Medical Policy. Description/Scope. Position Statement

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1 Subject: Document #: Current Effective Date: 03/29/2017 Status: Reviewed Last Review Date: 02/02/2017 Description/Scope This document addresses preconceptional or prenatal genetic testing on a parent or prospective parent to determine carrier status of an autosomal recessive disorder, an x-linked disorder, or a disorder with variable penetrance. The testing is typically done prior to pregnancy to guide reproductive decisions. Notes: This document is limited to the use of molecular genetic testing and does not provide criteria for karyotype analysis or biochemical testing. When there is a document addressing a specific genetic test, that document should be used to determine whether the genetic test is medically necessary. Other related documents include: GENE Preimplantation Genetic Diagnosis Testing GENE Cell-Free Fetal DNA-Based Prenatal Testing Position Statement Medically Necessary: A. Preconceptional or prenatal genetic testing of a parent or prospective parent to determine carrier status of cystic fibrosis is considered medically necessary. B. Preconceptional or prenatal genetic testing of a parent or prospective parent to determine carrier status of other inherited disorders is considered medically necessary when BOTH sets (#1 and #2) of the following criteria are met: 1. Criteria based on family history Genetic testing of the parents or prospective parents is considered medically necessary when ONE of the following criteria is met. a. An affected child is identified with either an autosomal recessive disorder, an x-linked disorder, or an inherited disorder with variable penetrance and genetic testing is performed to determine the pattern of inheritance and to guide subsequent reproductive decisions; or b. One or both parents or prospective parent(s) have another first or a second degree relative who is affected, or the first degree relative has an affected child, with either an autosomal recessive disorder, an x-linked disorder, or an inherited disorder with variable penetrance and genetic testing is performed to determine the pattern of inheritance and to guide subsequent reproductive decisions; or Page 1 of 17

2 c. The parent or prospective parent is at high risk for a genetic disorder with a late onset presentation, and genetic testing is performed to determine carrier status and to guide subsequent reproductive decisions; or d. The parents or prospective parents are members of an ethnic group with a high risk of a specific genetic disorder with an autosomal recessive pattern of inheritance and genetic testing is performed to determine carrier status and to guide subsequent reproductive decisions, including but not limited to Tay-Sach s disease, Canavan disease, mucolipidosis IV, Nieman Pick Disease Type A, Fanconi anemia group C, Bloom syndrome or Gaucher s disease. 2. Criteria for Specific Genetic Test In parents or prospective parents who meet one of the applicable criteria above, specific genetic testing is considered medically necessary when ALL of the following criteria are met: a. A specific mutation, or set of mutations, has been established in the scientific literature to be reliably associated with the disease; and b. The genetic disorder is associated with a potentially severe disability or has a lethal natural history; and c. A biochemical or other test is identified but the results are indeterminate, or the genetic disorder cannot be identified through biochemical or other testing; and d. Testing is accompanied by genetic counseling. Investigational and Not Medically Necessary: Preconceptional or prenatal genetic testing for inherited medical disorders including but not limited to amyotrophic lateral sclerosis (ALS, Lou Gehrig s disease), that do not meet the above criteria is considered investigational and not medically necessary. Preconceptional or prenatal genetic testing using panels of genes (with or without next generation sequencing), including but not limited to whole genome and whole exome sequencing, is considered investigational and not medically necessary unless all components of the panel have been determined to be medically necessary based on the criteria above. However, individual components of a panel may be considered medically necessary when criteria above are met. Rationale Carrier testing for inherited genetic conditions is a key component of preconceptional and prenatal care. Carrier testing is conducted to identify an individual or a couple at risk (parent or prospective parent) for passing on genetic conditions to their offspring. Carriers are asymptomatic individuals who are typically not at risk for developing the disease, but possess the potential to pass the gene mutation to their offspring. Carrier testing is frequently performed on the parent or prospective parent before conception or during a pregnancy. Carrier screening may be conducted for conditions that are found in the general population (panethnic), for diseases that are more common in a particular population, or based on family history. Panethnic screening (population screening) for carrier status is done for single-gene disorders that are common in the population. Page 2 of 17

3 Preconceptional or prenatal genetic testing of a parent or prospective parent is a common practice to determine carrier status. For example, due to the high prevalence of carriers of cystic fibrosis, the American College of Obstetrics and Gynecology (ACOG) and the American College of Medical Genetics (ACMG) recommend that DNA screening for cystic fibrosis be made available to all couples seeking preconception or prenatal care regardless of personal or family history for the disease or carrier status. The ACOG and the ACMG recommend carrier screening for Tay-Sach s disease, Canavan disease, mucolipidosis IV, Nieman Pick Disease Type A, Fanconi anemia group C, Bloom syndrome, Gaucher s disease and familial dysautonomia among individuals of Ashkenazi Jewish descent (ACOG, 2009; Gross, 2008). With regards to fragile X syndrome, the ACMG provides guidance on prenatal and preconceptional testing and ACOG has published a Committee Opinion for carrier screening (Sherman, 2005; ACOG, 2010). There has also been a growing interest in the use of genetic testing for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig s disease. ALS is a progressive neurodegenerative disorder that affects nerve cells in the spinal cord and brain which eventually results in paralysis and death. Advances in genetic testing technologies have led to the development and use of large-scale DNA sequencing, including but not limited to expanded carrier panels, whole genome sequencing and whole exome sequencing. Expanded Carrier Screening and Panels Generally, carrier screening guidelines have focused on the assessment of individual conditions and ancestry. However, the effectiveness of this approach can be impacted by limited or inaccurate knowledge of ancestry and an increasingly multiethnic society. Approaches to screening have also been influenced by the recognition that while some genetic conditions occur more frequently in certain populations, genetic disorders are not limited to specific ethnic groups (Edwards, 2015). According to the American College of Medical Genetics and Genomics: The completion of the full human genome sequence, followed by dramatic improvement in the speed and cost of DNA sequencing and microarray hybridization analysis, has enabled the ascertainment of an unprecedented quantity of disease-specific genetic variants in a time frame suited to prenatal/preconception screening and diagnosis. Now it is possible, using new technologies, to screen for mutations in many genes for approximately the same cost as previously required to detect mutations in a single gene or a relatively small number of population-specific mutations in several genes. Commercial laboratories have begun to offer such expanded carrier screening panels to physicians and the public, but there has been no professional guidance on which disease genes and mutations to include (Grody, 2013). Previously, testing for a specific genetically linked condition typically began by identifying the most commonly associated genetic variants first and, if there was a high degree of suspicion, progressed in a step-wise fashion to identify variants that are less common. However, recent advances in next-generation sequencing (also known as massively parallel sequencing) technologies permit the sequencing of millions of fragments of DNA in a relatively short period of time and enable the efficient screening of vast numbers of conditions simultaneously. As a result of Page 3 of 17

4 the advances made in the area of next generation sequencing (NGS), researchers have been exploring the use of expanded carrier screening (ECS) tests that utilize next generation sequencing technologies to access carrier status for a host of genetic conditions simultaneously. ECS has been described as the practice of screening all individuals for dozens to hundreds of diseases, some with lower frequencies or severity grades, typically without tailoring to a person s reported ethnicity (Edwards, 2015; Lazarin, 2015). Next generation sequencing (NGS) provides information pertaining to conditions beyond those that are currently recommended in screening guidelines. At present, professional practice guidelines recommend offering carrier screening for individual conditions based on the severity of the condition, race or ethnicity, prevalence, carrier frequency, detection rates, and residual risk. Currently, the American College of Obstetricians and Gynecologists, American College of Medical Genetics and Genomics and National Society of Genetic Counselors recommend panethnic screening for cystic fibrosis based on ethnicity. Similarly, the American College of Medical Genetics and Genomics recommends panethnic screening for spinal muscular atrophy (ACOG, 2011; Langfelder-Schwind, 2014; Prior, 2008). The 2013 ACMG Position Statement on Prenatal/Preconception Expanded Carrier Screening indicates that the proper selection of appropriate disease-causing targets for general population-based carrier screening (that is, absence of a family history of the disorder) should be developed using clear criteria, rather than simply including as many disorders as possible. In order for a particular disorder to be included in carrier screening, the following criteria should be fulfilled: 1. Disorders should be of a nature that most at-risk patients and their partners identified in the screening program would consider having a prenatal diagnosis to facilitate making decisions surrounding reproduction. The inclusion of disorders characterized by variable expressivity or incomplete penetrance and those known to be associated with a mild phenotype should be optional and made transparent when using these technologies for screening. This recommendation is guided by the ethical principle of nonmaleficence. 2. When adult-onset disorders (disorders that could affect the offspring of the individual undergoing carrier screening once the offspring reaches adult life) are included in screening panels, patients must provide consent to screening for these conditions, especially when there may be implications for the health of the individual being screened or other family members. This recommendation follows the ethical principles of autonomy and nonmaleficence. 3. For each disorder, the causative gene(s), mutations, and mutation frequencies should be known in the population being tested, so that meaningful residual risk in individuals who test negative can be assessed. Laboratories should specify in their marketing literature and test results how residual risk was calculated using panethnic population data or a specific race/ethnic group. The calculation of residual risk requires knowledge of two factors: one is the carrier frequency within a population, the other is the proportion of disease-causing alleles detected using the specific testing platform. Laboratories using multiplex platforms often have limited knowledge of one or both factors. Laboratories offering expanded carrier screening should keep data prospectively and regularly report findings that allow Page 4 of 17

5 computation of residual risk estimates for all disorders being offered. When data are inadequate, patient materials must stress that negative results should not be overinterpreted. 4. There must be validated clinical association between the mutation(s) detected and the severity of the disorder. Patient and provider materials must include specific citations that support inclusion of the mutations for which screening is being performed. 5. Compliance with the American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories, including quality control and proficiency testing. Quality control should include the entire test process, including preanalytical, analytical, and postanalytical phases. Test performance characteristics should be available to patients and providers accessing testing (Grody, 2013). The joint statement issued by the American College of Medical Genetics and Genomics, the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, the National Society of Genetic Counselors, and the Perinatal Quality Foundation stops short of endorsing the use of ECS tests and provides a general overview of the expanded screening paradigm. This collaborative statement points out several limitations of ECS. In the context of ECS, all individuals, regardless of ethnicity or race, are offered screening for the same set of conditions and ECSPs, (also known as expanded carrier screening panels, expanded panels and expanded carrier panels [ECPs]) which may include more than 100 genetic conditions, most of which are rare. Although the majority of conditions on current expanded panels are autosomal-recessive, it is possible that some may be X- linked or autosomal-dominant single-gene conditions. The authors also maintain that while expanded screening panels include most of the conditions recommended in current guidelines, the molecular methods used in ECS are not as accurate as methods recommended in current guidelines for the hemoglobinopathies and Tay-Sachs disease (Edwards, 2015). While ECS delivers more comprehensive screening, this method presents challenges in clinical management. Traditional methods of carrier screening generally have focused on conditions that have a significant impact on the quality of life as a result of physical or cognitive disabilities, require lifelong medical therapies and have a fetal, neonatal or early childhood onset as well as a well-defined phenotype. In contrast, the ECPs often include conditions for which carrier screening of the general population is not recommended by current practice guidelines (for example factor V Leiden and hemochromatosis). While some genetic variants on expanded panels have a relatively consistent phenotype, others are less clearly defined. ECPs may also include other conditions that have significant variation in their presentation and variable age of onset. Additionally, expanded panels may include rare conditions for which the precise carrier frequency of condition-causing variants may be unknown (Edwards, 2015; Grody, 2001; Monaghan, 2013; USPSTF, 2006). Finally, the authors point out that: Expanded carrier screening panels may include rare conditions; for such disorders, the precise carrier frequency as well as the proportion of condition-causing variants that can be detected may be unknown. Therefore, calculation of residual risk after a negative screening test may not be possible for all conditions (Edwards, 2015). Page 5 of 17

6 Despite the fact that ECS tests are increasingly being utilized, there is currently a lack of guidance from specialty associations and societies identifying the population that is appropriate to undergo screening using these tests or which genes should be included in the panels. While many of the targeted carrier screening tests have reported high analytic validity, the analytic validity of ECSPs is either unknown or cannot be sufficiently assessed due to weakness in assay validation. It is also difficult to determine the clinical validity of carrier screening because by definition, carriers have no symptoms of the diseases being tested, and thus the association of the carrier state is impossible to define. For this reason, it is impossible to determine whether a negative test is a true-negative or a false-negative due to the inability to define the carrier state in clinical terms. Lastly, with regards to clinical utility, there is a lack of evidence demonstrating that expanded carrier testing in individuals who are asymptomatic but at risk for having an offspring with a genetic disease, results in improved clinical outcomes (for example, reduces the number of births with an inherited disorder) or impacts management (for example, changes family planning decisions). Clinical laboratories may develop and validate screening tests or panels in-house ( home-brew ) and market them as a laboratory service; such tests or panels are subject to the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). There are currently several commercially available laboratory developed tests for carrier screening. These tests range from tests designed to test for individual diseases, to panels based on ethnicity as recommended in specialty association or society guidelines, to large expanded panels that test for many diseases beyond those recommended in practice guidelines. These panels include but are not necessarily limited to the following: Counsyl (Counsy, South San Francisco, CA), tests for more than 100 diseases which may lead to shortened life span, intellectual disability, have limited treatment options, or can lead to intellectual disability. GoodStart Select (GoodStart Genetics, Cambridge MA), provides a customized testing panel for each patient based on family history, ethnicity and provider testing preferences. Inherigen (GenPath Diagnostics, Elmwood Park, NJ) offers a panethnic test for 164 autosomal recessive and X-linked inherited diseases, including Ashkenazi Jewish Diseases. The InheriGen Plus includes these 164 diseases and also screens for Fragile X syndrome, spinal muscular atrophy and cystic fibrosis carrier status. The InheriGenTx screens for 67 autosomal recessive and X-linked inherited diseases. Inheritest SM Carrier Screen (LabCorp, Burlington, NC) tests for more than 90 autosomal recessive inherited diseases. The Inheritest Select Carrier Screen evaluates diseases for patients of Ashkenazi Jewish descent. Natera Horizon (Natera, San Carlos, CA) provides screening for up to 274 autosomal recessive and X-linked genetic conditions. Screening can be customized for all of these conditions or for a select few based on ethnic background and the physician s recommendation. Whole Genome Sequencing Whole genome sequencing (WGS), also known as full genome sequencing (FGS), complete genome sequencing, or entire genome sequencing, is a laboratory procedure which seeks to determine an individual's entire DNA sequence, specifying the order of every base pair within the genome at a single time. WGS allows researchers to study the 98% of the genome that does not generally contain protein-coding genes. In the clinical setting, this process frequently involves obtaining a DNA sample from the individual (typically from blood, saliva or bone marrow) and Page 6 of 17

7 sequencing an individual's entire chromosomal and mitochondrial DNA. Because of the large volume of genomic data involved in this process, the genomic information is processed by and stored on microprocessors and computers. The clinical role of WGS has yet to be established. Research is still being done to determine if WGS can be used to accurately identify the presence of a disease, predict the development of a particular disease in asymptomatic individuals as well as how an individual might respond to pharmacological therapy. It has been theorized that WGS might eventually improve clinical outcomes by preventing the development of disease. Whole Exome Sequencing While similar to whole genome sequencing, whole-exome sequencing (WES) reads only the parts of the human genome that encode proteins, leaving the other regions of the genome unread (Choi, 2009). Since most of the errors that occur in DNA sequences that then lead to genetic disorders are located in the exons, sequencing of the exome is being explored as a more efficient method of analyzing an individual's DNA to discover the genetic cause of diseases or disabilities. It has been theorized that sequencing of the human exome can be used to identify genetic variants in individuals in order to diagnose diseases without the high cost associated with WGS. A potential major indication for use is molecular diagnosis of individuals with a phenotype that is suspicious for a genetic disorder or for individuals with known genetic disorders that have a large degree of genetic heterogeneity involving substantial gene complexity. Such individuals may be left without a clinical diagnosis of their disorder, despite a lengthy diagnostic work-up involving a variety of traditional molecular and other types of conventional diagnostic tests. For some of these individuals, WES, after initial conventional testing has failed to make the diagnosis, may return a likely pathogenic variant. While some of the potential advantages of WES include the fact that it can be carried out more quickly than traditional genetic testing and it may be less expensive than some other tests (for example, WGS), it is not without limitations. WES typically covers only 85 95% of the exome and has no, or limited coverage of other areas of the genome. Areas of concern with this technology include: (1) gaps in the identification of exons prior to sequencing; (2) the need to narrow the large initial number of variants to manageable numbers without losing the likely candidate mutation; (3) difficulty identifying the potential causative variant when large numbers of variants of unknown significance are generated for each individual. It is more difficult to detect chromosomal changes, duplications, large deletions, rearrangements, epigenetic changes or nucleotide repeats from WES data compared with other genomic technologies (ACMG, 2012; National Cancer Institute, 2012; Teer, 2010[a]; Teer, 2010[b]). At this time, there are limitations to WES that prohibit its use in routine clinical care. The limited experience with WES on a population level leads to gaps in understanding and interpreting ancillary information and variants of uncertain significance. As a result, the risk/benefit ratio of WES testing is poorly defined. Because the peerreviewed literature on WES for clinical purposes consists primarily of case reports and small case series, the clinical applications of WES have yet to be established (Bilguvar, 2010; Choi, 2009; Clayton-Smith, 2011, Saitsu, 2011; Vissers, 2011). Page 7 of 17

8 WES and WGS present ethical questions about informing individuals about incidental findings that have clinical significance. Ongoing discussions continue to explore whether or not, and how to inform individuals about medically relevant mutations in genes unrelated to the diagnostic question (that is, mutations of unknown significance, non-paternity and sex chromosome abnormalities). This type of information may not only affect the individual being tested, but may also implicate family members. In 2013, the American College of Medical Genetics and Genomics (AMCG) charged a Working Group with evaluating the need for principles that would govern recommendations for analyzing and reporting incidental findings from genome and exome sequencing in the clinical context. However, the Work Group recommendations do not address preconception sequencing, prenatal sequencing, newborn sequencing, or sequencing of healthy children and adults (Green, 2013). The ACMG (2012) published a position statement addressing points to consider in the clinical application of genomic sequencing. The policy statement: Was developed primarily as an educational resource for clinical and laboratory geneticists to help them provide quality clinical and laboratory genetic services. Adherence to these Points to Consider is voluntary and, in determining the relevance of and weight to be given to any specific point, the clinical and laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. The document contains indications for whole genome and WES as both screening and diagnostic tools. The ACMG indicates that diagnostic testing using whole genome or WES is indicated for the following phenotypically affected individuals: The phenotype or family history data strongly implicate a genetic etiology, but the phenotype does not correspond with a specific disorder for which a genetic test targeting a specific gene is available on a clinical basis. A patient presents with a defined genetic disorder that demonstrates a high degree of genetic heterogeneity, making WES or WGS analysis of multiple genes simultaneously a more practical approach. A patient presents with a likely genetic disorder but specific genetic tests available for that phenotype have failed to arrive at a diagnosis. A fetus with a likely genetic disorder in which specific genetic tests, including targeted sequencing tests, available for that phenotype have failed to arrive at a diagnosis. Specifically regarding WES and WGS in the prenatal setting, the ACMG states the following: Prenatal diagnosis by genomic (i.e., next-generation whole-exome or whole-genome) sequencing has significant limitations. The current technology does not support short turnaround times, which are often expected in the prenatal setting. There are high rates of false positives, false negatives, and variants of unknown clinical significance. These can be expected to be significantly higher than seen when array CGH is used in prenatal diagnosis (2012). Page 8 of 17

9 Background/Overview Preconceptional or prenatal genetic testing of a parent or prospective parent is an accepted practice to determine carrier status (identify couples at risk for passing on specific genetic conditions to their children). There are a growing number of diseases for which a genetic basis has been identified. Genetic Counseling According to the National Society of Genetic Counselors (NSGC), genetic counseling is the process of assisting individuals to understand and adapt to the medical, psychological and familial ramifications of a genetic disease. This process typically includes the guidance of a specially trained professional who: A. Integrates the interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and B. Provides education about inheritance, genetic testing, disease management, prevention and resources; and C. Provides counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and D. Provides counseling for the psychological aspects of genetic testing (NSGC, 2006). Genetic counseling may be provided by counselors interacting with individuals and other healthcare professionals in a variety of clinical and non-clinical settings, including, but not limited to, private hospitals, university-based medical centers, private practice, and industry settings. Genetic counseling should be provided by an adequately trained healthcare professional. According to the American Board of Genetic Counseling (ABGC) the skills required to carry out the professional responsibilities of a genetic counselor can be obtained via completions of a graduate training programs accredited by the ABGC. However, the ABGC also acknowledges that competency in genetic counseling may also be obtained through professional experience and continuing education courses. The practice of genetic counseling is subject to regulatory oversight by federal, state and local governments. Definitions Amyotrophic lateral sclerosis (ALS, Lou Gehrig s disease): A progressive neurodegenerative disorder that affects nerve cells in the spinal cord and brain which eventually results in paralysis and death. Analytical validity: The accuracy with which a test identifies the presence or absence of a particular gene or genetic change (mutation). Ashkenazi Jewish: A term for people of eastern European Jewish heritage. Carrier: An individual who is asymptomatic (or has only mild symptoms) of a disorder but has the potential to pass on the gene for that disorder to his or her offspring. Clinical validity: The accuracy with which a test identifies or predicts an individual's clinical status. Page 9 of 17

10 Cystic fibrosis (CF): An inherited disease that affects the mucus and sweat glands of the body; thick mucus is formed in the breathing passages of the lungs that predisposes the person to chronic lung infections. Ethnicity: Coming from a large group that shares racial, national, language or cultural characteristics. Expanded panels: Genetic testing panels that employ next generation sequencing to screen for mutations in numerous genes, as opposed to gene-by-gene screening. First-degree relative: Any relative who is a parent, sibling, or offspring to another. Genetic counseling: A process involving the guidance of a specially trained professional in the evaluation of family history, medical records, and genetic test results, in assessing the risk of genetic diseases, understanding the ramifications of diagnosis, and explanation of available treatment options. Genetic molecular testing: A type of test that is used to determine the presence or absence of a specific gene or set of genes to help diagnose a disease, screen for specific health conditions, and for other purposes. Genome: An organism s entire set of DNA. Mutation: A change in DNA sequence. Next-generation sequencing: Any of the technologies that allow rapid sequencing of large numbers of segments of DNA, up to and including entire genomes. Panethnic screening: A screening approach that is done for single-gene disorders based on ethnicity, race, or both. Second-degree relative: Any relative who is a grandparent, grandchild, uncle, aunt, niece, nephew, or half-sibling to another. Coding The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member s contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. When services are Medically Necessary: CPT ASPA (aspartoacylase) (eg, Canavan disease) gene analysis, common variants (eg, E285A, Y231X) BLM (Bloom syndrome, RecQ helicase-like) (eg, Bloom syndrome) gene analysis, Page 10 of 17

11 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) F5 (coagulation Factor V) (eg, 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) GBA (glucosidase, beta, acid) (eg, Gaucher disease) gene analysis, common variants (eg, N370S, 84GG, L444P, IVS2+1G>A) GJB2 (gap junction protein, beta 2, 26kDa, connexin 26) (eg, nonsyndromic hearing loss) gene analysis; full gene sequence GJB2 (gap junction protein, beta 2, 26kDa, connexin 26) (eg, nonsyndromic hearing loss) gene analysis; known familial variants GJB2 (gap junction protein, beta 6, 30kDa, connexin 30) (eg, nonsyndromic hearing loss) gene analysis, common variants (eg, 309kb [del(gjb6-d13s1830)] and 232kb [del(gjb6- D13S1854)]) 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) MCOLN1 (mucolipin 1) (eg, Mucolipidosis, type IV) gene analysis, common variants (eg, IVS3-2A>G, del6.4kb) SMPD1(sphingomyelin phosphodiesterase 1, acid lysosomal) (eg, Niemann-Pick disease, Type A) gene analysis, common variants (eg, R496L, L302P, fsp330) Ashkenazi Jewish associated disorders (eg, Bloom syndrome, Canavan disease, cystic fibrosis, familial dysautonomia, Fanconi anemia group C, Gaucher disease, Tay-Sachs disease), genomic sequence analysis panel, must include sequencing of at least 9 genes, including ASPA, BLM, CFTR, FANCC, GBA, HEXA, IKBKAP, MCOLN1, and SMPD1 HCPCS S3841 Genetic testing for retinoblastoma Page 11 of 17

12 S3842 S3844 S3845 S3846 S3849 S3853 ICD-10 Diagnosis Genetic testing for von Hippel-Lindau disease DNA analysis of the connexin 26 gene (GJB2) for susceptibility to congenital, profound deafness Genetic testing for alpha-thalassemia Genetic testing for hemoglobin E beta-thalassemia Genetic testing for Niemann-Pick diseases Genetic testing for myotonic muscular dystrophy All diagnoses When services are also Medically Necessary: CPT Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) [when specified as the following]: HBB (hemoglobin, beta, beta-globin) (eg, beta thalassemia), duplication/deletion analysis Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) [when specified as the following]: HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia), duplication/deletion analysis HBB (hemoglobin, beta, Beta-Globin) (eg, thalassemia), full gene sequence Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of exons, regionally targeted cytogenomic array analysis) [when specified as the following]: HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, thalassemia), full gene sequence ICD-10 Diagnosis D56.0-D56.9 Thalassemia Z Encounter of female for testing for genetic disease carrier status for procreative management Z Encounter of male for testing for genetic disease carrier status for procreative management When services are Investigational and Not Medically Necessary: CPT Page 12 of 17

13 81403 Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) [when specified as the following]: ANG (angiogenin, ribonuclease, RNase A family, 5) (eg, amyotrophic lateral sclerosis), full gene sequence Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) [when specified as the following]: SOD1 (superoxide dismutase 1, soluble) (eg, amyotrophic lateral sclerosis), full gene sequence Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of exons, regionally targeted cytogenomic array analysis) [when specified as the following]: TARDBP (TAR DNA binding protein) (eg, amyotrophic lateral sclerosis), full gene sequence Molecular pathology procedure, Level 7 (eg, analysis of exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of exons, cytogenomic array analysis for neoplasia) [when specified as the following]: FUS (fused in sarcoma) (eg, amyotrophic lateral sclerosis), full gene sequence; OPTN (optineurin) (eg, amyotrophic lateral sclerosis), full gene sequence HCPCS S3800 Genetic testing for amyotrophic lateral sclerosis (ALS) ICD-10 Diagnosis G12.21 Amyotrophic lateral sclerosis When services are also Investigational and Not Medically Necessary: CPT Unlisted molecular pathology procedure [when specified as preconceptional or prenatal testing using panels of genes (with or without next generation sequencing)] Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator exome (eg, parents, siblings) Exome (eg, unexplained constitutional or heritable disorder or syndrome); re-evaluation of previously obtained exome sequence (eg, updated knowledge or unrelated condition/syndrome) Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis Page 13 of 17

14 81426 Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator exome (eg, parents, siblings) Genome (eg, unexplained constitutional or heritable disorder or syndrome); reevaluation of previously obtained genome sequence (eg, updated knowledge or unrelated condition/syndrome) ICD-10 Diagnosis All diagnoses References Peer Reviewed Publications: 1. Bilguvar K, Ozturk AK, Louvi A, et al. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature. 2010; 467(7312): Choi M, Scholl UI, Ji W, et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A. 2009; 106(45): Clayton-Smith J, O'Sullivan J, Daly S, et al. Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome. Am J Hum Genet. 2011; 89(5): Lazarin GA, Haque IS. Expanded carrier screening: A review of early implementation and literature. Semin Perinatol Dec 21. [Epub ahead of print]. 5. Rose NC, Wick M. Current recommendations: Screening for Mendelian disorders. Semin Perinatol 2015 Dec 16. [Epub ahead of print]. 6. Saitsu H, Osaka H, Sasaki M, et al. Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy. Am J Hum Genet. 2011; 89(5): Teer JK, Bonnycastle LL, Chines PS, et al. Systematic comparison of three genomic enrichment methods for massively parallel DNA sequencing. Genome Res. 2010(a) 20(10): Teer JK, Mullikin JC. Exome sequencing: the sweet spot before whole genomes. Hum Mol Genet. 2010(b) 19(R2):R Vissers LE, Fano V, Martinelli D, et al. Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA). Am J Med Genet A. 2011; 155A (11): Weinstein LB. Selected genetic disorders affecting Ashkenazi Jewish families. Fam Community Health (1): Government Agency, Medical Society, and Other Authoritative Publications: 1. American Board of Genetic Counselors. Genetic Counselors Scope of Practice. Available at: Accessed on Janaury 6, ACMG Board of Directors. Points to consider in the clinical application of genomic sequencing. Genet Med. 2012; 14(8): Page 14 of 17

15 3. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Obstet Gynecol. 2009; 114(4): Reaffirmed American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 469: Carrier screening for fragile X syndrome. Obstet Gynecol. 2010; 116(4): American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 486: Update on carrier screening for cystic fibrosis. Obstet Gynecol. 2011; 117(4): Reaffirmed Edwards JG, Feldman G, Goldberg J, et al. Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. Obstet Gynecol. 2015; 125(3): Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013; 15(7): Gross SJ1, Pletcher BA, Monaghan KG; et al. Carrier screening in individuals of Ashkenazi Jewish descent. Genet Med. 2008; 10(1): Grody WW, Griffin JH, Taylor AK, et al. American College of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med. 2001; 3(2): Grody WW, Thompson BH, Gregg AR, et al. ACMG position statement on prenatal/preconception expanded carrier screening. Genet Med. 2013; 15(6): Langfelder-Schwind E, Karczeski B, Strecker MN, et al. Molecular testing for cystic fibrosis carrier status practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Couns. 2014; 23(1): Monaghan KG, Lyon E, Spector EB; American College of Medical Genetics and Genomics. ACMG Standards and Guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics. Genet Med. 2013; 15(7): National Society of Genetic Counselors' Definition Task Force, Resta R, Biesecker BB, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns. 2006; 5(2): Prior TW; Professional Practice and Guidelines Committee. Carrier screening for spinal muscular atrophy. Genet Med. 2008; 10(11): Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. 2005; 7(8): U.S. Preventive Services Task Force. Screening for hemochromatosis: recommendation statement. Ann Intern Med. 2006; 145(3): Websites for Additional Information 1. The American College of Obstetricians and Gynecologists. Frequently asked questions. FAQ179. Pregnancy. Preconception Carrier Screening (2012). Available at: Accessed on January 6, Page 15 of 17

16 2. National Library of Medicine (NLM). Genetics Home Reference. What are the types of genetic tests? Published January 3, Available at: Accessed on January 6, Index Bloom Syndrome Canavan Disease Counsyl Expanded Carrier Panel Expanded Carrier Screening Fanconi Anemia Group C Gaucher's Disease Genetic Testing, Preconceptional or Prenatal GoodStart Select Inherigen Inheritest Carrier Screen Mucolipidosis IV Nieman Pick Disease Type A Tay-Sach's Disease Document History Status Date Action Reviewed 02/02/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated formatting in the Position Statement section. Updated review date, Background/Overview, References, Websites for Additional Information and History sections. Reviewed 02/04/2016 MPTAC review. Updated review date, Rationale, Definitions, Background/Overview, References, Index and History sections. 01/01/2016 Updated Coding section with 01/01/2016 CPT changes; removed ICD-9 codes. Reviewed 02/05/2015 MPTAC review. Updated review date, Description/Scope, Rationale, References and History sections. 01/01/2015 Updated Coding section with 01/01/2015 CPT changes. Revised 02/13/2014 Medical Policy & Technology Assessment Committee (MPTAC) review. Additional investigational and not medically necessary position statement added to address preconceptional or prenatal genetic testing using panels of genes (with or without next generation sequencing), including but not limited to whole genome and whole exome sequencing. Updated Rationale, Definitions, Coding, References and History sections. 01/01/2014 Updated Coding section with 01/01/2014 CPT descriptor changes. 07/01/2013 Updated Coding section with 07/01/2013 CPT changes. Reviewed 02/14/2013 MPTAC review. Updated review date, History and References sections. 01/01/2013 Updated Coding section with 01/01/2013 CPT changes; removed , deleted 12/31/2012. Page 16 of 17

17 Reviewed 02/16/2012 MPTAC review. Updated review date, History and Reference sections. Updated Coding section with 04/01/2012 HCPCS changes; removed codes S3835, S3837, S3843, S3847, S3848, S3851 deleted 03/31/ /01/2012 Updated Coding section with 01/01/2012 CPT changes. 07/13/2011 Updated Coding section; removed S3870 which is now addressed in GENE Reviewed 02/17/2011 MPTAC review. Updated review date, History and Reference sections. 01/12/2011 Updated Coding section; removed S3865, S3866 which are now addressed in GENE Reviewed 02/25/2010 MPTAC review. Updated review date, History and Reference sections. Added note to Description section clarifying that this document is limited to the use of molecular genetic testing and does not provide criteria for karyotype analysis or biochemical testing. Reviewed 02/26/2009 MPTAC review. Updated review date, History and References section. New 02/21/2008 MPTAC initial document development. Document created to addresses preconceptional or prenatal genetic testing of a parent or prospective parent, which was formerly addressed in GENE Page 17 of 17