Genetic Testing for Non-Cancerous Inheritable Diseases

Transcription

1 Genetic Testing for Non-Cancerous Inheritable Diseases Policy Number: Original Effective Date: MM /01/2010 Line(s) of Business: Current Effective Date: HMO; PPO; QUEST Integration 02/01/2016 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 nextgeneration 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. For the purpose of this policy, first-degree relatives are defined as 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. This policy does not address oncology-related genetic testing or pre-implantation genetic diagnosis (PGD). II. Criteria/Guidelines 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:

2 Genetic Testing for Non-Cancerous Inheritable Diseases 2 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) Down's syndrome 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.

3 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 2. Chromosomal microarray analysis as first line testing in initial postnatal evaluation of individuals with any of the following: a. Apparently nonsyndromic developmental delay/intellectual disability b. Autism spectrum disorder 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: a. Individuals with an intellectual disability, DD, or ASD b. Prenatal testing of fetuses of known carrier mothers c. Individuals planning a pregnancy who have either of the following; i. A first- or second- degree relative with fragile X syndrome, or ii. A first- or second- degree relative with undiagnosed intellectual disability 5. Carrier screening for Ashkenazi Jewish individuals for: 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:

4 Genetic Testing for Non-Cancerous Inheritable Diseases 4 a. 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. b. In individuals with a family history of hemochromatosis in a first degree relative. 7. Genetic testing for predisposition to hypertrophic cardiomyopathy (HCM) for individuals having one first-degree relative with established HCM when there is a known pathogenic gene mutation present in that affective relative. 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 Table I in the Appendix) 9. Genetic testing for Factor V Leiden and/or prothrombin G20210A mutations when any of the following criteria are met: 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. Venous thrombosis and a first-or second- degree relative with thrombotic disease f. Venous thrombosis in pregnant women or women taking oral contraceptives g. Women with recurrent pregnancy loss or unexplained severe preeclampsia, placental abruption, intrauterine fetal growth retardation or stillbirth h. Myocardial infarction in female smokers under age One-time genotypic or phenotypic analysis of the enzyme Thiopurine Methyltransferase (TPMT) is covered 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. 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 have failed a trial of iron therapy ii. Infants who are diagnosed on newborn screening as having a hemoglobinopathy b. For carrier testing in either of the following situations:

5 Genetic Testing for Non-Cancerous Inheritable Diseases 5 i. When there is an affected first- or second- degree relative with thalassemia or sickle cell disease ii. 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 12. 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 health outcomes: 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. 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. 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. Chromosomal microarray analysis is not covered to confirm the diagnosis of a disorder or syndrome that is routinely diagnosed based on clinical evaluation alone. 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)

6 Genetic Testing for Non-Cancerous Inheritable Diseases 6 1. Counsyl 2. GoodStart Select 3. Inherigen 4. Inheritest 5. Natera One Disease Panel 6. Progenity CFnxt 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 Description ASPA (aspartoacylase) (e.g. Canavan disease) gene analysis, common variants (e.g. E285A, Y231X) CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis ;known familial variants CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis; duplication/deletion variants CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis; full gene sequence CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis;; intron 8 poly-t analysis 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) Cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities

7 Genetic Testing for Non-Cancerous Inheritable Diseases F2 (prothrombin, coagulation factor II) (e.g. hereditary hypercoagulability) gene analysis, 20210G>A variant F5 (coagulation factor V) (e.g. hereditary hypercoagulability) gene analysis, Leiden variant FMR1 (fragile X mental retardation 1) (e.g. fragile X mental retardation) gene analysis; evaluation to detect abnormal alleles FMR1 (fragile X mental retardation 1) (e.g. fragile X mental retardation) gene analysis; characterization of alleles GBA (glucosidase, beta, acid) (e.g., Gaucher disease) gene analysis, common variants (e.g., N370S, 84GG, l444p, IVS2+1G>A) HEXA (hexosaminidase A [alpha polypeptide]) (e.g., Tay-Sachs disease) gene analysis, common variants (e.g., 1278insTATC, G>C, G269S) HFE (hemochromatosis) gene analysis, common variants (e.g., C282Y, H63D) 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) Ikbkap (inhibitor of kappa light polypeptide gene enhancer in b-cells, kinase complex-associated protein) (eg, familial dysautonomia) gene analysis, common variants (eg, t>c, r696p) Long QT syndrome gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1 and ANK2); full sequence analysis Long QT syndrome gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1 and ANK2); known familial sequence variant Long QT syndrome gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1 and ANK2); duplication/deletion variants Ashkenazi jewish associated disorders (eg, bloom syndrome, canavan disease, cystic fibrosis, familial dysautonomia, fanconi anemia group c, gaucher disease, tay-sachs disease), genomic sequence analysis panel, must include sequencing of at least 9 genes, including ASPA, BLM, CFTR, FANCC, GBA, HEXA, IKBKAP, MCOLN1, AND SMPD X-linked intellectual disability (XLID) (eg, syndromic and non-syndromic XLID); genomic sequence analysis panel, must include sequencing of at least 60 genes, including ARX, ATRX, CDKL5, FGD1, FMR1, HUWE1,

8 Genetic Testing for Non-Cancerous Inheritable Diseases 8 IL1RAPL, KDM5C, L1CAM, MECP2, MED12, MID1, OCRL, RPS6KA3, and SLC16A2 (New ) X-linked intellectual disability (XLID) (eg, 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 ) S3845 S3846 S3850 S3861 S3865 S3866 S9870 Genetic testing for alpha-thalassemia Genetic testing for hemoglobin E beta-thalassemia Genetic testing for sickle cell anemia Genetic testing, sodium channel, voltage-gated, type v, alpha subunit (scn5a) and variants for suspected Brugada syndrome Comprehensive gene sequence analysis for hypertrophic cardiomyopathy Genetic analysis for a specific gene mutation for hypertrophic cardiomyopathy (HCM) in an individual with a known HCM mutation in the family Comparative genomic hybridization (CGH) microarray test for developmental delay/ autism spectrum disorder and/or mental retardation Hb-SS disease without crisis Hb-SS disease with crisis Sickle-cell/Hb-C disease Other hemoglobinopathies (hemoglobin C) Autistic disorder, current or active state or residual state Specific delays in development code range Intellectual disabilities code range Cerebral lipidoses (Tay-Sachs disease) Spinal muscular atrophy (SBMA,SMN) Hypertrophic obstructive cardiomyopathy Long QT syndrome Regional enteritis, code range Ulcerative colitis, code range

9 Genetic Testing for Non-Cancerous Inheritable Diseases Habitual aborter; unspecified, with or without mention of antepartum condition (defined as two or more consecutive pregnancy losses)* Habitual aborter; antepartum condition or complication(defined as two or more consecutive pregnancy losses)* Fragile X syndrome Delayed milestone V12.51 Personal history of venous thrombosis and embolism V17.41 Family history of sudden cardiac death (SCD) V82.4 Maternal postnatal screening for chromosomal anomalies * Definition from the American College of Obstetricians and Gynecologists: Practice Bulletin #24 D. Codes that do not require precertification: CPT Description DMD (dystrophin) (eg, Duchenne/Becker muscular dystrophy) deletion analysis, and duplication analysis, if performed BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (e.g. Maple syrup urine disease) gene analysis, common variants (e.g. R183P, G278S, E422X) CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis; common variants MCOLN1 (mucolipin 1) (eg, mucolipidosis, type iv) gene analysis, common variants (eg, ivs3-2a>g, del6.4kb) PMP22 (peripheral myelin protein 22) (e.g., Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; duplication/deletion analysis PMP22 (peripheral myelin protein 22) (e.g., Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; full sequence analysis PMP22 (peripheral myelin protein 22) (e.g., Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis ;known familial variant SMPD1(sphingomyelin phosphodiesterase 1, acid lysosomal) (e.g., Niemann- Pick disease, type A) gene analysis, common variants (e.g., R496L, L302P,

10 Genetic Testing for Non-Cancerous Inheritable Diseases 10 fsp330) SNRPN/UBE3A (small nuclear ribonucleoprotein polypeptide N and ubiquitin protein ligase E3A) (e.g., Prader-Willi syndrome and/or Angelman syndrome), methylation analysis HCPCS S3842 S3849 S3853 Description Genetic testing for Von Hippel-Lindau disease Genetic testing for Niemann-Pick disease Genetic testing for myotonic muscular dystrophy ICD-9 Description Neurofibromatosis, type 1 (neurofibromin) Neurofibromatosis, type 2 (Merlin) Dwarfism, not elsewhere classified [hypochondroplasia, thanatophoric dysplasia (FGFR3)] Phenylkentonuria (PKU) Other disturbances of aromatic amino-acid metabolism (includes albinism) Disturbances of branched-chain amino acid metabolism (includes maple syrup urine disease) Disturbances of suphur-bearing amino-acid metabolism (includes homocystinuria) Mucopolysaccharidosis (MPS-1) Congenital factor VIII disorder (hemophilia A/VWF) Congenital factor IX disorder([hemophilia B) Von Willebrand's disease Leukodystrophy Huntington's chorea (Huntington's disease) Friedreich's ataxia (frataxin) Peroneal muscular atrophy (Charcot-Marie-Tooth disease) Hereditary progressive muscular dystrophy( [Duchene (dystrophin)] [Becker's type] [limb girdle muscular dystrophy (LGMD1, LGMD2)] [oculopharyngeal muscular dystrophy (OPMD)]) Myotonic disorders (myotonic dystrophy {CMPK, ZNF-9}) Reduction deformities of brain (classical lissencephaly)

11 Genetic Testing for Non-Cancerous Inheritable Diseases Cystic kidney disease (including polycystic kidney, autosomal dominant) Chondrodystrophy (achondroplasia) Osteogenesis imperfecta Down's syndrome Autosomal deletion syndromes; cri-du-chat syndrome Velo-cardio-facial syndrome [22q11 deletion syndrome (CATCH-22)] Gonadal dysgenesis (ovarian dysgenesis, Turner's syndrome, XO syndrome) Klinefelter's syndrome Other hamartoses, not elsewhere classified (Von Hippel Lindau syndrome) 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 V77.6 Screening for Cystic Fibrosis V77.7 Special screening for other inborn errors of metabolism V83.01 Asymptomatic hemophilia A carrier V83.02 Symptomatic hemophilia A carrier V83.81 Cystic fibrosis gene carrier E. Codes that do not meet payment determination criteria CPT Description 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 MTHFR (5, 10-methylenetetrahydrofolate reductase) (e.g., hereditary hypercoagulability) gene analysis, common variants (e.g., 677T, 1298C) VKORC1 (vitamin K epoxide reductase complex, subunit 1) (e.g., warfarin metabolism), gene analysis, common variants (eg, -1639/3673) S3852 Dna analysis for apoe epsilon 4 allele for susceptibility to alzheimer's disease Note: Molecular diagnostic testing (codes , ) and cytogenetic studies (codes ) can be reported prior to January 1, 2013 when there is no specific genetic testing CPT/HCPCS code.

12 Genetic Testing for Non-Cancerous Inheritable Diseases 12 ICD-10 Description Q85.01 Neurofibromatosis, type 1 Q85.02 Neurofibromatosis, type 2 E34.3 Short stature due to endocrine disorder E70.0 Classical phenylketonuria E70.1 Other hyperphenylalaninemias E70.20 Disorder of tyrosine metabolism, unspecified E70.21 Tyrosinemia E70.29 Other disorders of tyrosine metabolism E70.30 Albinism, unspecified E X-linked ocular albinism E Autosomal recessive ocular albinism E Other ocular albinism E Ocular albinism, unspecified E Tyrosinase negative oculocutaneous albinism E Tyrosinase positive oculocutaneous albinism E Other oculocutaneous albinism E Oculocutaneous albinism, unspecified E Chediak-Higashi syndrome E Hermansky-Pudlak syndrome E Other albinism with hematologic abnormality E Albinism with hematologic abnormality, unspecified E70.39 Other specified albinism E70.5 Disorders of tryptophan metabolism E70.8 Other disorders of aromatic amino-acid metabolism E70.9 Disorder of aromatic amino-acid metabolism, unspecified E71.0 Maple-syrup-urine disease E Isovaleric acidemia E methylglutaconic aciduria E Other branched-chain organic acidurias E Methylmalonic acidemia E Propionic acidemia E Other disorders of propionate metabolism E71.19 Other disorders of branched-chain amino-acid metabolism E71.2 Disorder of branched-chain amino-acid metabolism, unspecified 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

13 Genetic Testing for Non-Cancerous Inheritable Diseases 13 E75.21 Fabry (-Anderson) disease E75.22 Gaucher disease E Niemann-Pick disease type A E Niemann-Pick disease type B E Niemann-Pick disease type C E Niemann-Pick disease type D E Other Niemann-Pick disease E Niemann-Pick disease, unspecified E75.3 Sphingolipidosis, unspecified E77.0 Defects in post-translational modification of lysosomal enzymes E77.1 Defects in glycoprotein degradation E77.8 Other disorders of glycoprotein metabolism E77.9 Disorder of glycoprotein metabolism, unspecified E Hereditary hemochromatosis E84.9 Cystic fibrosis, unspecified E84.11 Meconium ileus in cystic fibrosis E84.0 Cystic fibrosis with pulmonary manifestations E84.19 Cystic fibrosis with other intestinal manifestations E84.8 Cystic fibrosis with other manifestations E76.01 Hurler's syndrome E76.02 Hurler-Scheie syndrome E76.03 Scheie's syndrome E76.1 Mucopolysaccharidosis, type II E Morquio A mucopolysaccharidoses E Morquio B mucopolysaccharidoses E Morquio mucopolysaccharidoses, unspecified E76.22 Sanfilippo mucopolysaccharidoses E76.29 Other mucopolysaccharidoses E76.3 Mucopolysaccharidosis, unspecified E76.8 Other disorders of glucosaminoglycan metabolism E76.9 Glucosaminoglycan metabolism disorder, unspecified D56.9 Thalassemia, unspecified D57.40 Sickle-cell thalassemia without crisis D Sickle-cell thalassemia with acute chest syndrome D Sickle-cell thalassemia with splenic sequestration D Sickle-cell thalassemia with crisis, unspecified D56.0 Alpha thalassemia D56.1 Beta thalassemia D56.2 Delta-beta thalassemia D56.3 Thalassemia minor D56.5 Hemoglobin E-beta thalassemia

14 Genetic Testing for Non-Cancerous Inheritable Diseases 14 D56.8 Other thalassemias D57.3 Sickle-cell trait D57.1 Sickle-cell disease without crisis 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 D57.20 Sickle-cell/Hb-C disease without crisis D56.4 Hereditary persistence of fetal hemoglobin [HPFH] D58.2 Other hemoglobinopathies D66 Hereditary factor VIII deficiency D67 Hereditary factor IX deficiency D68.0 Von Willebrand's disease F84.0 Autistic disorder F84.0 Autistic disorder F70 Mild intellectual disabilities F71 Moderate intellectual disabilities F72 Severe intellectual disabilities F73 Profound intellectual disabilities F78 Other intellectual disabilities F79 Unspecified intellectual disabilities E75.23 Krabbe disease E75.25 Metachromatic leukodystrophy E75.29 Other sphingolipidosis E75.00 GM2 gangliosidosis, unspecified E75.01 Sandhoff disease E75.02 Tay-Sachs disease E75.09 Other GM2 gangliosidosis E75.10 Unspecified gangliosidosis E75.11 Mucolipidosis IV E75.19 Other gangliosidosis E75.4 Neuronal ceroid lipofuscinosis G10 Huntington's disease G11.1 Early-onset cerebellar ataxia G12.9 Spinal muscular atrophy, unspecified G12.1 Other inherited spinal muscular atrophy G12.8 Other spinal muscular atrophies and related syndromes G60.0 Hereditary motor and sensory neuropathy G71.0 Muscular dystrophy G71.11 Myotonic muscular dystrophy G71.12 Myotonia congenita G71.13 Myotonic chondrodystrophy

15 Genetic Testing for Non-Cancerous Inheritable Diseases 15 G71.14 Drug induced myotonia G71.19 Other specified myotonic disorders I42.1 Obstructive hypertrophic cardiomyopathy I45.81 Long QT syndrome K50.00 Crohn's disease of small intestine without complications K Crohn's disease of small intestine with rectal bleeding K Crohn's disease of small intestine with intestinal obstruction K Crohn's disease of small intestine with fistula K Crohn's disease of small intestine with abscess K Crohn's disease of small intestine with other complication K Crohn's disease of small intestine with unspecified complications K50.10 Crohn's disease of large intestine without complications K Crohn's disease of large intestine with rectal bleeding K Crohn's disease of large intestine with intestinal obstruction K Crohn's disease of large intestine with fistula K Crohn's disease of large intestine with abscess K Crohn's disease of large intestine with other complication K Crohn's disease of large intestine with unspecified complications K50.80 Crohn's disease of both small and large intestine without complications K Crohn's disease of both small and large intestine with rectal bleeding K Crohn's disease of both small and large intestine with intestinal obstruction K Crohn's disease of both small and large intestine with fistula K Crohn's disease of both small and large intestine with abscess K Crohn's disease of both small and large intestine with other complication K Crohn's disease of both small and large intestine with unspecified complications K50.90 Crohn's disease, unspecified, without complications K Crohn's disease, unspecified, with rectal bleeding K Crohn's disease, unspecified, with intestinal obstruction K Crohn's disease, unspecified, with fistula K Crohn's disease, unspecified, with abscess K Crohn's disease, unspecified, with other complication K Crohn's disease, unspecified, with unspecified complications K51.80 Other ulcerative colitis without complications K51.80 Other ulcerative colitis without complications K51.20 Ulcerative (chronic) proctitis without complications K Ulcerative (chronic) proctitis with rectal bleeding K Ulcerative (chronic) proctitis with intestinal obstruction K Ulcerative (chronic) proctitis with fistula K Ulcerative (chronic) proctitis with abscess

16 Genetic Testing for Non-Cancerous Inheritable Diseases 16 K Ulcerative (chronic) proctitis with other complication K Ulcerative (chronic) proctitis with unspecified complications K51.30 Ulcerative (chronic) rectosigmoiditis without complications K Ulcerative (chronic) rectosigmoiditis with rectal bleeding K Ulcerative (chronic) rectosigmoiditis with intestinal obstruction K Ulcerative (chronic) rectosigmoiditis with fistula K Ulcerative (chronic) rectosigmoiditis with abscess K Ulcerative (chronic) rectosigmoiditis with other complication K Ulcerative (chronic) rectosigmoiditis with unspecified complications K51.40 Inflammatory polyps of colon without complications K Inflammatory polyps of colon with rectal bleeding K Inflammatory polyps of colon with intestinal obstruction K Inflammatory polyps of colon with fistula K Inflammatory polyps of colon with abscess K Inflammatory polyps of colon with other complication K Inflammatory polyps of colon with unspecified complications K51.50 Left sided colitis without complications K Left sided colitis with rectal bleeding K Left sided colitis with intestinal obstruction K Left sided colitis with fistula K Left sided colitis with abscess K Left sided colitis with other complication K Left sided colitis with unspecified complications K51.00 Ulcerative (chronic) pancolitis without complications K Ulcerative (chronic) pancolitis with rectal bleeding K Ulcerative (chronic) pancolitis with intestinal obstruction K Ulcerative (chronic) pancolitis with fistula K Ulcerative (chronic) pancolitis with abscess K Ulcerative (chronic) pancolitis with other complication K Ulcerative (chronic) pancolitis with unspecified complications K51.80 Other ulcerative colitis without complications K Other ulcerative colitis with rectal bleeding K Other ulcerative colitis with intestinal obstruction K Other ulcerative colitis with fistula K Other ulcerative colitis with abscess K Other ulcerative colitis with other complication K Other ulcerative colitis with unspecified complications K51.90 Ulcerative colitis, unspecified, without complications K Ulcerative colitis, unspecified with rectal bleeding K Ulcerative colitis, unspecified with intestinal obstruction K Ulcerative colitis, unspecified with fistula

17 Genetic Testing for Non-Cancerous Inheritable Diseases 17 K Ulcerative colitis, unspecified with abscess K Ulcerative colitis, unspecified with other complication K Ulcerative colitis, unspecified with unspecified complications O26.20 Pregnancy care for patient with recurrent pregnancy loss, unspecified trimester O26.21 Pregnancy care for patient with recurrent pregnancy loss, first trimester O26.22 Pregnancy care for patient with recurrent pregnancy loss, second trimester O26.23 Pregnancy care for patient with recurrent pregnancy loss, third trimester Q04.0 Congenital malformations of corpus callosum Q04.1 Arhinencephaly Q04.2 Holoprosencephaly Q04.3 Other reduction deformities of brain Q61.00 Congenital renal cyst, unspecified Q61.9 Cystic kidney disease, unspecified Q61.01 Congenital single renal cyst Q61.3 Polycystic kidney, unspecified Q61.2 Polycystic kidney, adult type Q61.11 Cystic dilatation of collecting ducts Q61.19 Other polycystic kidney, infantile type Q61.4 Renal dysplasia Q61.5 Medullary cystic kidney Q61.5 Medullary cystic kidney Q61.02 Congenital multiple renal cysts Q61.8 Other cystic kidney diseases Q77.0 Achondrogenesis Q77.1 Thanatophoric short stature Q77.4 Achondroplasia Q77.5 Diastrophic dysplasia Q77.7 Spondyloepiphyseal dysplasia Q77.8 Other osteochondrodysplasia with defects of growth of tubular bones and spine Q77.9 Osteochondrodysplasia with defects of growth of tubular bones and spine, unspecified Q78.4 Enchondromatosis Q78.0 Osteogenesis imperfecta Q90.0 Trisomy 21, nonmosaicism (meiotic nondisjunction) Q90.1 Trisomy 21, mosaicism (mitotic nondisjunction) Q90.2 Trisomy 21, translocation Q90.9 Down syndrome, unspecified

18 Genetic Testing for Non-Cancerous Inheritable Diseases 18 Q93.4 Deletion of short arm of chromosome 5 Q93.81 Velo-cardio-facial syndrome Q96.0 Karyotype 45, X Q96.1 Karyotype 46, X iso (Xq) Q96.2 Karyotype 46, X with abnormal sex chromosome, except iso (Xq) Q96.3 Mosaicism, 45, X/46, XX or XY Q96.4 Mosaicism, 45, X/other cell line(s) with abnormal sex chromosome Q96.8 Other variants of Turner's syndrome Q96.9 Turner's syndrome, unspecified Q98.0 Klinefelter syndrome karyotype 47, XXY Q98.1 Klinefelter syndrome, male with more than two X chromosomes Q98.3 Other male with 46, XX karyotype Q98.4 Klinefelter syndrome, unspecified Q85.8 Other phakomatoses, not elsewhere classified Q85.9 Phakomatosis, unspecified Q87.1 Congenital malformation syndromes predominantly associated with short stature Q99.2 Fragile X chromosome R62.0 Delayed milestone in childhood Z Personal history of other venous thrombosis and embolism Z Personal history of other (corrected) congenital malformations Z82.41 Family history of sudden cardiac death Z82.71 Family history of polycystic kidney Z Encounter for screening for other metabolic disorders 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 Z Encounter of female for testing for genetic disease carrier status for procreative management Z34.91 Encounter for supervision of normal pregnancy, unspecified, first trimester Z34.92 Encounter for supervision of normal pregnancy, unspecified, second trimester 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

19 Genetic Testing for Non-Cancerous Inheritable Diseases 19 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.

20 Genetic Testing for Non-Cancerous Inheritable Diseases 20 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 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 which 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

21 Genetic Testing for Non-Cancerous Inheritable Diseases 21 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. 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 actionability 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. 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.

22 Genetic Testing for Non-Cancerous Inheritable Diseases 22 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 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, January 31, National Institute of Health. Verified 10/25/ ACMG Policy Statement: Cystic fibrosis Population Carrier Screening: 2004 Revision of ACMG mutation panel. Reaffirmed ACMG Practice Guidelines: Carrier screening in individuals of Ashkenazi descent. Genet Med 2008:10(1): Reaffirmed ACOG committee opinion No. 432: spinal muscular atrophy. ACOG Committee on Genetics Obstet Gynecol. 2009;113(5): ACMG Practice Guidelines; Clinical genetics evaluation in identifying the etiology of autism spectrum disorders Guideline Revisions 6. ACMG Practice Guidelines; Fragile X Syndrome: Diagnostic and carrier testing. October ACMG Consensus Statement on Factor V Leiden Mutation testing. Reaffirmed 05/14/ BCBSA Medical Policy Reference Manual. Pharmacogenetic and Metabolite Markers for Patients Treated with Thiopurines # Last reviewed May 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 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):65ra BCBSA Medical Advisory Panel. Special Report: Evaluating evidence supporting a role for genetic markers assessing disease predisposition and prognosis, or predicting response to therapy. June 10, BCBSA Technology Evaluation Center Genetic testing for long QT syndrome. TEC Assessment 2007; volume 22 tab American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics (ACMG). Preconception and Prenatal Carrier Screening for Cystic Fibrosis: Clinical and Laboratory Provider Guidelines. ACOG/ACMG Position Statement. ACOG; Genetic testing for HFE gene mutations related to hereditary hemochromatosis. BCBSA Technology Evaluation Center. Chicago, IL: April 2002; 16(22)