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Genetic Testing for Non-Cancerous Inheritable Diseases I. Policy University Health Alliance (UHA) will reimburse for Genetic Testing for Non-Cancerous Inheritable Diseases when determined to be medically necessary and within the medical criteria guidelines (subject to limitations and exclusions) indicated below. II. Criteria/Guidelines A. Genetic testing for all the inheritable diseases listed below must meet the following criteria (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 is covered (subject to Limitations/Exclusions and Administrative Guidelines) if after history, physical exam, pedigree analysis, and completion of conventional diagnostic studies, a definitive diagnosis remains uncertain and one of the following diagnoses are suspected. These include but are not limited to: • • Achrondroplasia (FGFR3) • Amino acid metabolic disturbances • Classical lissencephaly • Congenital hydrocephalus • Charcot-Marie Tooth disease (PMP22) Cri-du-chat • Fabry disease Cystic kidney disease (including polycystic kidney, autosomal dominant) Gonadal dysgenesis (Turner’s, XO syndrome) • Down's syndrome • Dwarfism • Factor XIII (F13) deficiency, congenital (Factor XIII beta globulin) • Friedreich’s ataxia (FRDA [frataxin]) • Von Willebrand’s disease • Neurofibromatosis type 2 (Merlin) • • Osteogenesis imperfecta • Phenylketonuria (PKU) Prader-Willi-Angelman syndrome (SNRPN, GABRA5, NIPA1, UBE3A, ANCR, GABRA) • Peutz-jeghers • Thanatophoric dysplasia (FGFR3) • Tuberous sclerosis • Turners syndrome • Velo cardio facial syndrome(catch 22) • Von Hippel-Lindau syndrome (VHL) • Hereditary progressive muscular dystrophy (Duchene[dystrophin]-Becker’s type(limb girdle muscular dystrophy [LGMD1, LGMD2])-Oculopharyngeal muscular dystrophy [OPMD])) • • Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy Policy number M.DIA.04.121120, effective 12/01/2015 Page 1 The following genetic tests are covered (subject to Limitations/Exclusions and Administrative Guidelines) with prior authorization: C. Genetic testing for cystic fibrosis (CF) 1. Genetic testing for cystic fibrosis using the American College of Medical Genetics (ACMG) mutation core panel (AMCG 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. 2. Complete analysis of the cystic fibrosis gene if covered (subject to Limitations and Exclusions) 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 mutations testing, using the standard 23-mutations panel, has a negative result. D. Chromosomal microarray analysis as first line testing in initial postnatal evaluation of individuals with any of the following: 1. Apparently nonsyndromic developmental delay/intellectual disability. 2. Autism Spectrum Disorder 3. Multiple congenital anomalies not specific to a well-delineated genetic syndrome E. 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: 1. Individuals with a positive family history of SMA, limited to first- or second-degree relatives 2. Reproductive partner of an individual with SMA or is a known SMA carrier 3. Individuals with a first-degree relative identified as a SMA carrier F. 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: 1. Individuals with an intellectual disability, DD, or ASD 2. Prenatal testing of fetuses of known carrier mothers 3. Individuals planning a pregnancy who have either of the following; a. A first- or second-degree relative with fragile X syndrome, or b. A first- or second-degree relative with undiagnosed intellectual disability G. carrier screening for Ashkenazi Jewish individuals for: 1. Tay-Sachs disease 2. Canavan disease 3. Familial Dysautomia 4. Fanconi anemia 5. Niemann-Pick (Type A) 6. Bloom Syndrome 7. Gaucher disease Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy Policy number M.DIA.04.121120, effective 12/01/2015 Page 2 8. Mucolipidosis IV H. Genetic testing for HFE-gene mutations related to hereditary hemochromatosis (HHC):s: 1. For diagnostic testing when the individual with symptoms consistent with hemochromatosis and serum transferrin iron saturation is greater than or equal to 45%, but the diagnosis remain uncertain after completion of conventional testing 2. In individuals with a family history of hemochromatosis in a first degree relative. I. Genetic testing for predisposition to hypertrophic cardiomyopathy (HCM) for individuals having one firstdegree relative with established HCM when there is a known pathogenic gene mutation present in that affective relative. J. 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: 1. A first- or second-degree relative with a known LQTS mutation 2. A first- or second-degree relative diagnosed with LQTS by clinical means whose genetic status is unavailable 3. Signs and/or symptoms indicating a moderate to high pretest probability of LQTS, defined as a Schwartz score of 2-3. (See Table I in the Appendix) K. Genetic testing for Factor V Leiden and/or prothrombin G20210A mutation when any of the following criteria are met: 1. Age less than 50, any venous thrombosis, and in patients who develop acute arterial thrombosis in the absence of other risk factors for atherosclerotic arterial occlusive disease 2. Recurrent venous thrombosis 3. Venous thrombosis and a first-or second-degree relative with thrombotic disease 4. Venous thrombosis in pregnant women or women taking oral contraceptives. Women with recurrent pregnancy loss or unexplained severe preeclampsia, placental abruption, intrauterine fetal growth retardation or sillbirth. 5. Myocardial infarction in female smokers under age 50 L. Genotypic or phenotypic analysis of the Thiopurine Methyltransferase (TPMT) gene is covered on a one time basis in patients beginning therapy with azathioprine (AZA), mercaptopurine (6-MP) or thioguanine (6-TG), or in patients on thiopurine therapy with abnormal complete blood count results that do not respond to dose reduction. . M. Genetic testing for hemoglobinopathies (i.e., thalassemias and sickle cell disease) is covered when one of the following criteria are met: 1. For confirmation of a diagnosis in either of the following situations: a. Individuals with clinical features suggestive of a hemoglobinopathy when test results from conventional studies (e.g., electrophoresis, anemia, iron deficiency) are inconclusive and have failed a trial of iron therapy b. Infants who are diagnosed on newborn screening as having a hemoglobinopathy 2. For carrier testing in either of the following situations: a. When there is an affected first- or second-degree relative that has thalassemia or sickle cell disease. Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy Policy number M.DIA.04.121120, effective 12/01/2015 Page 3 b. When the patient is the reproductive partner of a known carrier (disease-causing mutation of gene HBB, HBA1, or HBA2) and the couple has the capacity and intention to reproduce. N. Because of the rapidly evolving field of genetic testing, this policy does not address every genetic test available. All other conditions not mentioned in this policy will be reviewed based on medical necessity and the policy criteria (IIA 1-3). III. Limitations/Exclusions A. The following genetic tests are not covered because they have not been shown to improve health outcomes (this list is not all inclusive): 1. Genetic testing to determine preterm labor 2. Genetic testing to determine Warfarin sensitivity 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. 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. UHA will cover pre and post test genetic counseling with a physician or a certified genetic counselor as medically necessary for an individual recommended for covered heritable genetic testing. 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. J. For a known deleterious mutation, UHA 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. Chromosomal microarray analysis is not covered to confirm the diagnosis of a disorder or syndrome that is routinely diagnosed based on clinical evaluation alone. Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy Policy number M.DIA.04.121120, effective 12/01/2015 Page 4 L. The following expanded prenatal panel tests are not covered because the clinical utility has not been established: (This is not an all-inclusive list) 1. Counsyl 2. GoodStart Select 3. Inherigen 4. Inheritest 5. Natera One Disease Panel 6. Progenity CFnxt M. NOTE: This UHA payment policy is a guide to coverage, the need for prior authorization and other administrative directives. It is not meant to provide instruction in the practice of medicine and it should not deter a provider from expressing his/her judgment. Even though this payment policy may indicate that a particular service or supply is considered covered, specific provider contract terms and/or member’s individual benefit plans may apply, and this policy is not a guarantee of payment UHA reserves the right to apply this payment policy to all UHA companies and subsidiaries. UHA understands that opinions about and approaches to clinical problems may vary. Questions concerning medical necessity (see Hawaii Revised Statutes §432E-1.4) are welcome. A provider may request that UHA reconsider the application of the medical necessity criteria in light of any supporting documentation. IV. Administrative Guidelines A. Prior authorization for the genetic tests is required and must be submitted by a properly certified/licensed and credentialed genetic specialist (i.e., board certified neurologist (MD), boardcertified medical geneticist (MD), board-certified clinical geneticist (PhD), board-certified genetic counselor (MS and/or CGC), or licensed advanced practice registered nurse in genetics (APRN).) B. Complete UHA’s Prior Authorization Request and Notification Form and include 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 C. To request prior authorization, please go to UHA’s website: https://uhahealth.com/page/priorauthorization-forms#pa-medical or you may submit an electronic prior authorization at https://uhahealth.com/page/prior-authorization-forms and submit it: Via Fax: 1-866-572-4384 Via Mail: UHA Health Care Services 700 Bishop Street, Suite 300 Honolulu, HI 96813 Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy Policy number M.DIA.04.121120, effective 12/01/2015 Page 5 D. Applicable HCPCS and ICD-9 codes requiring prior authorization: HCPCS Code Description 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 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 S3870 Comparative genomic hybridization (CGH) microarray test for developmental delay/ autism spectrum disorder and/or mental retardation ICD-9 Codes Description 272.7 Lipidoses 275.01 Hereditary hemochomatosis 277.00277.09 Cystic Fibrosis (CTFR) 282.40 282.49 Thalassemia(alpha globin/beta globin/hemoglobin E) 282.5 Sickle-cell trait (hemoglobin S) 282.61 Hb-SS disease without crisis 282.62 Hb-SS disease with crisis 282.63 Sickle-cell/Hb-C disease 282.7 Other hemoglobinopathies (hemoglobin C) 299.00299.01 Autistic disorder, current or active state or residual state 317-319 Mental retardation 330.1 Cerebral lipidoses (Tay-Sachs disease) 335.10335.19 Spinal muscular atrophy (SBMA,SMN) 425.11 Hypertrophic obstructive cardiomyopathy 425.18 Other hypertrophic cardiomyopathy 425.4 Other primary cardiomyopathies (including familial and hypertrophic cardiomyopathy not otherwise specified) 426.82 Long QT syndrome 555.0555.9 Regional enteritis Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy Policy number M.DIA.04.121120, effective 12/01/2015 Page 6 556.0556.9 Ulcerative colitis 643.30 Habitual aborter; unspecified, with or without mention of antepartum condition (defined as two or more consecutive pregnancy losses)* 646.33 Habitual aborter; antepartum condition or complication(defined as two or more consecutive pregnancy losses)* 746.89 Other congenital anomalies of the heart (Brugada syndrome) 759.83 Fragile X syndrome 783.42 Delayed milestone V12.51 Personal history of venous thrombosis and embolism V17.41 Family history of sudden cardiac death (SCD) V17.49 Family history of other cardiovascular diseases V18.9 Family history of genetic disease carrier V19.5 Family history of congenital anomalies V26.31 Genetic testing of female for genetic disease carrier status V26.34 Genetic testing of male for genetic disease carrier status V77.6 Special screening for cystic fibrosis V77.7 Special screening for other inborn errors of metabolism V77.91 Screening for lipoid disorders V79.2 Special screening for mental retardation V82.4 Maternal postnatal screening for chromosomal anomalies V83.81 Cystic fibrosis gene carrier V83.89 Other genetic carrier screening V84.89 Genetic susceptibility to other disease E. These codes are no longer effective for services rendered after 04/01/2012 HCPCS Description S3835 Complete gene sequence analysis for cystic fibrosis genetic testing S3837 Complete gene sequence analysis for hemochromatosis genetic testing S3843 DNA analysis of F5 gene for susceptibility to Factor V Leiden thrombophilia S3847 Genetic testing for Tay-Sachs disease S3848 Genetic testing for Gaucher disease S3851 Genetic testing for Canavan disease S3860 Genetic testing, comprehensive cardiac ion channel analysis, for variants in 5 major cardiac ion channel genes for individuals with high index of suspicion for familial LQTS or related syndromes S3862 Genetic testing, family-specific ion channel analysis, for blood-relatives of individuals (index case) who have previously tested positive for a genetic variant of a cardiac ion channel syndrome using Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy Policy number M.DIA.04.121120, effective 12/01/2015 Page 7 either one of the above test configurations or confirmed results from another laboratory. * Definition from the American College of Obstetricians and Gynecologists: Practice Bulletin #24 F. HCPCS and ICD-9 codes that do not require prior authorization HCPCS Code Description S3842 Genetic testing for Von Hippel-Lindau disease S3849 Genetic testing for Niemann-Pick disease S3853 Genetic testing for myotonic muscular dystrophy ICD-9 Code Description 237.71 Neurofibromatosis, type 1 (neurofibromin) 237.72 Neurofibromatosis, type 2 (Merlin) 259.4 Dwarfism, not elsewhere classified [hypochondroplasia , thanatophoric dysplasia (FGFR3)] 270.1 Phenylkentonuria (PKU) 270.2 Other disturbances of aromatic amino-acid metabolism (includes albinism) 270.3 Disturbances of branched-chain amino acid metabolism (includes maple syrup urine disease) 270.4 Disturbances of suphur-bearing amino-acid metabolism (includes homocystinuria) 277.5 Mucopolysaccharidosis (MPS-1) 286.0 Congenital factor VIII disorder (hemophilia A/VWF) 286.1 Congenital factor IX disorder([hemophilia B) 286.4 Von Willebrand’s disease 330.0 Leukodystrophy 333.4 Huntington’s chorea (Huntington's disease) 334.0 Friedreich’s ataxia (frataxin) 356.1 Peroneal muscular atrophy (Charcot-Marie-Tooth disease) 359.1 Hereditary progressive muscular dystrophy( [Duchene (dystrophin)] [Becker’s type] [limb girdle muscular dystrophy (LGMD1, LGMD2)] [oculopharyngeal muscular dystrophy (OPMD)]) 359.21359.29 742.2 753.10753.19 Myotonic disorders (myotonic dystrophy {CMPK, ZNF-9}) Reduction deformities of brain (classical lissencephaly) Cystic kidney disease (including polycystic kidney, autosomal dominant) 756.4 Chondrodystrophy (achondroplasia) 756.51 Osteogenesis imperfecta 758.0 Down’s syndrome 758.31 Autosomal deletion syndromes; cri-du-chat syndrome Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy Policy number M.DIA.04.121120, effective 12/01/2015 Page 8 758.32 Velo-cardio-facial syndrome [22q11 deletion syndrome (CATCH-22)] 758.6 Gonadal dysgenesis (ovarian dysgenesis, Turner's syndrome, XO syndrome) 758.7 Klinefelter’s syndrome 759.6 Other hamartoses, not elsewhere classified (Von Hippel Lindau syndrome) 759.81 Prader-Willi syndrome (GABRA, SNRPN) V13.69 Personal history of other congenital malformations V18.61 Family history of polycystic kidney disease V77.3 Special screening for PKU V77.7 Special screening for other inborn errors of metabolism V83.01 Asymptomatic hemophilia A carrier V83.02 Symptomatic hemophilia A carrier Note: Molecular diagnostic testing (codes 83890-83914, 88384-88386) and cytogenetic studies (codes 88230-88291) can be reported when there is no specific genetic testing CPT/HCPCS code. A genetic testing code modifier specifying the probe type or the condition being tested can be appended to the CPT code to provide complete and precise information regarding the genetic test being performed. See Table II in the Appendix for a list of modifiers applicable to this policy. ICD-10 codes are provided for your information. These will not become effective until 10/1/2014: ICD-10 Code Description E34.3 Short stature due to endocrine disorder E70.0 Classical phenylketonuria E70.21 Tyrosinemia E70.29 Other disorders of tyrosine metabolism E70.30 Albinism, unspecified E70.8 Other disorders of aromatic amino-acid metabolism E71.0 Maple-syrup-urine disease E71.120 Methylmalonic acidemia E71.19 Other disorders of branched-chain amino-acid metabolism E71.2 Disorder of branched-chain amino-acid metabolism, unspecified E70.83 Other disorders of tyrosine metabolism E72.10 Disorders of sulfur-bearing amino-acid metabolism, unspecified E72.11 Homocystinuria E72.12 Methylenetetrahydrofolate reductase deficiency E72.19 Other disorders of sulfur-bearing amino-acid metabolism E75.02 Tay-Sachs disease E75.21 Fabry (-Anderson) disease Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy Policy number M.DIA.04.121120, effective 12/01/2015 Page 9 E75.22 Gaucher disease E75.249 Niemann-Pick disease, unspecified E76.01 Hurler’s syndrome E76.02 Hurler-Scheie E76.03 Scheie’s syndrome E76.1 Mucopolysaccharidosis, type II E76.210 Morquio A mucopolysaccharidoses E76.211 Morquio B mucopolysaccharidoses E76.219 Morquio mucopolysaccharidoses, unspecified E76.22 Sanfilippo mucopolysaccharidoses E76.3 Other mucopolysaccharidoses E76.3 Mucopolysaccharidosis, unspecified D56.0 Alpha thalassemia D56.1 Beta thalassemia D57.00 Hb-SS disease with crisis, unspecified D57.01 Hb-SS disease with acute chest syndrome D57.02 Hb-SS disease with splenic sequestration D57.1 Sickle-cell disease without crisis D57.20 Sickle-cell/Hb-C disease without crisis D57.211 Sickle-cell/Hb-C disease with acute chest syndrome D57.212 Sickle-cell/Hb-C disease with splenic sequestration D57.219 Sickle-cell/Hb-C disease with crisis, unspecified D57.3 Sickle-cell trait D57.40 Sickle-cell thalassemia without crisis D66 Hereditary factor VIII deficiency D67 Hereditary factor IX deficiency D68.0 Von Willebrand’s disease E75.23 Krabbe disease E75.25 Metachromatic leukodystrophy E75.29 Other sphingolipidosis E77.0 Defects in post-translational modification of lysosomal enzymes E77.1 Defects in glycoprotein degradation E83.110 Hereditary hemochromatosis E84.0 Cystic fibrosis with pulmonary manifestations E84.19 Cystic fibrosis with other intestinal manifestations E84.8 Cystic fibrosis with other manifestations Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy Policy number M.DIA.04.121120, effective 12/01/2015 Page 10 E84.0 F70-F79 G10 Autistic disorder Mental retardation, code range Huntington’s disease G11.1 Early-onset cerebellar ataxia G12.9 Spinal muscular atrophy, unspecified G60.0 Hereditary motor and sensory neuropathy G71.0 Muscular dystrophy G71.11 Myotonic muscular dystrophy G71.12 Myotonia congenita G71.13 Myotonic chondrodystrophy G71.14 Drug induced myotonia G71.19 Other specified myotonic disorders I45.81 Long QT syndrome K50.00 Crohn’s disease of small intestine without complications K51.80 Other ulcerative colitis without complications O26.20 Pregnancy care for patient with recurrent pregnancy loss, unspecified trimester O26.21O26.23 Pregnancy care for patient with recurrent pregnancy loss (first, second, third trimester) Q04.1 Arhinencephaly Q04.2 Holoprosencephaly Q04.3 Other reduction deformities of brain Q55.4 Other congenital malformations of vas deferens, epididymis, seminal vesicles and prostate Q61.19 Other polycystic kidney, infantile type Q61.2 Polycystic kidney, adult type Q77.1 Thanatophoric short stature Q77.4 Achondroplasia Q77.8 Other osteochondrodysplasia with defects of growth of tubular bones and spine Q78.0 Osteogenesis imperfecta Q85.01 Neurofibromatosis, type 1 Q85.02 Neurofibromatosis, type 2 Q85.8 Other phakomatoses, not elsewhere classified Q87.1 Congenital malformation syndromes predominantly associated with short stature Q93.4 Deletion of short arm of chromosome Q93.81 Velo-cardio-facial syndrome Q96.9 Turner’s syndrome, unspecified Q98.4 Klinefelter syndrome, unspecified Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy Policy number M.DIA.04.121120, effective 12/01/2015 Page 11 Q99.2 Fragile X chromosome R62.0 Delayed milestone in childhood Z13.220 Encounter for screening for lipoid disorders Z13.228 Encounter for screening for other metabolic disorders Z13.4 Encounter for screening for certain developmental disorders in childhood Z13.89 Encounter for screening for other disorder Z14.01 Asymptomatic hemophilia A carrier Z14.02 Symptomatic hemophilia A carrier Z14.1 Cystic fibrosis carrier Z15.89 Genetic susceptibility to other disease Z31.430 Encounter of female for testing for genetic disease carrier status for procreative management Z31.440 Encounter of male for testing for genetic disease carrier status for procreative management Z82.41 Family history of sudden cardiac death Z86.71 Family history of polycystic kidney Z82.79 Family history of other congenital malformations, deformations and chromosomal abnormalities Z84.81 Family history of carrier of genetic disease Z86.71 Personal history of venous thrombosis and embolism Z87.798 Personal history of other (corrected) congenital malformations V. Appendix A. Table 1: LQTS Clinical Probability Score Card (i.e., Schwartz Score) Finding Points History Clinical history of syncope* without stress with stress 1 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) 460-470 ms >480 ms Torsade de pointes** T-wave alternans >3 Leads with notched T waves Bradycardia (<second percentile for age) Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy Policy number M.DIA.04.121120, effective 12/01/2015 1 2 3 2 1 1 0.5 Page 12 B. Table II : Genetic code modifiers: Modifier Description OC Neurofibromin (Neurofibromatosis, type 1) OD Merlin (Neurofibromatosis, type 2) OF VHL (Von Hippel Lindau disease) 3A F5 commonly called Factor V (Leiden, others) (Hypercoagulable state) 3D HBB, beta globin (Thalassemia, Sickle cell anemia, other hemoglobinopathies) 3E HBA, commonly called alpha globin (Thalassemia) 3F MTHFR (Elevated homocystinemia) 3G F2, commonly called prothrombin (20210, others)(Hypercoagulable state) Prothrombin (Factor II, 20210A)Hypercoagulable state 3H F8, commonly called Factor VIII (Hemophilia A/VWF) 3I F9, commonly called Factor IX (Hemophilia B) 3K F13, commonly called Factor XIII (bleeding or hypercoagulable state) Beta globin 5A ASPA, commonly called Aspartoacylase A (Canavan disease) 5B FMR-1 (Fragile X, FRAXA, syndrome) 5C FRDA commonly called Frataxin (Freidreich ataxia) 5D HD commonly called Huntington (Huntington's disease) 5E GABRA5, NIPA1, UBE3A, or ANCR GABRA (Prader Willi-Angelman syndrome) 5H SNRPN (Prader Willi-Angelman syndrome) 5N PMP-22(Charcot-Marie-Tooth disease, type 1A) 6A DMD (Duchenne/Becker muscular dystrophy) 6B DMPK (Myotonic dystrophy, type 1) 6C ZNF-9 (Myotonic dystrophy, type 2) 6D SMN1/SMN2 (Autosomal recessive spinal muscular atrophy) 7B NPC1 or NPC2 (Nieman-Pick disease) 7C GBA (Gaucher disease) 8A CFRT (Cystic fibrosis) 8C LQTS, KCN (Jervell and Lange-Nielsen syndromes, types 1, 2, 5, and 6) and SCN (Brugada syndrome, SIDS and type 3) 9A TPMT, Patients on antimetabolite therapy 9N FGFR2 (Crouzon, Jackson-Weiss, Apert, Saethre-Chotzen syndromes) 9O FGFR3 (Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia, types I and II, Crouzon syndrome with acanthosis nigricans, Muencke syndromes) 9Q DGCR, commonly Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy Policy number M.DIA.04.121120, effective 12/01/2015 Page 13 VI. Policy History Policy Number: M.DIA.04.121120 Current Effective Date: 12/01/2015 Original Document Effective Date: 11/20/2012 Previous Revision Dates: N/A 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 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. Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy Policy number M.DIA.04.121120, effective 12/01/2015 Page 14 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 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. Expanded Carrier Screening Panels A 2011 study by Bell et al described the development of an ECS panel for 448 severe recessive diseases of childhood, using next generation sequencing (NGS). The authors tested 104 unrelated DNA samples. They noted that although technical standards and guidelines for laboratory-developed genetic testing for rare disorders in accredited laboratories have been established, there are several challenges in their adoption for NGS and for bioinformatic-based testing of many conditions. Specific national standards for quality assurance, quality control, test accessioning and reporting, and proficiency evaluation do not currently exist. Also, issues of specificity and false positives are complex when hundreds of genes are being sequenced simultaneously and need to be addressed. Lazarin et al (2013) reported on carrier status from an ethnically diverse clinical sample of 23,452 individuals. Using the Counsyl test screening platform, they assayed 417 disease-causing mutations associated with 108 recessive diseases. Of the individuals tested, 5633 (24%) were heterozygous for at least 1 condition, and 5.2% were identified as carriers for multiple disorders. Of 127 carrier couples identified (ie, pairs of individuals identified as partners by self-report who were both found to share heterozygosity for at least 1 disease), 47 (37%) were for alpha-1 antitrypsin deficiency, a condition Genetic Testing for Non-Cancerous IInheritable Diseases 21 has reduced penetrance, variable severity, and uncertain clinical presentation in the newborn period and into adulthood. The American Thoracic Society discourages genetic testing for alpha-1 antitrypsin deficiency in asymptomatic adults with no increased risk for this disease. In March 2011, six U.S. academic centers convened focus groups to examine genetics professionals’ views on ECS. Forty genetics professionals, including those specializing in medical genetics, pediatric genetics, genetic counseling, public health genetics, primary care, laboratory medicine, and law and bioethics, aimed to clarify how genetics professionals view potential benefits and challenges of ECS. Overall, participants agreed that there was financial value in ECS panels compared with conventional carrier screening. However, their findings highlighted major limitations of ECS. Concerns included the following: Use of ECS panels would be a significant departure from clinical practice guidelines in genetic and reproductive healthcare in the U.S., and carrier screening guidelines currently exist for only a few of the genetic disorders evaluated by ECS panels. Technical limitations of ECS include the inability to fully rule out the possibility of severe recessive diseases due to rare mutations that could be identified by alternative methods such as DNA sequencing, and, there are gaps in coverage of both specific genes and individual mutations included in the ECS panels. Current ECS panels typically examine only a fraction of the many genes associated with genetic disorders and limit their evaluation to common genetic mutations within those genes. Reproductive healthcare providers might fail to recommend more conventional forms of targeted genetic evaluation, such as screening tests indicated by a couple’s ethnicity, based on erroneous perceptions about the coverage of ECS products being marketed as universal in scope. Less common mutations in specific ethnic populations may not be included, and couples may be falsely reassured by “negative” results. As the number of individual assays on a multiplexed genetic test increases, the likelihood of erroneous results (eg, false positives) and clinically ambiguous findings (eg, variants of unknown significance) increases significantly. Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy Policy number M.DIA.04.121120, effective 12/01/2015 Page 15 As carrier screening panels expand to include less common genetic diseases, interpretation of mutation results is hindered by lack of data on clinical phenotypes associated with rare variants. In 2013, Wienke et al issued a commentary on the limitations of using ECS panels. The authors stated that: Patients may not understand the nature of every disease on the panel, confounding the process of informed consent. In practice, it is infeasible to inform patients of the nature of each condition tested, and many healthcare providers are unfamiliar with some of the conditions tested, making it difficult to communicate residual risk and action ability of information obtained. It is possible that a test primarily designed to assess reproductive risk will inadvertently identify an asymptomatic individual with the disease, which poses many challenges. These include unanticipated psychosocial burden to patients, and a burden to the healthcare system in general as a person identified through this method may undergo additional baseline testing for the disease and receive follow-up for the disease that may otherwise have been unnecessary. Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy Policy number M.DIA.04.121120, effective 12/01/2015 Page 16