GG, l444P, IVS2+1G>A) 81255 HEXA (hexosaminidase A [alpha polypeptide]) (e.g., Tay-Sachs disease) gene analysis, common variants (e.g., 1278insTATC, 1421+1G>C, G269S) 81256 HFE (hemochromatosis) gene analysis, common variants (e.g., C282Y, H63D) 81257 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis, for common deletions or variant (e.g., Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2, alpha20.5, and constant spring) 81260 Ikbkap (inhibitor of kappa light polypeptide gene enhancer in b-cells, kinase complex-associated protein) (e.g., familial dysautonomia) gene analysis, common variants (e.g., 2507+6t>c, r696p) 81280 Long QT syndrome gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1 and ANK2); full sequence analysis 81281 Long QT syndrome gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1 and ANK2); known familial sequence variant 81282 Long QT syndrome gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1 and ANK2); duplication/deletion variants
81470 X-linked intellectual disability (XLID) (e.g., syndromic and non-syndromic XLID); genomic sequence analysis panel, must include sequencing of at least 60 genes, including ARX, ATRX, CDKL5, FGD1, FMR1, HUWE1, IL1RAPL, KDM5C, L1CAM, MECP2, MED12, MID1, OCRL, RPS6KA3, and SLC16A2 (New 01-01-2015) Genetic Testing for Non-Cancerous Inheritable Diseases 9
81471 X-linked intellectual disability (XLID) (e.g., syndromic and non-syndromic XLID); duplication/deletion gene analysis, must include analysis of at least 60 genes, including ARX, ATRX, CDKL5, FGD1, FMR1, HUWE1, IL1RAPL, KDM5C, L1CAM, MECP2, MED12, MID1, OCRL, RPS6KA3, and SLC16A2 (New 01-01-2015) S3845 Genetic testing for alpha-thalassemia S3846 Genetic testing for hemoglobin E beta-thalassemia S3850 Genetic testing for sickle cell anemia S3861 Genetic testing, sodium channel, voltage-gated, type v, alpha subunit (scn5a) and variants for suspected Brugada syndrome not covered by BCBSA and we have no criteria for this S3865 Comprehensive gene sequence analysis for hypertrophic cardiomyopathy S3866 Genetic analysis for a specific gene mutation for hypertrophic cardiomyopathy (HCM) in an individual with a known HCM mutation in the family D. Codes that do not require precertification: CPT Codes Description 81161 DMD (dystrophin) (e.g., Duchenne/Becker muscular dystrophy) deletion analysis, and duplication analysis, if performed 81205 BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (e.g. Maple syrup urine disease) gene analysis, common variants (e.g. R183P, G278S, E422X) 81220 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis; common variants 81290 MCOLN1 (mucolipin 1) (e.g., mucolipidosis, type iv) gene analysis, common variants (e.g., ivs3-2a>g, del6.4kb) 81324 PMP22 (peripheral myelin protein 22) (e.g., Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; duplication/deletion analysis 81325 PMP22 (peripheral myelin protein 22) (e.g., Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; full sequence analysis 81326 PMP22 (peripheral myelin protein 22) (e.g., Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis ;known familial variant 81330 SMPD1(sphingomyelin phosphodiesterase 1, acid lysosomal) (e.g., Niemann- Pick disease, type A) gene analysis, common variants (e.g., R496L, L302P, Genetic Testing for Non-Cancerous Inheritable Diseases 10
fsP330) 81331 SNRPN/UBE3A (small nuclear ribonucleoprotein polypeptide N and ubiquitin protein ligase E3A) (e.g., Prader-Willi syndrome and/or Angelman syndrome), methylation analysis HCPCS Codes Description S3842 Genetic testing for Von Hippel-Lindau disease S3849 Genetic testing for Niemann-Pick disease S3853 Genetic testing for myotonic muscular dystrophy
E. Codes that do not meet payment determination criteria CPT Codes Description 81227 CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *5, *6) used in warfarin testing 81291 MTHFR (5, 10-methylenetetrahydrofolate reductase) (e.g., hereditary hypercoagulability) gene analysis, common variants (e.g., 677T, 1298C) 81355 VKORC1 (vitamin K epoxide reductase complex, subunit 1) (e.g., warfarin metabolism), gene analysis, common variants (e.g., -1639/3673) S3852 DNA analysis for APOE epsilon 4 allele for susceptibility to Alzheimer's disease
V. Scientific Background This policy is based primarily on recommendations in the Final Report of the Task Force on Genetic Testing and the Secretary's Advisory Committee on Genetic Testing. The Task Force on Genetic Testing was an official government advisory group reporting to the National Advisory Council for Human Genome Research of the National Human Genome Research Institute, the National Institutes of Health. The Secretary's Advisory Committee on Genetic Testing (SACGT) was established to advise the Department of Health and Human Services on the medical, scientific, ethical, legal, and social issues raised by the development and use of genetic tests. Many genetic tests are imperfect predictors of either existing disease or disease susceptibility, particularly when used in the context of population screening, where individuals without family histories of disease, risk factors or symptoms are tested. For example, the probability exists that a disease may still occur, even when a negative test result is obtained. Conversely, a specific disease may not occur when there is a positive test result. While these concepts hold true for at-risk individuals as well, the probability of both these occurrences is greater in population screening, so test results are more difficult to interpret in a manner that will meaningfully impact health outcomes. With a few limited exceptions (e.g., PKU testing), general screening of populations for diseases that can be attributed to genetic mutations is not advocated in the published scientific literature. Ideally, peer-reviewed literature on the performance and indications for the test should be available. The evaluation of a genetic test focuses on these main principles: Analytic validity (technical accuracy Genetic Testing for Non-Cancerous Inheritable Diseases 11
of the test in detecting a mutation that is present or in excluding a mutation that is absent); Clinical validity (diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease); and clinical utility (how results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes). Analytical validity Analytical validity is an indicator of how well a test measures the property or characteristic it is intended to measure, and it is made up of three components Analytical sensitivity: the test is positive when the relevant gene mutation is present. Analytical specificity: the test is negative when the gene mutation is absent and reliability: the test obtains the same result each time. Clinical Validity Clinical validity in genetic testing is a measurement of the accuracy with which a test identifies or predicts a clinical condition and involves the following: 1. Clinical sensitivity: the probability that the test is positive if the individual being tested actually has the disease or a predisposition to the disease. 2. Clinical specificity: the probability that the test is negative if the individual does not have the disease or a predisposition to the disease. 3. Positive predictive value: the probability that an individual with positive test results will get the disease. 4. Negative predictive value: the probability that an individual with negative test results will not get the disease. 5. Heterogeneity: different mutations within the same gene may cause the same disease and can result in different degrees of disease severity; a failure to detect all disease-related mutations reduces a test's clinical sensitivity. 6. Penetrance: the probability that the disease will appear when a disease-related genotype is present. Penetrance is incomplete when other genetic or environmental factors must be present for a disease to develop. The clinical utility of the test must be established. The development of genetic tests that can diagnose or predict disease occurrence has far outpaced the development of interventions to treat, ameliorate or prevent those same diseases. Clinical utility refers to the ability of genetic test results, either positive or negative, to provide information that is of value in the clinical setting. Specifically for positive test results, this could involve instituting treatments or surveillance measures, making decisions concerning future conception, or avoiding harmful treatments. Negative test results can have clinical utility in that unnecessary treatments or surveillance can be avoided. In the absence of such interventions, the benefits of testing are limited, and in fact, can cause psychological harm. Genetic testing of children to confirm current symptomatology or predict adult onset diseases is not considered medically necessary unless direct medical benefit will accrue to the child and in the case of adult onset disease, this benefit would be lost by waiting until the child has reached adulthood. It is generally accepted in the published literature that unless useful medical intervention can be offered to children as a result of testing, formal testing should wait until the child is old enough to Genetic Testing for Non-Cancerous Inheritable Diseases 12
understand the consequences of testing and request it for him or herself. Ethical concerns related to the testing of children include the breach of confidentiality that is required by revealing test results to parents, the lack of ability to counsel the child in a meaningful way regarding the risks and benefits of testing, the impact a positive test could have in terms of discrimination, and the potential psychological damage that could occur from distorting a family’s perception of the child. Hypertrophic Cardiomyopathy (HCM) The genetic basis for HCM is a defect in the cardiac sarcomere, which is the basic contractile unit of cardiac myocytes and is composed of different protein structures. Around 1400 disease-associated variants in at least 18 different genes have been identified. About 90% of pathogenic variants are missense (ie, 1 amino acid is replaced for another), and the strongest evidence for pathogenicity is available for 11 genes coding for thick filament proteins (MYH7, MYL2, MYL3), thin filament proteins (TNNT2, TNNI3, TNNC1, TPM1, ACTC), intermediate filament proteins (MYBPC3), and the Z-disc adjoining the sarcomere (ACTN2, MYOZ2). Variants in myosin heavy chain (MYH7) and myosinbinding protein C (MYBPC3) are the most common and account for roughly 80% of sarcomeric HCM. These genetic defects are inherited in an autosomal dominant pattern with rare exceptions. In patients with clinically documented HCM, genetic abnormalities can be identified in approximately 60%. Most patients with the clinically documented disease are demonstrated to have a familial pattern, although some exceptions are found presumably due to de novo variants.
Venous thromboembolism For patients with unprovoked venous thromboembolism (VTE) at a young age, VTE at an unusual site, arterial thrombosis, or pregnancy morbidity, testing for antiphospholipid antibodies, JAK2 mutation, and paroxysmal nocturnal hemoglobinuria may be beneficial.
The American College of Medical Genetics and Genomics (2015) noted the following: “Don’t order MTHFR genetic testing for the risk assessment of hereditary thrombophilia. The common MTHFR gene variants, 677C>T and 1298A>G, are prevalent in the general population. Recent meta-analyses have disproven an association between the presence of these variants and venous thromboembolism.”
VI. Important Reminder The purpose of this Medical Policy is to provide a guide to coverage. This Medical Policy is not intended to dictate to providers how to practice medicine. Nothing in this Medical Policy is intended to discourage or prohibit providing other medical advice or treatment deemed appropriate by the treating physician. Benefit determinations are subject to applicable member contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. This Medical Policy has been developed through consideration of the medical necessity criteria under Hawaii’s Patients’ Bill of Rights and Responsibilities Act (Hawaii Revised Statutes §432E-1.4), generally accepted standards of medical practice and review of medical literature and government approval status. HMSA has determined that services not covered under this Medical Policy will not be medically necessary under Hawaii law in most cases. If a treating physician disagrees with HMSA’s Genetic Testing for Non-Cancerous Inheritable Diseases 13
determination as to medical necessity in a given case, the physician may request that HMSA consider the application of this Medical Policy to the case at issue.
VII. References 1. Secretary's Advisory Committee on Genetic Testing. A public consultation on oversight of genetic tests. December 1, 1999 January 31, 2000. National Institute of Health. Verified 10/25/2010. 2. ACMG Policy Statement: Cystic fibrosis Population Carrier Screening: 2004 Revision of ACMG mutation panel. Reaffirmed 2013. 3. ACMG Practice Guidelines: Carrier screening in individuals of Ashkenazi descent. Genet Med 2008:10(1):54 –56. Reaffirmed 2013. 4. ACMG Practice Guidelines; Clinical genetics evaluation in identifying the etiology of autism spectrum disorders. 2013 Guideline Revisions. 5. ACMG Practice Guidelines; Fragile X Syndrome: Diagnostic and carrier testing. October 2005. 6. 2.04.83 BCBS Association Medical Policy Reference Manual. Genetic Testing for FMR1 Variants Including Fragile X Syndrome. #2.04.83. Last reviewed January 2018. 7. ACMG Consensus Statement on Factor V Leiden Mutation testing. Reaffirmed 05/14/2007. 8. BCBSA Medical Policy Reference Manual. Pharmacogenetic and Metabolite Markers for Patients Treated with Thiopurines #2.04.19. Last reviewed May 2015. 9. ACMG Standards and Guidelines for Clinical Genetics Laboratories. Technical Standards and Guidelines: Venous Thromboembolism (Factor V Leiden and Prothrombin 20210G>A Testing): A Disease-Specific Supplement to the Standards and Guidelines for Clinical Genetics Laboratories. 2006. 10. Bell CJ, Dinwiddie DL, Miller NA et al. Carrier testing for severe childhood recessive diseases by next generation sequencing. Sci Transl Med 2011; 3(65):65ra4. 11. BCBSA Technology Evaluation Center Genetic testing for long QT syndrome. TEC Assessment 2007; volume 22 tab 9. 12. Genetic testing for HFE gene mutations related to hereditary hemochromatosis. BCBSA Technology Evaluation Center. Chicago, IL: April 2002; 16(22). 13. Special Report: Molecular karyotyping by array comparative genomic hybridization (aCGH) for the genetic evaluation of patients with developmental delay/mental retardation and autism spectrum disorder. BCBSA Medical Advisory Panel. December 2008. 14. ACOG. Practice Bulletin #24. Testing guidelines for early recurrent pregnancy loss. 15. BCBSA Medical Policy Reference Manual. Genetic Testing for Helicobacter pylori Treatment- Archived. #2.04.50. Reviewed July 2012 Archived. 16. BCBSA Medical Policy Reference Manual. Genetic Testing for Cardiac Ion Channelopathies. # 2.04.43. Last Review December 2017. 17. BCBSA Medical Policy Reference Manual. Genetic Testing for Hereditary Hemochromatosis. #2.04.80. Reviewed May 2017. 18. BCBSA Medical Policy Reference Manual. Chromosomal Microarray (CMA) Analysis for the Genetic Evaluation of Patients with Developmental Delay/Intellectual Disability or Autism Spectrum Disorder. #2.04.59. Reviewed August 2016. 19. BCBSA Medical Policy Reference Manual. Genetic Testing for Predisposition to Inherited Hypertrophic Cardiomyopathy. # 2.02.28 .Reviewed March 2017. Genetic Testing for Non-Cancerous Inheritable Diseases 14
20. National Institute of Health. Genetics Home Reference. Sickle cell disease. Reviewed February 2007. 21. BCBSA Medical Policy Reference Manual. Genetic Testing for FMR1 Mutations (Including Fragile X Syndrome). #2.04.83. Reviewed June 2017. 22. BCBSA Medical Policy Reference Manual. Genetic Testing for Predisposition to Inherited Hypertrophic Cardiomyopathy. #2.02.28. Reviewed December 2017. 23. Genetic Testing for Cystic Fibrosis. NIH Consensus Statement 1997 Apr 14-16; 15(4): 1-37. 24. ACMG Practice Guideline: Lack of Evidence for MTHFR Polymorphism Testing. Genet Med 2013:15(2):153–156. 25. ACOG. Practice Bulletin #124. Inherited Thrombophilia in Pregnancy. September 11, 2011. 26. Morales A, Salguti S, Miao CL, et al. Relationship between 6 mercaptopurine dose and 6 thioguanine nucleotide levels in patients with inflammatory bowel disease. Inflamm Bowel Dis. April 2007;13(4): 380-385. PMID 17206711 27. American Association For the Study of Liver Disease, 2011 Practice guidelines for Hereditary Hemochromatosis/ HFE mutation. Included in Bacon, BR, Adams, PC, Kowdley, KV, Powell, LW, Tavill, AS. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011 Jul;54(1):328-43. PMID: 21452290 28. 3.Authors/Task Force m, Elliott PM, Anastasakis A, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. Oct 14 2014;35(39):2733-2779. PMID 25173338 34. 29. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. Aug 2011;8(8):1308-1339. PMID 21787999 30. Thrombophilia Testing in Provoked Venous Thromboembolism: A Teachable Moment. JAMA Intern Med. June 6, 2017.
Genetic Testing for Non-Cancerous Inheritable Diseases 15
VIII. Appendix I LQTS Clinical Probability Score Card (i.e., Schwartz Score)
Finding Points History Clinical history of syncope*without stress 1 Clinical history of syncope* with stress 2 Congenital deafness 0.5 Family history of LQTS* 1 Unexplained sudden death in a first-degree family < 30 yrs. old* 0.5 ECG Corrected QT interval (QTc by Bazett’s formula) 450 ms (in males) 1 460-470 ms 2 >480 ms 3
Torsade de pointes** 2 T-wave alternans 1 >3 Leads with notched T waves 1 Bradycardia (