National Medical Policy

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1 National Medical Policy Subject: Policy Number: Genetic Testing Indications NMP486 Effective Date*: April 2004 Updated: September 2017 This National Medical Policy s subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State s Medicaid manual(s), publication(s), citation(s), and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link X National Coverage Determination (NCD) Cytogenetic Studies (190.3): National Coverage Manual Citation X Local Coverage Determination (LCD)* Genetic Testing for Hypercoagulability /Thrombophilia (Factor V Leiden, Factor II Prothrombin, and MTHFR) : X Article (Local)* Molecular Genetic Testing: X Other Medicare MLN Matters: MM7654, Calendar Year (CY) 2012 Annual Update for Clinical Laboratory Fee Schedule and Laboratory Services Subject to Reasonable Charge Payment: oads/mm7654.pdf None Use Health Net Policy Instructions Genetic Testing Indications for Sept 17 1

2 Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Current Policy Statement (Please refer to other policies for more information on specific genetic tests such as BRCA1 and BRCA2, Tay-Sach Disease etc.) In general, Health Net, Inc. considers genetic testing medically necessary when the following are met: 1. For carrier testing in specific circumstances, or if the individual has personal or family history features suggestive of an inheritable condition, and 2. There is evidence in the published peer-reviewed medical literature that the test is clinically valid and can be adequately interpreted, and 3. Alternative laboratory or clinical tests to definitively diagnose risk for the genetic disorder are unavailable or results are equivocal, and 4. The disease is treatable and/or preventable, and 5. Individual has not previously received confirmatory genetic testing for the disease, and 6. The results of the test (knowledge of the presence or absence of the condition) will impact the diagnosis or medical management of the individual and or family member with a resulting improvement in health outcomes, and 7. When testing panels, including but not limited to, multiple genes or multiple conditions, and in cases where a tiered approach/method is clinically available, testing would be covered ONLY for the number of genes or tests deemed medically necessary to establish a diagnosis. Specifically, Health Net, Inc. considers genetic testing medically necessary for any of the following: 1. Unexplained developmental delay or mental retardation 2. Unusual facial appearance or other dysmorphic features, especially accompanied by failure to thrive or sub-optimal psychomotor development 3. Movement disorder 4. Positive newborn screen, i.e., phenylketonuria (PKU), congenital hypothyroidism, congenital adrenal hyperplasia (CAH), biotinidase deficiency, maple syrup urine disease, galactosemia, homocystinuria, sickle cell anemia, medium chain acyl- CoA dehydrogenase deficiency (MCAD) and hearing loss. Genetic Testing Indications for Sept 17 2

3 5. Common birth defects such as cleft lip/palate, neural tube defects, clubfoot, congenital heart disease, congenital kidney defect, etc. 6. Known or suspected metabolic disorder, including symptoms such as neonatal death, failure to thrive, organomegaly, and loss of previously acquired developmental milestones. 7. Abnormal sexual development, primary amenorrhea, aspermia, infertility, or multiple miscarriages 8. Ambiguous genitalia 9. Growth retardation or failure to thrive, especially if accompanied by any of the above indications 10. Sensory impairment, especially if accompanied by any of the above indications 11. Two or more close relatives with the same disease or related diseases, such as cancer, mental illness, neurologic disorders, etc. 12. Familial cancer (e.g., retinoblastoma, Wilms tumor, renal carcinoma, optic glioma, acoustic neuroma, etc.) 13. Cystic fibrosis (CF) screening and spinal muscular atrophy (SMA) according to the Centene Clinical Policy on Carrier Testing for Pregnancy 14. Fragile X screening for women with a family history of fragile X-related disorders, unexplained mental retardation or developmental delay, autism, or premature ovarian insufficiency; and for woman with ovarian insufficiency or failure or an elevated follicle-stimulating hormone level before age 40 years without a known cause. 15. For SDHB and SDHD gene testing in patients with paraganglioma-syndromes (PGLs) and/or pheochromocytoma syndrome (PCCs), in order to diagnose a hereditary PGL/PCC syndrome. 16. Carrier testing (see Health Net s Medical Policies on genetic testing for specific disorders for additional information): Individuals of Eastern European Jewish descent (Ashkenazi Jews) should be offered screening for Tay Sachs disease, Canavan disease, familial dysautonomia, and cystic fibrosis, mucolipidosis IV, Niemann Pick disease type A, Fanconi anemia group C, Bloom syndrome, and Gaucher disease. Individuals of African, Mediterranean, and Southeast Asian heritage should be offered screening for thalassemias and sickle cell disease. 18. For alpha-thalassemia genetic carrier testing in an individual with a positive hematological test, from a family with confirmed alpha-thalassemia, from a highrisk ethnic background, or who is the reproductive partner of a known alphathalassemia carrier; also for prenatal diagnosis or preimplantation genetic diagnosis (PGD) to identify a fetus or embryo affected with alpha-thalassemia in a couple with known variants. 19. For an oncology patient with unexplained or preexisting familial neuropathy consistent with Charcot Marie Tooth disease (CMT), and for prenatal or preimplantation genetic diagnosis of Charcot Marie Tooth disease Type 1A (CMT1A). 20. Factor V Leiden (FVL) or prothrombin gene (ie G20210) mutation testing for oral contraceptive use in women with a personal history of VTE, or a family history of VTE that includes a first-degree relative with VTE associated with Factor V Leiden or deficiency of antithrombin, protein C or protein S; or history of VTE from an unknown cause, particularly at a younger age (<50 years). Routine screening for factor V Leiden and similar types genetic testing is not recommended in Genetic Testing Indications for Sept 17 3

4 women who are contemplating or using oral contraceptives if there is no personal or family history as noted. Not Medically Necessary Health Net considers the GYNPlus panel not medically necessary at this time. There is a paucity of published peer reviewed studies that evaluated the use of the combination of genes included in the GYNPlus panel to assess cancer risk. There is currently insufficient evidence to determine the impact of this test on individuals with familial ovarian or uterine cancer or hereditary cancer syndromes. Health Net, Inc. considers genetic testing of CHD7 variants for CHARGE Syndrome not medically necessary in all of the following situations: To confirm a diagnosis in an individual who meets established diagnostic criteria for CHARGE syndrome. To confirm a diagnosis in an individual who has some features suggestive of CHARGE syndrome, including an individual with an overlapping clinical disorder (e.g., Kallman syndrome), who does not meet established diagnostic criteria for CHARGE syndrome. To confirm CHARGE syndrome in a fetus that is at risk for CHARGE syndrome based on a family member who has an identified CHD7 gene variant and/or due to abnormalities identified on ultrasound examination, or for preimplantation genetic diagnosis (PGD) when a familial variant has been identified. Health Net, Inc. considers alpha-thalassemia genetic testing not medically necessary for postnatal confirmation of diagnosis in an individual with clinical features of Hb Bart hydrops fetalis syndrome. Alpha-thalassemia genetic testing is not recommended for this the Hb Bart syndrome since this severe form of alphathalassemia can be readily identified by physical and hematological features. Investigational Health Net, Inc. considers genetic testing for hereditary paragangliomapheochromocytoma syndromes (PGL/PCC) investigational in the following situations: For SDHA, SDHC, SDHAF2, MAX, and TMEM127 gene testing in the apparently asymptomatic at-risk relatives of patients with previously identified SDHA, SDHC, SDHAF2, MAX, or TMEM127 gene variants. For prenatal testing or preimplantation genetic diagnosis of hereditary PGL/PCC syndromes in families transmitting a known PGL/PCC-related gene variants. Health Net, Inc. considers genetic testing for LactoTYPE, alpha-mannosidosis, the ThyroSec test, the Epilepsy and Seizure Disorders Sequencing Panel and the Epilepsy and Seizure Disorders Deletion/Duplication Panel as investigational since there is a paucity of peer reviewed scientific literature to support them. Health Net, Inc. considers ELANE gene testing investigational for individuals with symptoms consistent with ELANE-related neutropenia, and for this prenatal diagnosis in families with a confirmed ELANE variant, since there is a paucity of peer-reviewed literature to support the efficacy and clinical utility. Genetic Testing Indications for Sept 17 4

5 Health Net, Inc. considers the MNG Laboratories Comprehensive Intellectual Disability NextGen DNA Screening panel (362 genes), the GynecologoGeneBV testing, the Autism & Intellectual Disability NGS Panel (Transgenomic Inc.), and the devact Clinical Management Panel, investigational since there are insufficient data on analytical validity, clinical validity, and clinical utility, in the peer-reviewed literature. Health Net, Inc. considers the Craniosynostosis NGS Panel (Connective Tissue Gene Tests) investigational since there is a paucity of peer-reviewed literature to support the long-term safety and efficacy of this test. Additional peer-reviewed studies are necessary to determine and review the impact of this genetic testing on patient management. Health Net, Inc. considers genetic testing for the Saethre-Chotzen Syndrome (TWIST) Sequencing and MLPA (Greenwood Genetic Center) investigational since there is a paucity of peer-reviewed literature to support it. This syndrome is a genetic disorder characterized by craniosynostosis most frequently related to prematurely fused skull bones along the coronal suture. Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. ICD-10 (not an all-inclusive list) D56.0-D56.9 Thalassemia D Sickle cell disorders D D58.0-D58.9 Other hereditary hemolytic anemias D66 Hereditary factor VIII deficiency D67 Hereditary factor IX deficiency D68.0-D68.9 Other coagulation defects D70.0-D71 Neutropenia E75.00-E75.6 Disorders of sphingolipid metabolism and other lipid storage disorders (i.e., Tay Sachs, Gaucher disease, Niemann-Pick disease, etc.) F70-F79 Intellectual Disabilities G10-G14 Systemic atrophies primarily affecting the CNS (i.e., Huntington s disease, spinal muscular atrophy, etc.) G60.0-G65.2 Polyneuropathies and other disorders of the peripheral nervous system (i.e., hereditary and idiopathic neuropathy, etc.) G47.35 Congenital central alveolar hypoventilation Q75.0-Q75.9 Other congenital malformations of skull and face bones Z13.0-Z13.89 Encounter for screening for other diseases and disorders Z80.0-Z80.9 Family history of primary malignant neoplasm Z82.0-Z82.8 Family history of certain disabilities and chronic diseases (leading to disablement) Genetic Testing Indications for Sept 17 5

6 CPT CODES: (not an all-inclusive list) NOTE: THESES CODES MAY NOT BE CONSIDERED MEDICALLY NECESSARY UNDER ALL CIRCUMSTANCES. PLEASE READ THE POLICY STATEMENT FOR GUIDANCE DMD (dystrophin) (eg, Duchenne/Becker muscular dystrophy) deletion analysis, and duplication analysis, if performed ASPA (aspartoacylase) (eg, Canavan disease) gene analysis, common variants (eg, E285A, Y231X) BCKDHB (branched-chain keto acid dehydrongenase E1, beta polypeptide) (e.g., Maple syrup urine disease) gene analysis, common variants (E.g., R183P, G278S, E422X) BLM (Bloom syndrome, RecQ helicase-like) (eg, Bloom syndrome) gene analysis, 2281del6ins7 variant) CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; common variants (eg, ACMG/ACOG guidelines) CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; known familial variants CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; duplication/deletion variants CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; full gene sequence CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; intron 8 poly-t analysis (eg, male infertility) 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 FANCC (Fanconi anemia, complementation group C) (eg, Fanconi anemia, type C) gene analysis, common variant (eg, IVS4+4A>T) FRM1 (Fragile X mental retardation 1) (eg, fragile X mental retardation) gene analysis; evaluation to detect abnormal (eg, expanded) alleles FMR1 (Fragile X mental retardation 1) (eg, fragile X mental retardation) gene analysis; characterization of alleles (eg, expanded size and methylation status) G6PC (glucose-6-phosphatase, catalytic subunit) (eg, Glycogen storage disease, Type 1a, von Gierke disease) gene analysis, common variants (eg, R83C, Q347X) GBA (glucosidase, beta, acid) (eg, Gaucher disease) gene analysis, common variants (eg, N370S, 84GG, L444P, IVS2+1G>A) HEXA (hexosaminidase A [alpha polypeptide]) (eg, Tay-Sachs disease) gene analysis, common variants (eg, 1278insTATC, G>C, G269S) HFE (hemochromatosis) (eg, hereditary hemochromatosis) gene analysis, common variants (eg, C282Y, H63D) HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis, for common deletions or variant (eg, 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) MGMT (0-6-methylguanine-DNA methyltransferase) (eg, glioblastoma multiforme), methylation analysis Genetic Testing Indications for Sept 17 6

7 81288 MLH1 (mutl homolog 1, colon cancer, Nonpolyposis type 2) (eg. Hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis MCOLN1 (mucolipin 1) (eg, Mucolipidosis, type IV) gene analysis, common variants (eg, IVS3-2A>G, del6.4kb) MTHFR (5, 10-methylenetetrahydrofolate reductase) (e.g., hereditary hypercoagulability) gene analysis, common variants (e.g., 677T, 1298C) MECP2 (methyl CpG binding protein 2) (eg Rett syndrome) gene analysis PTEN (phosphatase and tensin homolog) (eg, Cowden syndrome, PTEN hamartoma tumor syndrome PMP22 (peripheral myelin protein 22) (eg, Charcot-Marie-Tooth, hereditary neuropathy SMPD1(sphingomyelin phosphodiesterase 1, acid lysosomal) (eg, Niemann- Pick disease, Type A) gene analysis, common variants (eg, R496L, L302P, fsp330) SNRPN/UBE3A (small nuclear ribonucleoprotein polypeptide N and ubiquitin protein ligase E3A) (eg, Prader-Willi syndrome and/or Angelman syndrome), methylation analysis SERPINA1 (serpin peptidase inhibitor, clade A, alpha-1 antiproteinase, antitrypsin, member 1) (eg, alpha-1-antitrypsin deficiency), gene analysis, common variants (eg, *S and *Z) UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide A1) (eg, irinotecan metabolism), gene analysis, common variants (eg, *28, *36, *37) HLA Class I and II typing, low resolution (eg, antigen equivalents); HLA-A, -B, and DRB1 (eg, verification typing) (Code revised in 2014) HLA Class II typing, low resolution (eg, antigen equivalents); one locus (eg, HLA- DRB1, DRB3/4/5, -DQB1, DQA1, -DPB1, or DPA1), each (Code revised in 2014) HLA Class II typing, high resolution (i.e., alleles or allele groups); one locus (eg, HLA-DRB1, -DRB3/4/5, -DQB1, -DQA1, -DPB1, or DPA1), each (Code revised in 2014) Molecular pathology procedure (various levels) (CPT Codes and revised in 2016) 2016 CPT Codes 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, IKBAP, MCOLN1, and SMPD Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); genomic sequence analysis panel, must include sequencing of at least 14 genes, including ATM, BRCA1, BRCA2, BRIP1, CDH1, MLH1, MSH2, MSH6, NBN, PALB2, PTEN, RAD51C, STK11, and TP Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); duplication/deletion analysis panel, must include analysis for BRCA1, BRCA2, MLH1, MSH2, and STK Hereditary neuroendocrine disorders (eg, medullary thyroid carcinoma, parathyroid carcinoma, malignant pheochromocytoma or paraganglioma); Genetic Testing Indications for Sept 17 7

8 genomic sequence analysis panel, must include sequencing of at least 6 genes, including MAX, SDHB, SDHC,SDHD, TMEM127, and VHL Hereditary neuroendocrine disorders (eg, medullary thyroid carcinoma, parathyroid carcinoma, malignant pheochromocytoma or paraganglioma); duplication/deletion analysis panel, must include analysis for SDHB, SDHC, SDHC, and VHL Noonan spectrum disorders (eg, Noonan syndrome, cardio-facio cutaneous syndrome, Costello syndrome, LEOPARD syndrome, Noonan-like syndrome); genomic sequence analysis panel, must include sequencing of at least 12 genes, including BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, RIT1, SHOC2, SOS1. Genetic Testing Indications for Sept 17 8

9 Scientific Rationale Update April 2016 Craniosynostosis is characterized by the premature fusion of the skull joints before the brain is fully developed. This leads to misshapen head structure and may impact brain development. Craniosynostosis can generally be categorized as nonsyndromic or syndromic. Nonsyndromic craniosynostosis is the most common type, and the cause is unknown. Syndromic craniosynostosis may be caused by different genetic disorders, such as Apert syndrome, Pfeiffer syndrome, or Crouzon syndrome. A physical examination and imaging (e.g., computed tomography scan) of the skull to identify the premature fusion of skull bones are used to diagnose craniosynostosis. If a syndromic etiology is suspected, genetic testing may be ordered. The Connective Tissue Gene Tests (CTGT) Craniosynostosis NGS Panel is a nextgeneration sequencing (NGS) panel of 22 genes that the laboratory reports as being associated with craniosynostosis. In addition to the NGS panel, CTGT offers a highdensity targeted (HDT) deletion/duplication microarray assay of the same genes as the NGS panel, either as a separate test or as a comprehensive test comprising both the NGS panel and the deletion/duplication HDT microarray. Although this test is promising, there is a paucity of peer-reviewed studies that have been completed. Additional peer-reviewed studies are necessary to review the impact of this genetic testing on patient management. At this time, this test is considered investigational. Scientific Rationale Update October 2015 The Comprehensive Intellectual Disability NextGen DNA Screening Panel offered by MNG Laboratories analyzes 362 genes by next-generation sequencing (NGS). Specimens that may be submitted for testing include whole blood, extracted DNA, flasks of fibroblasts, snap frozen muscle samples, skin biopsy, or buccal cells. However, there is a paucity of peer reviewed studies to support this testing so at this time it is considered investigational. Bacterial vaginosis (BV) is an infection caused by an overgrowth in atypical bacteria, which disrupts the normal balance of the bacteria in the vagina. BV is the most common vaginal infection in women aged 15 to 44 years. The GynecoloGene BV test is done by AIBiotech and uses a custom-designed, proprietary, next-generation sequencing (NGS) approach, which includes the 16s rrna gene, as a diagnostic for BV. According to the laboratory website, this test will identify all bacteria, all parasites, all fungi, and targeted viruses as well as drug resistance markers. However, there is insufficient peer-reviewed evidence regarding the GynecoloGene BV test. Therefore, at this time, it is considered investigational. Scientific Rationale Update September 2015 Venous thromboembolism (VTE) includes deep vein thrombosis (DVT) and pulmonary embolism (PE) is a common condition that affects 48 to 66 per 100,000 individuals annually. It results from a combination of hereditary and acquired risk factors, also known as thrombophilia or hypercoagulable states and may be precipitated by many different environmental and situational factors, including major trauma, recent surgery, malignancy, prolonged immobilization, pregnancy, and the use of oral contraceptives or hormone replacement therapy (HRT). Heritable conditions (thrombophilias) are identified in approximately 30% to 50% of patients with VTE. Factor V Leiden (FVL), which refers to a specific variant in the gene encoding the factor V protein (F5), is the most common genetic variant associated with VTE. The frequency of this variant varies depending on ethnic background, but is highest (approximately 5%) in white populations. The Factor V Genetic Testing Indications for Sept 17 9

10 Leiden mutation can be diagnosed by DNA analysis and also be detected in an abnormal activated protein C resistance assay. The prothrombin gene mutation (G20210A) is the second most common genetic risk factor for VT and is found almost exclusively in Caucasians and in 6% of patients with venous thromboembolism. It causes an abnormally elevated prothrombin level, which results in a venous thromboembolism rate three times higher than baseline. Deficiencies in protein S, protein C, and antithrombin account for most of the remaining cases. Homozygosity for methylenetetrahydrofolate reductase (MTHFR) polymorphisms (C677T, A1298C) is a relatively common cause of mildly elevated plasma homocysteine levels, but these mutations do not appear to increase the risk of VTE in pregnant or nonpregnant women and therefore would not be expected to increase the risk of VTE in women using estrogen-progestin contraception. HAYES notes that FVL testing may be considered in asymptomatic individuals with an increased risk for VTE, such as the relatives of known FVL carriers, individuals with a strong family history of VTE, or women considering oral contraception or HRT. The American College of Medical Genetics (2007) recommends the following: Factor V Leiden testing is recommended in women with venous thromboembolism during pregnancy or oral contraceptive use. In contrast to general screening before administration of oral contraceptives, targeted testing of women with a personal or family history of venous thrombosis is advisable. Routine screening for factor V Leiden in asymptomatic women contemplating or using oral contraceptives is not recommended, except for those with a personal history of thromboembolism or other medical risk factors. Those women with a family history of thromboembolism, APC resistance, or documented factor V Leiden mutation should be counseled about their risks and options and considered for testing depending on the overall clinical situation. Women with a history of recurrent late-trimester fetal loss should also be considered for testing. Whether or not the woman smokes would not alter these recommendations. Screening of asymptomatic individuals with other recognized environmental risk factors such as surgery, trauma, paralysis, and malignancy is not necessary or recommended, since all such individuals should receive appropriate medical prophylaxis for thrombosis regardless of carrier status. UptoDate also does not recommend screening for inherited thrombophilia in women who are considering the use of estrogen-progestin contraceptives without family history of VTE. Family history includes a first degree relative with a history of VTE associated with deficiency of antithrombin, protein C, or protein S; or multiple firstdegree relatives have a history of VTE, particularly at a younger age (<50 years). They also note that they do not recommend estrogen-progestin contraceptives for women who have had a previous thrombotic episode because of the risk of recurrent VTE, and therefore do not see the need for screening for inherited thrombophilia in women with a personal history of VTE when the purpose of screening is to inform counseling about estrogen-progestin contraceptives as a contraception option. The American Congress of OB/GYN (ACOG) Practice Bulletin on the use of hormone contraception in women with coexisting medical conditions states that women with familial thrombophilic syndromes including factor V Leiden mutation, prothrombin G2010A mutation, protein C or S or antithrombin deficiency have an increased risk of VTE during oral contraceptive use and also develop VTE earlier during use than lower Genetic Testing Indications for Sept 17 10

11 risk. However, they also note that the absolute incidence of thromboembolic events is low and fatal VTE events are rare. Scientific Rationale Update July 2015 The American College of Obstetricians and Gynecologists (ACOG) does not have any information on prenatal or preimplantation genetic diagnosis of Charcot Marie Tooth disease Type 1A (CMT1A). Treatment for CMT1A is usually symptomatic and can include pain management, exercise, orthotics, or orthopedic surgery for foot and ankle problems. For this reason, molecular diagnosis will not affect the course of treatment for this disease. An exception is in oncology patients with a possible family or personal history of peripheral neuropathy, as a result of the toxicity of chemotherapy drugs such as vincristine. It has been established that treatment with chemotherapeutic agents in a patient with preexisting neuropathy can quickly induce debilitating symptoms. NCCN Task Force Report: Management of Neuropathy in Cancer, notes the following: Vinca alkaloids (i.e. Vincristine) are known to induce severe acute neurotoxicity in patients with Charcot-Marie-Tooth disease, a hereditary sensorimotor neuropathy. The genetic mutations involved in this disorder are also linked to malfunction in microtubules and axonal transport. Of special concern are patients with hereditary motor and sensory neuropathies, such as Charcot-Marie-Tooth disease, who may develop severe neuropathic paralysis when receiving vincristine. Personal and family history of hereditary neuropathy (i.e., patients with Charcot-Marie Tooth disease should avoid vincristine-based chemotherapy). A number of case reports have also examined the devastating effects of vincristine on individuals with the CMT1A duplication. In one study of patients who developed severe neuropathy symptoms after receiving safe doses of chemotherapy, 1 patient with CMT received 2 mg of vincristine and subsequently developed severe paralysis. It is suggested that there is no dose of this chemotherapy drug that can be considered safe for use in individuals with CMT. Nakamura et al. (2012) completed a study with the goal to identify mutations in any CMT-associated genes in a patient with hypersensitivity to VCR. The authors performed clinical, electrophysiological, and genetic examinations of a 23-year-old woman, who was hypersensitive to low-dose VCR, and her healthy mother. DNA analysis was performed using specially designed resequencing array that simultaneously screens for 28 CMT-associated genes. Electrophysiological studies revealed that the patient and her healthy mother had demyelinating polyneuropathy. Furthermore, they showed the same novel mutation in the early growth response 2 (EGR2) gene. Recognizing pre-existing asymptomatic CMT by electrophysiological studies and genetic analysis before VCR treatment allowed the authors to prevent severe VCR-induced neuropathy. In summary, neurotoxicity is a common side effect of vincristine (VCR) treatment. Severe exacerbations of neuropathy have been reported in patients with Charcot- Marie-tooth disease (CMT) 1A with duplication of the peripheral myelin protein 22 (PMP22) gene. However, whether or not VCR exacerbates neuropathies through Genetic Testing Indications for Sept 17 11

12 mutations in other CMT-associated genes besides PMP22 duplication has not been well studied. Congenital and cyclic neutropenia are a spectrum of diseases due to variants in the ELANE gene, also known as ELA2, collectively called ELANE-related neutropenia. They produce severe hematologic disorders of neutrophil production that result in lifelong recurrent fever, and inflammation of the skin, mouth and throat. Although studies on ELANE gene testing have been done, they are primarily case series and case reports which have not confirmed the efficacy or clinical utility. Therefore, at this time, this type of genetic testing should be considered investigational. Scientific Rationale Update May 2015 Alpha-mannosidosis is a rare lysosomal storage disorder caused by deficiency of the hydrolase lysosomal alpha-mannosidase (MAN2B1 or LAMAN). It is inherited in an autosomal recessive manner, meaning a variant copy of MAN2B1 must be passed down from both parents in order for disease to manifest. Each sibling of an individual with alpha-mannosidosis is at 25% chance of being affected, 50% chance of being an asymptomatic carrier of a MAN2B1 variant, and 25% chance of being entirely unaffected. This condition includes clinical findings from mild to severe. Three clinical subtypes include: A mild form recognized after age ten years with absence of skeletal abnormalities, myopathy, and slow progression (type 1); A moderate form recognized before age ten years with presence of skeletal abnormalities, myopathy, and slow progression (type 2); and A severe form manifested as prenatal loss or early death from progressive central nervous system involvement (type 3). Individuals with a milder alpha-mannosidosis phenotype have mild-to-moderate intellectual disability, impaired hearing, characteristic coarse features, clinical or radiographic skeletal abnormalities, immunodeficiency, and primary central nervous system disease, mainly cerebellar involvement causing ataxia. Periods of psychiatric symptoms are common. Associated medical problems can include corneal opacities, hepatosplenomegaly, aseptic destructive arthritis, and metabolic myopathy. Alphamannosidosis is insidiously progressive, but some individuals may live into the sixth decade. The diagnosis of alpha-mannosidosis relies on demonstration of deficient acid alpha-mannosidase enzyme activity in peripheral blood leukocytes or other nucleated cells such as fibroblasts. However, carrier testing by this method is unreliable because of overlap of enzyme activity between carriers and non-carriers. MAN2B1 is the only gene known to be associated with alpha-mannosidosis. Diagnosis of alpha-mannosidosis is typically performed by demonstration of deficient alphamannosidase activity in peripheral white blood cells. Molecular genetic testing for MAN2B1 variants is available from U.S. clinical laboratories and is typically performed by sequence analysis, next-generation sequencing (NGS), targeted variant analysis, and/or deletion/duplication analysis. There is insufficient published evidence to support genetic testing for alpha-mannosidosis, therefore, it cannot be recommended for use at this time. The ThyroSeq test evaluates FNA specimens for the presence of numerous different genetic alterations that have been associated with thyroid malignancy. There is insufficient published evidence to perform a Genetic Test Evaluation (GTE) health technology assessment of the ThyroSeq assay; therefore, it cannot be recommended for use at this time. Genetic Testing Indications for Sept 17 12

13 Both the Epilepsy and Seizure Disorders Sequencing Panel and Epilepsy and Seizure Disorders Deletion/Duplication Panel are proposed as secondary tests following chromosomal microarray testing for syndromic and nonsyndromic causes of seizures. However, no peer reviewed studies have been published regarding the impact of using this panel on the care of individuals with epilepsy. Scientific Rationale Update April 2015 Prometheus s LactoType is a commercially available polymerase chain reaction (PCR)-based genetic test that assesses the most common lactase non-persistence genetic variant, C/T-13910, in patients with suspected lactose intolerance. Demonstration of the genotype is proposed by the manufacturer as indirect evidence of lactase insufficiency and lactose malabsorption. Testing may assist with stratifying patients with suspected lactose intolerance into those with a genetic predisposition and those whose underlying cause may be due to other disease potentially requiring further diagnostic workup. However, there is a paucity of published peer-reviewed literature to support LactoTYPE genetic testing at this time. There is insufficient data on analytical validity, clinical validity, and clinical utility, so this will be considered investigational. Scientific Rationale Update March 2015 Alpha-thalassemia usually results from a gene deletion of two or more copies of the four α-globin genes. Deletion of one α-globin gene is clinically unrecognizable, and laboratory testing yields normal results. Deletion of two α-globin genes causes α- thalassemia trait, a mild asymptomatic microcytic anemia. The deletions can be on the same chromosome or on each chromosome. Individuals with these chromosomal abnormalities are referred to as carriers and are at an increased risk for having a child with a more severe form of thalassemia caused by deletions of three or four copies of the α-globin gene. Alpha-thalassemia trait (α-thalassemia minor) is common among individuals of Southeast Asian, African, and West Indian descent, and those with Mediterranean ancestry. Individuals with Southeast Asian ancestry are more likely to carry two gene deletions in cis or on the same chromosome and are at an increased risk for offspring with Hb Bart's or Hb H disease. Hemoglobin H disease, which is caused by the deletion of three α-globin genes, usually is associated with mild to moderate hemolytic anemia. Alpha-thalassemia major (Hb Bart's) results in the absence of α-globin and is associated with hydrops fetalis, intrauterine death, and preeclampsia. Because of high clinical validity, and moderate clinical utility, the most appropriate alpha-thalassemia genetic testing is for carrier testing in asymptomatic individuals with a family history of alpha-thalassemia, individuals with positive hematological tests suggestive of thalassemia, those who are from a high-risk ethnicity, or those who are the reproductive carriers of known alpha-thalassemia carriers. Prenatal diagnosis and PGD studies have shown considerable modification in decisions regarding how to proceed with a pregnancy, and are based on evidence of high clinical validity, and moderate clinical utility. Hb Bart syndrome is typically a fatal condition characterized by edema and ascites, pleural and pericardial effusion, and severe anemia in a fetus, typically in the late second trimester of pregnancy. There are rare cases in which a fetus has been identified in utero and received transfusions, surviving to birth. However, hematopoietic stem cell transplantation is needed for survival, otherwise lifelong transfusions are required. Alpha-thalassemia genetic testing is not recommended for Genetic Testing Indications for Sept 17 13

14 the Hb Bart syndrome since this severe form of alpha-thalassemia can be readily identified by physical and hematological features Per ACOG (reaffirmed in 2013) Couples at risk for having a child with a hemoglobinopathy may benefit from genetic counseling to review the natural history of these disorders, prospects for treatment and cure, their risk, availability of prenatal genetic testing, and reproductive options. Prenatal diagnostic testing for the single mutation responsible for sickle cell disease is widely available. Testing for α- and β-thalassemia is possible if the mutations and deletions have been previously identified in both parents. These DNA-based tests can be performed using chorionic villi obtained by chorionic villus sampling (CVS) at weeks of gestation or using cultured amniotic fluid cells obtained by amniocentesis after 15 weeks of gestation. For some couples, preimplantation genetic diagnosis in combination with in vitro fertilization may be a desirable alternative to avoid termination of an affected pregnancy. Preimplantation genetic diagnosis has been successfully performed for sickle cell disease and most cases of β-thalassemia. Scientific Rationale Update October 2014 CHARGE syndrome is a rare hereditary disorder characterized by coloboma of the eye or CNS anomalies, heart anomalies, nasal choanal atresia, growth retardation, genital defect (i.e., hypogonadism), and ear anomalies (i.e., deafness, dysmorphic ears, and hypoplasia of the semicircular canals), may be associated with Kallmann's syndrome or normosmic IHH. In approximately 60% of cases, CHARGE syndrome is caused by a mutation in the chromodomain helicase DNA binding protein 7 (CHD7) gene, which encodes for a chromatin remodeling protein. CDH7 mutations have been found in approximately 3% to 4% of men with Kallmann's syndrome or normosmic IHH, and it is hypothesized that IHH may be a mild variant of the CHARGE syndrome. There is a paucity of peer-reviewed scientific studies that were done to determine the analytical validity and clinical utility of CHD7 variant testing for CHARGE syndrome. The studies that were done were small cohort studies, case studies, and review articles describing the frequency of CHD7 variants in individuals with a suspected or clinical diagnosis of CHARGE syndrome. The criteria used to identify individuals with CHARGE syndrome varied among studies, as did the testing methodologies utilized. Often there were not enough clinical data to consistently apply diagnostic criteria. Additional peer-reviewed, comparative controlled clinical trials are necessary to determine if this type of genetic testing for CHARGE syndrome is medically necessary. Scientific Rationale Update September 2014 According to Ambry Genetics Corp., manufacturer of the GYNPlus panel, results of testing may help guide treatment, screening, and/or management decisions in ovarian and/or uterine cancer patients or their at-risk relatives. GYNPlus is a nextgeneration sequencing multi-gene test of nine genes associated with high risk for ovarian and/or uterine cancer (BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PMS2, PTEN, and TP53). These nine genes are associated with four hereditary cancer syndromes (i.e., Hereditary Breast and Ovarian Cancer [HBOC], Lynch syndrome, Cowden syndrome and Li-Fraumeni syndrome). Individuals with a personal and/or family history of ovarian and/or uterine cancer may also have a personal and/or family history of breast and/or colorectal cancer and may be suspicious for more than one of the above syndromes. There is a paucity of published peer reviewed Genetic Testing Indications for Sept 17 14

15 studies that evaluated the use of the combination of genes included in the GYNPlus panel to assess cancer risk. There is currently insufficient evidence to determine the impact of this test on individuals with familial ovarian or uterine cancer or hereditary cancer syndromes. There is no mention of GYNPlus in NCCN Clinical Practice Guidelines in Oncology on Genetic / Familial High Risk Assessment: Breast and Ovarian and Colorectal Cancer (Version1.2014). Scientific Rationale Update August 2014 Paragangliomas are rare neuroendocrine tumors that arise from the extra-adrenal autonomic paraganglia, small organs consisting mainly of neuroendocrine cells that are derived from the embryonic neural crest and have the ability to secrete catecholamines. Paragangliomas are closely related to pheochromocytomas, which are sometimes referred to as intra-adrenal paragangliomas, and are indistinguishable at the cellular level. Catecholamine-secreting paragangliomas often present clinically like pheochromocytomas with hypertension, episodic headache, sweating, and tachycardia. However, the distinction between pheochromocytoma and paraganglioma is an important one because of implications for associated neoplasms, risk for malignancy, and genetic testing. Even with modern genetic testing, the majority of paragangliomas appear to be sporadic. However, approximately one-third to one-half are associated with an inherited syndrome with the likelihood of an inherited paraganglioma being higher, about 40% in children. Some hereditary paragangliomas, particularly those arising in the head and neck, have been linked to mutations in the genes encoding different subunits of the succinate dehydrogenase (SDH) enzyme complex. In addition, susceptibility to pheochromocytomas and paragangliomas is an established component of four genetic syndromes, multiple endocrine neoplasia types 2A and 2B (MEN2), neurofibromatosis type 1 (NF1), von Hippel Lindau (VHL), and Carney- Stratakis dyad. Most cases of hereditary paraganglioma are accounted for by mutations in SDHD, SDHB, and SDHC, VHL, and NF1. Mannelli et al. (2009) examined 501 consecutive patients with pheochromocytomas and/or paragangliomas (secreting or nonsecreting). Complete medical and family histories, as well as the results of clinical, laboratory, and imaging studies, were recorded in a database. Patients were divided into different groups according to their family history, the presence of lesions outside adrenals/paraganglia considered syndromic for VHL disease, MEN2, and NF1, and the number and types of pheochromocytomas and/or paragangliomas. Germ-line mutations in known susceptibility genes were investigated by gene sequencing (VHL, RET, SDHB, SDHC, SDHD) or diagnosed according to phenotype (NF1).In 160 patients younger than 50 yr with a wild-type profile, multiplex ligation-dependent probe amplification assays were performed to detect genomic rearrangements. Germline mutations were detected in 32.1% of cases, but frequencies varied widely depending on the classification criteria and ranged from 100% in patients with associated syndromic lesions to 11.6% in patients with a single tumor and a negative family history. The types and number of pheochromocytomas/paragangliomas as well as age at presentation and malignancy suggest which gene should be screened first. Genomic rearrangements were found in two of 160 patients (1.2%). The frequency of the hereditary forms of pheochromocytoma/paraganglioma varies depending on the family history and the clinical presentation. A positive family history and an accurate Genetic Testing Indications for Sept 17 15

16 clinical evaluation of patients are strong indicators of which genes should be screened first. Gill et al. (2010) Up to 30% of pheochromocytomas and paragangliomas are associated with germline RET, Von Hippel-Lindau (VHL), neurofibromatosis type I (NF1), and succinate dehydrogenase subunits (SDHB, SDHC, and SDHD) mutations. Genetic testing allows familial counseling and identifies subjects at high risk of malignancy (i.e., SDHB mutations) or significant multiorgan disease (i.e., RET, VHL, or NF1). However, conventional genetic testing for all loci is burdensome and costly. We performed immunohistochemistry for SDHB on 58 tumors with known SDH mutation status. The authors defined positive as granular cytoplasmic staining, with a mitochondrial pattern, weak diffuse as a cytoplasmic blush lacking definite granularity, and negative as completely absent staining in the presence of an internal positive control. All 12 SDH mutated tumors (6 SDHB, 5 SDHD, and 1 SDHC) showed weak diffuse or negative staining. Nine of 10 tumors with known mutations of VHL, RET, or NF1 showed positive staining. One VHL associated tumor showed weak diffuse staining. Of 36 tumors without germline mutations, 34 showed positive staining. One paraganglioma with no known SDH mutation but clinical features suggesting familial disease was negative, and one showed weak diffuse staining. We also performed immunohistochemistry for SDHB on143 consecutive unselected tumors of which 21 were weak diffuse or negative. As SDH mutations are virtually always germline, we conclude that approximately 15% of all pheochromocytomas or paragangliomas are associated with germline SDH mutation and that immunohistochemistry can be used to triage genetic testing. Completely absent staining is more commonly found with SDHB mutation, whereas weak diffuse staining often occurs with SDHD mutation. Per Lin et al. (2014, UpToDate) the authors advise germline mutation testing for all patients with paraganglioma. Genetic testing is available for mutations in RET, VHL, NF-1, SDHD, SDHC, SDHB, SDHA, SDHAF2, and MAX. Genetic testing assists in estimating the chance of recurrence, either metachronous or malignant, and in determining the correct follow-up algorithm for associated syndromic manifestations. As an example, in a series of 417 patients with pheochromocytoma or paraganglioma of the skull base and neck without features suggesting an inherited syndrome, 12% carried SDHD or SDHB mutations. SDHD carriers had a higher incidence of skull base and neck paragangliomas and multifocality while those with SDHB mutations had an increased frequency of malignant disease. Genetic counseling before and after germline mutation testing is a key step so that patients and families understand the implications of genetic testing, impact on diagnosis and treatment, and the familial risk of transmission. There is no mention of paraganglioma on the NCCN site for Central Nervous System Cancers. Scientific Rationale Update July 2014 Cystic Fibrosis Per the American College of Obstetricians Gynecologists (ACOG, 2011) in their Committee Opinion on Carrier Screening for Cystic Fibrosis it is noted that prenatal and preconception carrier screening for CF was introduced into routine obstetric practice in The goal of CF carrier screening is to identify couples at risk of having a child with classic CF, which is defined by significant pulmonary disease and pancreatic insufficiency. The sensitivity of the screening test varies among different ethnic groups, ranging from less than 50% in those of Asian Genetic Testing Indications for Sept 17 16

17 ancestry to 94% in the Ashkenazi Jewish population. Therefore, screening is most efficacious in non-hispanic white and Ashkenazi Jewish populations. Because testing is offered for only the most common mutations, a negative screening test result reduces, but does not eliminate, the chance of being a CF carrier and having an affected offspring. Cystic fibrosis is an inherited condition that is caused by mutations in the CFTR gene. When a patient and her partner are both carriers of a mutation in the CFTR gene, they have a 1 in 4 chance of having a child with CF. To date, more than 1,700 mutations have been identified in the gene for CF. Screening for the 23 most common mutations is available and can greatly reduce a couple's risk of having a child with CF. The risk of being a carrier depends on an individual's race and ethnicity and family history. Cystic fibrosis is most common in non-hispanic white individuals and people of Ashkenazi Jewish ancestry The following are various carrier screening scenarios with associated management guidelines per ACOG: A woman is a carrier of a CF mutation and her partner is unavailable for testing or paternity is unknown. Genetic counseling to review the risk of having an affected child and prenatal testing options and limitations may be helpful. Prenatal diagnosis is being performed for other indications and CF carrier status is unknown. Cystic fibrosis screening can be performed concurrently on the patient and partner. Chorionic villi or amniocytes may be maintained in culture by the diagnostic laboratory until CF screening results are available for the patient or couple. If both partners are carriers, the sample can then be tested for CF. Both partners are CF carriers. Genetic counseling is recommended to review prenatal testing and reproductive options. Prenatal diagnosis should be offered for the couple's known specific mutations. Both partners are unaffected but one or both has a family history of CF. Genetic counseling and medical record review should be performed to identify if CFTR mutation analysis in the affected family member is available. A woman's reproductive partner has CF or apparently isolated congenital bilateral absence of the vas deferens. The couple should be referred to a genetics professional for mutation analysis and consultation. An individual has two CF mutations but has not previously received a diagnosis of CF. These individuals usually have a mild form of the disease and should be referred to a specialist for further evaluation. Genetic counseling is recommended. Based on the preceding information, the Committee on Genetics provides the following guidelines: It is important that CF screening continues to be offered to women of reproductive age. It is becoming increasingly difficult to assign a single ethnicity to individuals. It is reasonable, therefore, to offer CF carrier screening to all patients. Screening is most efficacious in the non-hispanic white and Ashkenazi Jewish populations. It is prudent to determine if the patient has been previously screened before ordering CF screening that may be redundant. If a patient has been screened previously, CF screening results should be documented but the test should not be repeated. Genetic Testing Indications for Sept 17 17