Preconception Testing for Carrier Status of Genetic Diseases

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1 MEDICAL POLICY Preconception Testing for Carrier Status of Genetic Diseases Effective Date: August 1, 2016 Last Revised: July 12, 2016 Replaces: RELATED MEDICAL POLICIES: Genetic Cancer Susceptibility Panels Using Next Generation Sequencing Genetic Testing for Alpha Thalassemia Introduction Genetic tests are laboratory tests that measure changes in human DNA, chromosomes, genes or gene products (proteins). Blood, skin, cheek swabs, and amniotic fluid are some common samples that can be tested. Genetic testing for carrier status is done on people planning a pregnancy. The goal is to see if they have a potential disease that could be passed onto their offspring. For certain disorders a carrier state exists where a person has no symptoms of the disease, but has the potential to pass the disease onto their children, because they carry a gene for the disease. Often it takes at least two copies of the gene for the disease to cause symptoms. Usually carrier testing is done before conception when individuals are planning a pregnancy, but may also be done in the early stages of pregnancy. Note: The Introduction section is for your general knowledge and is not to be construed as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs providers about when a service may be covered. Quick Links: Select a link below to be redirected to that section. CODING RELATED INFORMATION EVIDENCE REVIEW REFERENCES HISTORY Selecting the icon in the document returns you to this Quick Links menu. Carrier Status of Genetic Diseases

2 Policy Coverage Criteria Expanded Carrier Test Type Expanded Carrier Screening Panels Coverage Criteria Expanded carrier screening panels which test for mutations on many different genes are considered not medically necessary. Based on the individual tested, a subset of the panel may be covered when the policy criteria are met. Expanded carrier panel test names, and their individual mutation components, are rapidly evolving. Examples of tests addressed in this policy include but are not limited to: Counsyl (Counsyl) GoodStart Select (GoodStart Genetics) Inherigen (GenPath) InheriGen Plus Inheritest (LabCorp) Natera One Disease Panel (Natera) Notes: For GoodStart Select the provider may select/limit mutations to those which are targeted to a specific population and in some instances this would not be considered an expanded panel. American College of Medical Genetics (ACMG) defines expanded panels as those that use next generation sequencing to screen for mutations in many genes, as opposed to gene-by-gene screening (e.g., ethnic-specific screening or pan-ethnic 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.1expanded panels may include the diseases that are present with increased frequency in specific populations, but typically include testing for a wide range of diseases for which the patient is not at risk of being a carrier. The General Population

3 Genetic Disease Cystic Fibrosis Coverage Criteria Covered for all individuals with a panel that tests the most common genes (CPT 81220) Note: Carrier testing for cystic fibrosis using CPT CFTR (e.g. cystic fibrosis) gene analysis; full gene sequence is considered not medically necessary for carrier testing. Spinal Muscular Atrophy Covered for all individuals Specific Groups or Populations The following genetic testing may also be considered medically necessary due to an increased frequency of certain disorders in groups or populations: Genetic Disease Ashkenazi Jewish Founder Mutations: Bloom syndrome Canavan disease Cystic fibrosis Familial dysautonomia Fanconi anemia (group C) Gaucher disease Mucolipidosis IV Niemann-Pick (type A) Tay-Sachs disease Coverage Criteria When the individual meets one of the following criteria: Ashkenazi Jewish ancestry consisting of a minimum of one Jewish grandparent. If the Jewish partner has a positive carrier test result, the other partner (regardless of ethnic background) should be screened only for that identified mutation. Genetic testing for Askenazi Jewish Founder mutation is considered not medically necessary for all other uses. FMR1 Mutations (Including Fragile-X Syndrome) When any of the following criteria are met: Individuals of either sex with intellectual disability, developmental delay, or autism spectrum disorder Individuals with a family history of fragile X syndrome or a family history of undiagnosed intellectual disability Mothers who are known carriers to determine whether the fetus inherited the normal or mutant FMR1 gene Affected individuals or relatives of affected individuals who have had a positive cytogenetic fragile X test (less accurate historic test) result who are seeking further counseling related

4 to the risk of carrier status Alpha-Thalassemia Preconception (Carrier) Testing FMR1 Mutations (Including Fragile-X Syndrome) is considered not medically necessary for all other uses. When all of the following criteria are met: At least one parent is of a high-risk ethnic group, such as Southeast Asian, African or Mediterranean ancestry At least one parent has had abnormal biochemical testing which may include ANY of the following: o Anemia o Microcytosis ( a low MCV small blood cells) o Hypochromia (a low MCH or MCHC red blood cells with less hemoglobin) o Abnormal hemoglobin electrophoresis Genetic testing for hemoglobinopathies, except for alpha thalassemia, is considered not medically necessary. Other Inherited Disorders Carrier testing may be considered medically necessary based on the following general criteria: Genetic Disease Carrier Testing Specific Disorder Coverage Criteria When any of the following are present: One or both parents have a first- or second-degree relative who has the disorder: o 1st-degree relatives are parents, siblings, and children. o 2nd-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings. One parent is or both parents are a known carrier of the disorder. All of the following criteria must also be are met: The natural history of the disease is understood and the disease is likely to result in severe health problems in the homozygous or compound heterozygous state. Other biochemical or clinical tests to diagnose carrier status are

5 not available, or provide an indeterminate result or are less accurate than genetic testing. The genetic test has adequate sensitivity and specificity to guide clinical decision making and residual risk is understood o The American College of Medical Genetics and Genomics (ACMG) recommends testing for specific mutations, which will result in carrier detection rate of 95% or higher for most disorders. A clear association of the genetic change with the disorder has been established Genetic testing for other specific disorders is considered not medically necessary when the criteria above are not met. Coding If CPT Tier 1 or Tier 2 molecular pathology codes are available for the specific test, they should be used. If the test has not been codified by CPT, the unlisted molecular pathology code would be used. CPT CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; full gene sequence Ashkenazi Jewish associated disorders genomic sequence panel- Must include at least 9 genes including ASPA, BLM, CFTR, FANCC, GBA, HEXA, IKBKAP, MCOLN1, and SMPD HBA1/HBA2 ( alpha globulin 1 and alpha globulin 2) gene analysis Unlisted molecular pathology procedure

6 Related Information Definition of Terms 1st-, 2nd-, or 3rd-degree relative: For the purpose of familial assessment, 1st-, 2nd-, or 3rddegree relatives are blood relatives on the same side of the family (maternal or paternal).the maternal and paternal sides of the family should be considered independently for familial patterns of cancer. 1st-degree relatives are parents, siblings, and children. 2nd-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings. 3rd-degree relatives are great-grandparents, great-aunts, great-uncles, great-grandchildren, and first cousins Carrier testing: Carrier genetic testing is performed on people who display no symptoms for a genetic disorder but may be at risk for passing it on to their children. A carrier of a genetic disorder has one abnormal allele for a disorder. Carriers of an autosomal recessive mutation are typically unaffected. Offspring who inherit the mutation from both parents usually manifest the disorder. When associated with an autosomal dominant or an X- linked dominant disorder, the individual may be affected with the disorder or at high risk of developing the disorder later in life. Women with an X-linked recessive mutation are usually unaffected. Males receiving a chromosome with an X-linked recessive mutation usually manifest the disorder. Compound heterozygous: The presence of two different mutant alleles at a particular gene locus, one on each chromosome of a pair. Expressivity/expression: The degree to which a penetrant gene is expressed within an individual. Genetic testing involves the analysis of chromosomes, DNA, RNA, genes, or gene products to detect inherited (germline) or non-inherited (somatic) genetic variants related to disease or health. Homozygous: Having the same alleles at a particular gene locus on homologous chromosomes (chromosome pairs).

7 Penetrance: The proportion of individuals with a mutation that causes a particular disorder who exhibit clinical symptoms of that disorder. Residual risk: The risk that an individual is a carrier of a particular disease, but genetic testing for carrier status of the disease is negative (e.g., if the individual has a disease-causing mutation that wasn t included in the test assay). Testing sequence: Testing sequence of carrier testing for genetic diseases is generally, the mother or affected partner is first, and if positive, the other parent is tested. Evidence Review Carrier testing is performed to identify couples at risk of having offspring with a genetic disease. Carriers are usually not at risk of developing the disease, but have a risk of passing a pathogenic gene mutation to their offspring. Carrier testing may be performed before conception or during a pregnancy. This policy offers a framework for evaluating the utility of carrier genetic testing. This policy applies only if there is not a separate policy that outlines specific criteria for carrier testing. If a separate policy exists, then criteria for medical necessity in that policy supersede the guidelines in this policy (see Related Policies). Specific Patient Populations Carrier screening may be performed for conditions that are found in the general population (pan-ethnic), for diseases that are more common in particular populations, or based on family history. Pan-ethnic (population) screening for carrier status is done for single-gene disorders that are common in the population, such as cystic fibrosis. Carrier screening for specific genetic conditions may be done in members of an ethnic group with a high risk of a specific genetic disorder. For example, certain autosomal recessive conditions are more prevalent in individuals of Eastern European Jewish (Ashkenazi) descent.

8 Most individuals of Jewish ancestry in North America are descended from Ashkenazi Jewish communities and are therefore at increased risk of being carriers of one of these conditions. Many of these disorders are lethal in childhood or associated with significant morbidity. FMR1 Mutations/Fragile-X Syndrome Fragile-X syndrome is associated with the expansion of the CGG trinucleotide repeat in the fragile-x mental retardation 1 (FMR1) gene on the X chromosome. Fragile-X syndrome (FXS) is the most common cause of heritable intellectual disability, characterized by moderate intellectual disability in males and mild intellectual disability in females. FXS affects approximately 1 in 4000 males and 1 in 8000 females. In addition to intellectual impairment, patients present with typical facial features, such as an elongated face with prominent forehead, protruding jaw, and large ears. Connective tissue anomalies include hyperextensible finger and thumb joints, hand calluses, velvet-like skin, flat feet, and mitral valve prolapse. The characteristic appearance of adult males includes macroorchidism. Patients may show behavioral problems including autism spectrum disorders, sleeping problems, social anxiety, poor eye contact, mood disorders, and hand-flapping or biting. Another prominent feature of the disorder is neuronal hyperexcitability, manifested by hyperactivity, increased sensitivity to sensory stimuli, and a high incidence of epileptic seizures. Men who are premutation carriers are referred to as transmitting males. All of their daughters will inherit a premutation, but their sons will not inherit the premutation. Males with a full mutation usually have intellectual disability and decreased fertility. Alpha-Thalassemia Hemoglobin, is the major oxygen carrying protein molecule of red blood cells, consists of 2 alpha (α)-globin chains and 2 beta (β)-globin chains. Alpha-thalassemia refers to a group of syndromes that arise from deficient production of α-globin chains. Deficient α-globin production leads to an excess of β-globin chains, which results in anemia by a number of mechanisms: Ineffective erythropoiesis in the bone marrow. Production of nonfunctional hemoglobin molecules. Shortened survival of RBCs [red blood cells] due to intravascular hemolysis and increased uptake of the abnormal RBCs by the liver and spleen.

9 The physiologic basis of α-thalassemia is a genetic defect in the genes coding for α-globin production. Each individual carries four genes that code for α-globin (2 copies each of HBA1 and HBA2, located on chromosome 16), with the wild genotype (normal) being aa/aa. Genetic mutations may occur in any or all of these 4 α-globin genes. The number of genetic mutations determines the phenotype and severity of the α-thalassemia syndromes. The different syndromes are classified as follows: Silent carrier (α-thalassemia minima): This arises from one of four abnormal alpha genes (aa/a-), and is a silent carrier state. A small amount of abnormal hemoglobin can be detected in the peripheral blood, and there may be mild hypochromia and microcytosis present, but there is no anemia or other clinical manifestations. Thalassemia trait (α-thalassemia minor): This is also called α-thalassemia trait and arises from the loss of 2 α-globin genes, resulting on one of two genotypes (aa/--, or a-/a-). There is a mild anemia present, and red blood cells are hypochromic and microcytic. Clinical symptoms are usually absent and in most cases, the Hg electrophoresis is normal. Hemoglobin H disease (α-thalassemia intermedia): This syndrome results from three abnormal α-globin genes (a-/--), resulting in a moderate to severe anemia. In HgH disease, there is an imbalance in α- and β-globin gene chain synthesis, resulting in the precipitation of excess β chains into the characteristic hemoglobin H, or β-tetramer. This condition has marked phenotypic variability, but most individuals have mild disease and live a normal life without medical intervention. A minority of individuals may develop clinical symptoms of chronic hemolytic anemia. These include neonatal jaundice, hepatosplenomegaly, hyperbilirubinemia, leg ulcers, and premature development of biliary tract disease. Splenomegaly can lead to the need for splenectomy, and transfusion support may be required by the third to fourth decade of life. It has been estimated that approximately 25% of patients with HgH disease will require transfusion support during their lifetime. In addition, increased iron deposition can lead to premature damage to the liver and heart. Inappropriate iron therapy and oxidant drugs should be avoided in patients with HgH disease. There is an association between genotype and phenotype among patients with HgH disease. Individuals with a nondeletion mutation typically have an earlier presentation, more severe anemia, jaundice, and bone changes, and more frequently require transfusions.

10 Hemoglobin Bart syndrome (α-thalassemia major): This syndrome results from mutations in all 4 α-globin genes (--/--), resulting in absent production of α-globin chains. This condition causes hydrops fetalis, which often leads to intrauterine death, or death shortly after birth. There are also increased complications of pregnancy for a woman carrying a fetus with hydrops fetalis. These include hypertension, preeclampsia, antepartum hemorrhage, renal failure, premature labor, and abruption placenta. (See Rationale, Table 1 for probability of Hoemoglobin Bart Syndrome.) Alpha-thalassemia is a common genetic disorder, affecting approximately 5% of the world s population. The frequency of mutations is highly dependent on ethnicity, with the highest rates seen in Asians, and much lower rates in Northern Europeans. The carrier rate is estimated to be 1 in 20 in Southeast Asians, 1 in 30 for Africans, and between 1 in 30 and 1 in 50 for individuals of Mediterranean ancestry. In contrast, for individuals of northern European ancestry, the carrier rate is less than 1 in 1,000. Expanded Carrier Screening New technologies have made it possible to screen for mutations in many genes more efficiently than testing mutations in a single gene or a small number of population-specific mutations in several genes. Commercial laboratories offer expanded carrier screening (ECS) panels, which comprise a nontargeted approach to carrier screening. There is no standardization to the makeup of these genetic panels; panel composition varies among labs; and different commercial products for a single condition may test different sets of genes. Although ECS panels may include conditions that are routinely assessed in carrier testing, ECS panels include many conditions that are not routinely evaluated and for which there are no existing professional guidelines. Regulatory Status Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. There are a number of commercially available genetic tests for carrier screening, which range from testing for individual diseases, to small panels designed to address testing based on ethnicity as recommended by practice guidelines (American College of Obstetricians and

11 Gynecologists [ACOG], American College of Medical Genetics and Genomics [ACMG]), to large expanded panels that test for numerous diseases beyond those recommended in practice guidelines. The following is not a comprehensive list of some of the available panels: Counsyl (Counsyl): Tests for more than 100 diseases, which, according to the manufacturer website, lead to shortened lifespan, have limited treatment or can lead to intellectual disability. Diseases tested for include those recommended by ACOG, ACMG, as well as an Ashkenazi Jewish panel, Fragile-X syndrome, a 100-mutation CF panel, sickle cell disease, and metabolic disorders. GoodStart Select (GoodStart Genetics): Customizes the testing panel for each patient based on ethnicity, family history, and provider testing preferences. The test menu includes several ethnic panels, and includes testing for hemoglobinopathies, Fragile-X syndrome, CF, metabolic disorders, and others. Inherigen (GenPath): A pan-ethnic test for over 160 inherited disorders, typically those with childhood onset and severe symptoms, such as immunodeficiencies and several metabolic diseases, such as Tay-Sachs disease, glycogen storage diseases, and fatty acid oxidation disorders. InheriGen Plus includes all InheriGen diseases plus CF, SMA, and Fragile- X syndrome. Inheritest (LabCorp): A pan-ethnic test for more than 90 autosomal recessive inherited diseases. The Inheritest Select Carrier Screen is a test that evaluates diseases for patients of Ashkenazi Jewish descent. Natera One Disease Panel (Natera): Tests for 13 diseases, which include ACMGrecommended tests for carrier screening, plus Fragile-X syndrome, sickle cell anemia, hemoglobin C trait, and SMA. Natera Horizon has 5 different panels that screen for as few as 4 and up to 274 autosomal and X-linked genetic conditions. The panels are pan-ethnic, ancestry-based or expanded. Two CLIA-certified laboratories, Progenity (Ann Arbor, Michigan; formerly amdx Laboratory Sciences and Ascendant MDx) and Sequenom Laboratories (San Diego, CA), offer both single disease carrier testing (cystic fibrosis [CFnxt cystic fibrosis and HerediT Cystic Fibrosis Carrier Screen, respectively], fragile X syndrome [Fragile X syndrome and HerediT Cystic Fibrosis Carrier Screen, respectively], SMA [SMAnxt spinal muscular atrophy and HerediT Spinal Muscular Atrophy Carrier Screen, respectively) and disease panels for Ashkenazi Jewish patients (AJPnxt Basic [9 diseases] or AJPnxt Expanded [19 diseases] and HerediT Ashkenazi Jewish

12 Panel Carrier Screen [17 diseases], respectively). Progenity also offers nxtpanel for simultaneous CF, SMA, and fragile X syndrome testing. FMR1 Mutation/Fragile-X Syndrome Evidence on the clinical benefit of testing for Fragile-X syndrome is largely anecdotal. Clinical utility of genetic testing can be considered in the following clinical situations: (1) individuals with a clinical diagnosis of intellectual disability, developmental delay, or autism, especially if they have any physical or behavioral characteristics of Fragile-X syndrome, a family history of Fragile X syndrome, or male or female relatives with undiagnosed intellectual disability, and (2) individuals seeking reproductive counseling. Clinical utility for these patients depends on the ability of genetic testing to make a definitive diagnosis and for that diagnosis to lead to management changes that improve outcomes. No studies were identified that described how a molecular diagnosis of Fragile-X syndrome changed patient management. Therefore there is no direct evidence for clinical utility of genetic testing in these patients. Because there is no specific treatment for Fragile-X syndrome, making a definitive diagnosis will not lead to treatment that alters the natural history of the disorder. There are several potential ways in which adjunctive management might be changed after confirmation of the diagnosis by genetic testing. The American Academy of Pediatrics (AAP)5 and the American Academy of Neurology (AAN) recommend cytogenetic evaluation in individuals with developmental delay to look for certain chromosomal abnormalities that may be causally related to their condition. AAN guidelines note that only in occasional cases will an etiologic diagnosis lead to specific therapy that improves outcomes but suggest more immediate and general clinical benefits of achieving a specific genetic diagnosis from the clinical viewpoint, as follows: Limit additional diagnostic testing; Anticipate and manage associated medical and behavioral comorbidities; Improve understanding of treatment and prognosis; and Allow counseling regarding risk of recurrence in future offspring and help with reproductive planning. AAP and AAN guidelines also emphasize the importance of early diagnosis and intervention in an attempt to ameliorate or improve behavioral and cognitive outcomes over time. Guidelines from AAP recommend against routine fragile X testing for children with isolated attentiondeficit/hyperactivity disorder.

13 Alpha-Thalassemia Preconception (Carrier) Testing The major benefit of carrier testing is to define the likelihood of α-thalassemia major. Avoiding a pregnancy with α-thalassemia major is of benefit in that a prospective mother will avoid carrying a non-viable pregnancy, and will avoid the increased obstetrical complications associated with a fetus with α-thalassemia major. Carrier screening with biochemical testing is recommended for all patients who are from an ethnic groups with a high incidence of α-thalassemia. Biochemical screening consists of a CBC with peripheral smear analysis. If there are any abnormalities noted, such as anemia, microcytosis, or hypochromia, Hg electrophoresis is then performed to identify the specific types of Hg present and between HgH disease. As noted, the hemoglobin electrophoresis may be normal in the asymptomatic carrier and α-thalassemia trait states, but the states may be suspected based on CBC and peripheral smear analysis. Unlike for a clinical diagnosis, for carrier testing, it is important to distinguish between α- thalassemia carrier (one abnormal gene) and α-thalassemia trait (two abnormal genes), and also important to distinguish between the two variants of α-thalassemia trait, that is the aa/-- (cis variant) and the a-/a- (trans variant). This is because only when both parents have the aa/-- cis variant is there a risk for a fetus with α-thalassemia major. (17) When both parents are α- thalassemia carriers (aa/--), there is a 1 in 4 likelihood that an offspring will have α-thalassemia major and hydrops fetalis. These parents may decide to pursue pre-implantation genetic diagnosis in conjunction with in vitro fertilization to avoid a pregnancy with hydrops fetalis. In this situation, genetic testing has incremental utility over biochemical testing. Whereas biochemical testing can determine whether a silent carrier/trail syndrome is present, and can distinguish those syndromes from HgH disease, it cannot provide a precise determination of the number or pattern of abnormal alpha genes. As a result, using biochemical screening alone, the probability of developing a hemoglobin Bart fetus cannot be accurately assessed. In contrast, genetic testing can delineate the number of abnormal genes with certainty. In addition, genetic testing can determine whether an α-thalassemia trait exists as the cis (aa/--) variant or the trans (a-/a-) variant. Using this information from genetic testing, the probability of hemoglobin Bart syndrome can be determined according to Table 1. Clinical Diagnosis in Genotype Genotype Probability of Hg Bart Parents (Parent 1) (Parent 2) Syndrome, % Both parents silent aa/a- aa/a- 0

14 carriers One parent silent carrier, 1 parent trait aa/a- a-/a- 0 aa/a-- 0 Both parents trait aa/-- aa/-- 25 a-/a- 0 a-/a- aa/-- 0 a-/a- 0 One parent HgH, 1 parent silent carrier One parent HgH, 1 parent trait a-/-- aa/a- 0 a-/-- aa/-- 25 a-/a- 0 Both parents HgH a-/-- a-/-- 25 Hg: hemoglobin Parents can also determine the likelihood of HgH disease in an offspring through genetic testing. However, because this is in most cases a mild condition, it is less likely to be considered information that is actionable in terms of altering reproductive decision making. Preconception (carrier) testing is likely to have clinical utility by providing incremental diagnostic information over biochemical testing that can identify the pattern of abnormal alpha genes and estimate more precisely the risk of hydrops fetalis. Expanded Carrier Screening Panels Expanded carrier screening (ECS) panels may provide the opportunity to test carriers for a greatly expanded number of diseases for a lower cost than the conventional forms of carrier testing. However, current limitations of these expanded panels include technical and interpretive limitations and ethical and genetic counseling challenges, as outlined next. In 2015, a joint statement on ECS was issued by ACMG, ACOG, the National Society of Genetic Counselors, the Perinatal Quality Foundation and the Society for Maternal-Fetal Medicine. (13) The statement was not meant to replace current screening guidelines but to demonstrate an approach for health care providers and laboratories that are seeking to or are currently offering ECS panels. Some of the points to consider include the following:

15 ECS panels include most of the conditions recommended in current guidelines; however, molecular methods used in ECS are not as accurate as methods recommended in current guidelines for: the hemoglobinopathies, which require use of mean corpuscular volume and hemoglobin electrophoresis, and for Tay-Sachs disease. The detection rate for Tay-Sachs carrier status is low in non-ashkenazi populations using molecular testing for the 3 common Ashkenazi mutations-currently, hexoaminidase An enzyme analysis on blood is the best method to identify carriers in all ethnicities. Patients should be aware that newborn screening is mandated by all states and can identify some of genetic conditions in the newborn. However, newborn screening may include a different panel of conditions than ECS. Newborn screening does not usually detect children who are carriers for the conditions being screened so will not necessarily identify carrier parents at increased risk. ECS can be performed by genotyping, which searches for known pathogenic and likely pathogenic variants, or by DNA sequencing, which analyzes the entire coding region of the gene and identifies alterations from the normal sequence. Genotyping includes selected variants, but sequencing has the potential to identify benign and likely benign variants and variants of unknown significance, in addition to pathogenic variants. Therefore, ECS panels should only include genes and variants with a well-understood relationship with a phenotype. When carrier frequency and detection rate are both known, residual risk estimation should be provided in the lab report. Conditions with unclear value on preconception and prenatal screening panels include alpha-1-antitrypsin (A1AT), methylene tetrahydrofolate reductase (MTHFR) and hereditary hemochromatosis (HH). There is currently little evidence that addresses reproductive outcomes using ECS. Future research needs in ECS should focus on data collection and development of a curated data repository, and education of health care providers and patients. To improve the predictive value of ECS, previously unreported and relatively rare variants and full phenotypes of homozygous and compound heterozygotes should be collected and made available. Determining the frequency of variants in previously untested ethnic and racial groups is required because risks associated with gene variants may vary with different genetic backgrounds and in different environmental situations. Collaborative analysis among laboratories is necessary to further understanding of ECS. 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). (14) The authors tested 104

16 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 does 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. (15) Using the Counsyl test screening platform, they assayed 417 diseasecausing mutations associated with 108 recessive diseases. Of the individuals tested, 5,633 (24%) were heterozygous for at least one condition, and 5.2% were identified as carriers for multiple disorders. Of 127 carrier couples identified (i.e., pairs of individuals identified as partners by selfreport who were both found to share heterozygosity for at least one 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. (16) In March 2011, 6 U.S. academic centers convened focus groups to examine genetics professionals views on ECS. (17) Forty genetics professionals, including those specializing in medical genetics, pediatric genetics, genetic counseling, public health genetics, primary care, laboratory medicine, and law and bioethics, aimed to clarify how genetics professionals view potential benefits and challenges of ECS. Overall, participants agreed that there was financial value in ECS panels compared with conventional carrier screening. However, their findings highlighted major limitations of ECS. Concerns included the following: Use of ECS panels would be a significant departure from clinical practice guidelines in genetic and reproductive healthcare in the United States, 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.

17 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 (e.g., false positives) and clinically ambiguous findings (e.g., 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. (18) 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 take action on the information obtained. Panels usually include diseases with decreased penetrance and variable expressivity that are unlikely to be life-threatening in a patient with a negative family history (e.g., Factor V Leiden thrombophilia, hemochromatosis, methylenetetrahydrofolate reductase [MTHFR] deficiency). Screening for mutations that have unclear clinical significance has unclear implications in reproductive decision making. 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.

18 Genetic Counseling Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The Interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods. Ongoing and Unpublished Clinical Trials Some currently unpublished trials that might influence this review are listed in the table below. Table 1: Summary of Key Trials NCT No. Trial Name Planned Ongoing Enrollment Completion Date NCT Clinical Implementation of Carrier Status Using Next Generation Sequencing 400 May 2017 NCT: National Clinical Trial Summary of Evidence The evidence for carrier testing in individuals who are asymptomatic but at risk for having an offspring with a genetic disease includes mutation prevalence studies, general principles of carrier testing and accepted practice guidelines from major medical societies, which provides a framework for evaluating these tests; direct evidence on outcomes with carrier testing is lacking. Relevant outcomes are test accuracy, test validity and changes in reproductive decision making. Reported analytic validity (technical accuracy) of targeted carrier screening tests is high. Changes in management involve family planning decisions. Results of genetic testing can be used to assist individuals with reproductive decisions such as avoidance of pregnancy, preimplantation

19 genetic testing, adoption, etc. Therefore, the evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. The evidence for preconception (carrier) genetic testing for alpha-thalassemia includes case reports and case series that correlate pathogenic mutations with clinical disease. Relevant outcomes are test accuracy, test validity, and changes in reproductive decision making. Preconception carrier testing is intended to avoid the most serious form of α-thalassemia, hemoglobin Bart disease. This condition leads to intrauterine death or death shortly after birth and is associated with increased obstetrical risks for the mother. Screening of populations at risk is first done by biochemical tests, including hemoglobin electrophoresis and complete blood count and peripheral smear, but these tests cannot reliably distinguish between the carrier and trait syndromes and cannot determine which configuration of mutations is present in α- thalassemia trait. They therefore cannot completely determine the risk of a pregnancy with hemoglobin Bart syndrome and hydrops fetalis. Genetic testing can determine with certainty the number of abnormal genes present, and therefore can more precisely determine the risk of hydrops fetalis. Therefore, the evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. The evidence for FMR1 mutation testing (including Fragile X) in individuals with intellectual disability, developmental delay, or autism spectrum disorder or in affected individuals or at-risk relatives in whom testing will affect reproductive decision making includes studies evaluating the analytic and clinical validity of FMR1 mutation testing and a chain of indirect evidence for demonstration of clinical outcome improvements. Relevant outcomes are test accuracy, test validity, resource utilization, and changes in reproductive decision making. Analytic sensitivity and specificity for diagnosing these disorders has been demonstrated to be sufficiently high. The evidence demonstrates that FMR1 mutation testing can establish a definitive diagnosis of FXS when the test is positive for a pathogenic mutation. Following a definitive diagnosis, there are a variety of ways management may change. Providing a diagnosis can eliminate the need for further clinical workup. For certain mutations, results may aid in management of psychopharmacologic interventions, assist in informed reproductive decision making, or both. Although direct evidence for improved outcomes is insufficient, there is a chain of indirect evidence that supports improvements in outcomes following FMR1 mutation testing. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. The evidence for expanded carrier testing in individuals who are asymptomatic but at risk for having an offspring with a genetic disease includes mutation prevalence studies; direct evidence is lacking. Relevant outcomes are test accuracy, test validity and changes in reproductive decision making. analytic validity of expanded carrier screening (ECS) panels is unknown. ECS

20 panels have significant limitations, including increased false positives and variants of uncertain significance due to testing for many mutations, false negatives due to rare mutations not included in panel testing, the inclusion of diseases with decreased penetrance and variable expressivity that are unlikely to be life-threatening in a patient with a negative family history and difficulties with communicating residual risk and actionability of information obtained. Therefore, the evidence is insufficient to determine the effects of the technology on health outcomes. Practice Guidelines and Position Statements Ethnic groups with a higher carrier rate for a particular condition. Ashkenazi Jewish In 2014, the American Congress of Obstetricians and Gynecologists (ACOG) reaffirmed a 2009 committee opinion that carrier screening for Tay-Sachs disease, Canavan disease, cystic fibrosis, and familial dysautonomia should be offered to Ashkenazi Jewish individuals before conception or during pregnancy so that a couple has an opportunity to consider prenatal diagnostic testing options. (4,5) The committee opinion stated that individuals of Ashkenazi Jewish descent may inquire about the availability of carrier screening for other disorders found among individuals of Eastern European Jewish descent, and that carrier screening is available for mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia group C, Bloom syndrome, and Gaucher disease, and that patient education materials can be made available so that interested patients can make informed decisions about having additional screening tests. When only one partner is of Ashkenazi Jewish descent, that individual should be screened first. If that individual is a carrier, the other partner should be offered screening; however, the couple should be informed that because carrier frequency and detection rate in non-jewish individuals is unknown for all of these disorders (except for Tay-Sachs disease and cystic fibrosis), it is difficult to predict the couple s risk of having a child with one of the disorders. If an individual has a positive family history for one of these disorders, he or she should be offered carrier screening for that specific disorder. When both partners are carriers of one of these disorders, they should be referred for genetic counseling and offered prenatal diagnosis. In 2013, The American College of Medical Genetics and Genomics (ACMG) reaffirmed a 2008 guideline that recommended carrier screening for cystic fibrosis, Canavan disease, familial dysautonomia, and Tay-Sachs disease be offered to all individuals of Ashkenazi Jewish descent who are pregnant, or considering pregnancy. (2,3) ACMG also recommended that carrier

21 screening be offered for Fanconi anemia (group C), Niemann-Pick (type A), Bloom syndrome, mucolipidosis IV, and Gaucher disease. According to ACMG, if only 1 member of the couple is Jewish, ideally, that individual should be tested first. If the Jewish partner has a positive carrier test result, the other partner (regardless of ethnic background) should be screened for that particular disorder. One Jewish grandparent is sufficient to offer testing. Hemoglobinopathies Society of Obstetricians and Gynaecologists of Canada The Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada published guidelines on carrier testing for thalassemia in These guidelines included the following recommendations: Carrier screening for α-thalassemia should be offered to all woman from ethnic groups with an increased prevalence of α-thalassemia. Initial screening should consist of CBC, Hg electrophoresis (or hemoglobin high performance liquid chromatography), ferritin testing and examination of peripheral smear for the presence of H bodies. If a woman is found to have abnormal results on initial screen, testing of the partner should be performed using the same battery of tests. If both partners are found to be carriers of thalassemia, or combination of a thalassemia and hemoglobin variant, they should be referred for genetic counseling. Additional molecular studies may be required to clarify the carrier status of the parents and thus the risk to the fetus. In 2013, ACOG reaffirmed a 2007 guideline for hemoglobinopathies in pregnancy, which included recommendations for carrier screening. (6,7) For carrier screening, individuals of African, Southeast Asian, and Mediterranean descent are at risk for being carriers of hemoglobinopathies; ACOG recommended that individuals from these ethnic group should be offered carrier screening and, if both parents are determined to be carriers, genetic counseling. A complete blood count and hemoglobin electrophoresis are appropriate laboratory tests for screening for hemoglobinopathies.

22 Cystic Fibrosis The initial ACMG Cystic Fibrosis Carrier Screening Working Group recommended that laboratories use a pan-ethnic panel of 25 mutations present in at least 0.1% of patients with classic cystic fibrosis (CF). (19) Current guidelines, revised by ACMG in 2004 (9) and reaffirmed in 2013, (3) recommend a 23-mutation panel and were developed after assessing initial experiences on implementation of CF screening into clinical practice. CF screening also may identify 5T/7T/9T variants in the CFTR gene, which vary between individuals. Genetic counseling is important to discern whether the combination of mutations and variants would cause classic or atypical CF. Complete analysis of the CFTR gene by DNA sequencing is not appropriate for routine carrier screening because it may yield results that can be difficult to interpret. This type of testing is generally reserved for patients with CF, patients with a family history of CF, males with congenital bilateral absence of the vas deferens, or newborns with a positive newborn screening result when mutation testing, using the standard 23-mutation panel, has a negative result. Because carrier screening detects most mutations, sequence analysis should be considered only after discussion with a genetics professional to determine if sequencing will be informative after standard screening has been performed. In 2011, ACOG issued an update on carrier screening for CF, and the Committee on Genetics provided the following guidelines (8): It is important that CF screening continue 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 whether 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. Complete analysis of the CFTR gene by DNA sequencing is not appropriate for routine carrier screening. Newborn screening panels that include CF screening do not replace maternal carrier screening. If a woman with CF wants to become pregnant, a multidisciplinary team should be consulted to manage issues regarding pulmonary function, weight gain, infections, and increased risks of diabetes and preterm delivery.

23 For couples in which both partners are carriers, genetic counseling is recommended to review prenatal testing and reproductive options. For couples in which 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 whether CFTR mutation analysis in the affected family member is available. If 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. Spinal Muscular Atrophy Current practice guidelines for spinal muscular atrophy (SMA) carrier testing from ACMG and ACOG are in conflict. ACMG s 2008 guideline, reaffirmed in 2013, recommends carrier testing for SMA in all couples regardless of race or ethnicity. (3,10) ACOG s 2009 Committee on Genetics opinion statement limits SMA carrier screening (1) to those with a family history of SMA or SMAlike disease, and (2) to those who request SMA carrier screening and have completed genetic counseling to review sensitivity, specificity, and limitations of screening.11 The genetics of SMA is complex, involving 2 genes; 95% of patients have a deletion in SMN1, but variable copy number of SMN2 affects phenotypic expression (greater copy number is associated with milder disease). Further, copy number of SMN1 can vary, confounding interpretation of a negative (normal) result, e.g., 2 SMN1 copies on 1 chromosome may mask SMN1 deletion from the other chromosome. Because of this complexity and residual risk with a negative result, ACOG opinion authors recommended pilot studies to determine best practices for pre- and posttest education and counseling before implementing pan-ethnic SMA carrier screening. FMR1 Mutations/Fragile X Syndrome American College of Medical Genetics American College of Medical Genetics s (ACMG) Professional Practice and Guidelines Committee makes the following recommendations regarding diagnostic and carrier testing for FXS. The purpose of these recommendations is to provide general guidelines to aid clinicians in making referrals for testing the repeat region of the FMR1 gene. Individuals of either sex with intellectual disability, developmental delay, or autism, especially if they have (a) any physical or behavioral characteristics of fragile X syndrome, (b) a family

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