Medical Policy: 02.04.50
Original Effective Date: April 2015
Reviewed: March 2017
Revised: March 2017
Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
The evolution of next generation sequencing has spurred the development of tests that sequence multiple genes simultaneously. Whole exome sequencing (WES) consists of analysis of the protein-coding regions of the human genome, and are referred to as “exons”. The exome comprises about 1% of the genome and is, so far, the component most likely to include interpretable mutations that result in clinical phenotypes. Whole exome sequencing involves determination of the DNA sequence of most of these protein-encoding exons and may include some DNA regions that encode RNA molecules that are not involved in protein synthesis. Exome testing or analysis may be targeted to particular genes of clinical interest for a given application.
WES has been proposed in patients presenting with certain disorders or anomalies that have not been explained by a standard clinical workup (chromosomal microarray analysis, chromosomal karyotype, fluorescence in situ hybridization (FISH), metabolic testing, imaging, single gene tests, referrals to other specialists), and may be left without a clinical diagnosis despite a lengthy diagnostic workup (prolonged diagnostic odyssey). For a portion of these patients, WES may return a likely pathogenic variant. Determining genetic causality of disease and establishing a molecular diagnosis in clinical practice can: confirm a suspected or established clinical diagnosis; inform prognosis; aid in selecting treatment, surveillance or preventative options; reveal mode of inheritance; identify carrier/risk status of family members; and/or guide research regarding new therapies or patient management. WES is most commonly performed in tertiary medical centers under the care of large multidisciplinary teams.
American College of Medical Genetics and Genomics issued a policy statement regarding the use of genomic testing that recommends testing be considered in phenotypically affected individual when:
One of the most complex issues surrounding genomic testing is the risk of incidental or secondary finding, where mutations unrelated to the clinical phenotype or variants of uncertain significance are identified. While incidental identification of clinically significant mutations pose issues of informed consent, these findings often have medical management recommendations. However, even among the 56 genes recommended for the reporting of incidental findings by the ACMG, there are challenges in determining phenotype consequences of variants identified. Experts agree that the involvement of trained genetics professionals in consulting with patients and families are essential prior to and after ordering and completing genetic testing.
For individuals who have multiple unexplained congenital anomalies or a neurodevelopment phenotype who receive whole exome sequencing (WES), the evidence includes large case series and a within subject comparison. Patients who have multiple congenital anomalies or a neurodevelopment disorder with a suspected genetic etiology, but the specific alteration is unclear or unidentified by a standard clinical workup, may be left without a clinical diagnosis of their disorder, despite a lengthy clinical workup. For a portion of these patients, WES may return a likely pathogenic variant. Several large and smaller series have reported diagnostic yields of WES ranging from 25% to 60%, depending on the individual’s age, phenotype, and previous workup. One comparative study found a 44% increase in yield compared with standard testing strategies. Many of the studies have also reported changes in patient management, including medication changes, discontinuation of or additional testing, ending the diagnostic odyssey and family planning. The evidence is sufficient to determine that this testing results in meaningful improvement in the net health outcome for multiple congenital anomalies and neurodevelopmental disorders.
Epilepsy is a common neurological disorder affecting 1-1.5% of the world’s population and is more commonly diagnosed in children than adults. Epilepsy is often accompanied by cognitive and developmental delay. A detailed family history is mandatory as a family history of seizures may suggest a dominantly inherited epileptic disorder. If a genetic disorder is suspected as the cause of epilepsy or seizure disorder a timely diagnosis may reduce overall cost, limit the diagnostic odyssey, improve prognostication and lead to targeted therapy. Genetic counseling should be available to these patients, and the genetic evaluation should be undertaken at a tertiary level of care. Generally, genetic testing is not recommended in drug responsive epilepsy/seizure disorder or at epilepsy/seizure onset, although genomic hybridization (CHG – karyotype, FISH, CMA) and single gene sequencing can be used as first tier evaluation of patients with global developmental delay, which is a population that is at higher risk of epilepsy/seizure disorders.
Patients who have seizure or epilepsy disorder with a suspected genetic etiology, which is unclear or unidentified by standard clinical workup, may be left without a clinical diagnosis of their disorder and for a portion of these patients, WES may return a likely pathogenic variant. In common application, WES results may vary; one retrospective study reported 14.3% diagnosis based on WES in treatment-resistant pediatric epilepsy, and another reported 27% yield for patients with a variety of neurodevelopmental conditions, including epilepsy. For the most useful interpretation of a patient’s WES, it is preferable to also obtain testing from both biological parents to allow identification of de novo variants, which are more likely to be disease causing than variants inherited from unaffected parents. Studies have also reported changes in patient management, including medication changes, discontinuation of or additional testing, ending the diagnostic odyssey and family planning. The evidence is sufficient to determine that this testing results in meaningful improvement in the net health outcome for epilepsy/seizure disorders.
For individuals who have a suspected genetic disorder other than multiple congenital anomalies, neurodevelopmental disorders or epilepsy/seizure disorders who receive WES, the peer reviewed medical literature is limited and includes small case series. Relevant outcomes are test accuracy and validity, functional outcomes, changes in reproductive decision making, and resource utilization. Additional studies are needed to evaluate WES for other genetic disorders that includes diagnostic yield compared to standard clinical work up. The evidence is insufficient to determine the effects of this testing on net health outcomes for all other suspected genetic disorders.
Whole genome sequencing (WGS) consists of analysis of most of the DNA content in an individual’s genome. WGS has been used as a tool to establish a diagnosis in individuals with exceptionally complex and severe phenotypes and has also been used in the oncology setting to characterize tumor genomes. WGS is most commonly performed in tertiary medical centers under the care of large multidisciplinary teams, with a large research component significantly contributing to the diagnosis and evaluation process. High-quality clinical trial data are lacking in the published peer reviewed medical literature to inform on the use and effectiveness of whole genome sequencing in routine clinical practice. At this time the clinical utility of this testing to impact clinical management and improve health outcomes has not been established.
Due to the likelihood of the discovery of a variant of uncertain significance or other incidental findings, pre-and-post genetic counseling for any individual undergoing WES is required. This recommendation is consistently and widely published by multiple professional societies and experts. Genetic counseling by an independent provider can reduce unnecessary use of this test.
Genetic counseling is defined as the process of helping an individual understand and adapt to the medical, psychological and familial indications of genetic contributions to disease. Genetic counseling is recommended in both pre-and-post genetic testing to interpret family and medical histories to assess the change of disease occurrence and recurrence, educate regarding inheritance, testing, management prevention and resources and counsel to promote informed choices and adaption to risk or condition.
A variety of genetics professionals provide these services: Board-Certified or Board-Eligible Medical Geneticists, and American Board of Medical Genetics or American Board of Genetic Counseling-certified Genetic Counselor, and genetic nurses credentialed as either a Geneteic Clinical Nurse (GCN) or an Advanced-Practice Nurse in Genetics (APGN) by either the Genetic Nursing Credentialing Commission (GCNN) or the American Nurses Credentialing Center (ANCC). Individuals should not be employed by a commercial genetic testing laboratory unless they are employed by or contracted with a laboratory that is part of an integral Health System which routinely delivers health care services beyond just the laboratory test itself.
In 2012, The American College of Medical Genetics and Genomics (ACMG) issued a policy statement, Points to Consider in the Clinical Applications of Genomic Sequencing, which states that diagnostic testing with WES/WGS should be considered in the clinical diagnostic assessment of phenotypically affected individual when:
Pre-test counseling should be done by a medical geneticist or an affiliated genetic counselor and should include a formal consent process.
In 2013, ACMG board issued their recommendation for reporting incidental findings in clinical exome and genome sequencing. A working group determined that reporting some incidental findings would likely have medical benefit for the patients and families of patients undergoing clinical sequencing and recommended that when a report is issued for clinically indicated exome and genome sequencing, a minimum list of conditions, genes, and variants should be routinely evaluated and reported to the ordering clinician.
In 2015, ACMG issued a position statement on the clinical utility of genetic and genomic services which states: “We submit that the clinical utility of genetic testing should take into account effects on diagnostic or therapeutic management, implications for prognosis, health and psychological benefits to patients and their relatives. We believe that clinical utility must also take into account the value a diagnosis can bring to the individual, the family and society in general".
“ACMG believes there is great clinical value in arriving at a precise medical diagnosis, enabling, among other things, identification of a disorder’s cause and prognosis, as well as frequently informing preventative and treatment modalities. ACMG considers the following to be important clinical utilities related to genetic/genomic information”.
Clinical Utility for Individual Patients
Clinical Utility for Families
“Not only can genetic testing inform genetic risks in other family members, but testing of other family members can sometimes/often inform the interpretation of results in a patient. For example, information regarding whether a candidate variant is de novo or inherited provides powerful evidence of its potential pathogenicity, thereby giving the finding utility in other family members. Genome-scale testing of parents and patient (trio testing) also reduces the number of variants that have to be considered as causative, thereby facilitating better interpretation of testing results and minimizing reporting of costly (in terms of both patient well-being and economic terms) false-positive results.”
Prenatal diagnosis by genomics (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 false positive, false negative, and variants of unknown clinical significance rates. These rates can be expected to be significantly higher than seen when array comparative genomic hybridization is used in prenatal diagnosis. Published literature on the use of next generation whole exome and whole genome testing in the invasive prenatal setting is lacking. The evidence is insufficient to determine the effects of this testing on health outcomes.
Preimplantation genetic testing involves analysis of biopsied cells as part of an assisted reproductive procedure. It is generally considered to be divided into two categories. Preimplantation genetic diagnosis (PGD) is used to detect a specific inherited disorder and aims to prevent the birth of affected children to couples at high risk of transmitting a disorder. Preimplantation genetic screening (PGS) involves testing for potential genetic abnormalities in conjunction with in vitro fertilization for couples without a specific known inherited disorder.
The biopsy material can be analyzed in variety of ways:
The American Society for Reproductive Medicine (ASRM) issued a 2007 practice committee opinion that concluded that available evidence did not support the use of PGS as currently performed to improve live birth rates in patients with advanced maternal age, previous implantation failure, or recurrent pregnancy loss, or to reduce miscarriage rates in patients with recurrent pregnancy loss related to aneuploidy.
In 2009 (reaffirmed 2014), the American College of Obstetricians and Gynecologists (ACOG) issued an opinion on PGS for aneuploidy. They stated that current data do not support the use of PGS to screen for aneuploidy due solely to maternal age. ACOG also did not recommend PGS for recurrent unexplained miscarriage and recurrent implantation failures in the clinical setting; they recommended that use be limited to research studies.
In 2017, the American College of Obstetricians and Gynecologists (ACOG) issued a practice bulletin for prenatal diagnostic testing for genetic disorders that retains the recommendation from practice bulletins No. 77 and 88 that all women should be offered diagnostic testing regardless of maternal age or other risk factors. Testing within this recommendation includes the following: chorionic villus sampling, amniocentesis, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), preimplantation genetic diagnosis (PGD. Pretest and post-test genetic counseling is
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 Amendments (CLIA). Exome or genome sequencing tests as a clinical service are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.
Whole exome sequencing (WES) may be considered medically necessary for the evaluation of unexplained neurodevelopmental disorder, or multiple congenital anomalies, or epilepsy/seizure disorder in children when ALL of the following criteria are met:
Required Documentation: The individual’s medical records must reflect the medical necessity for the care provided. The medical record should include, but are not limited to: records from health care professionals office, test reports to include all prior genetic testing and results as indicated above, how the testing will directly impact clinical decision making and clinical outcome for the individual being tested, the results will preclude the further need for multiple and/or invasive testing and the records support the individual(s) being tested have received genetic counseling, to include that they have also been evaluated and the test was ordered by a board certified genetic counselor or board certified medical geneticist or other board certified physician with expertise in clinical genetics.
Repeat testing for whole exome sequencing (WES) for the above indications is considered not medically necessary.
Whole exome sequencing (WES) is considered investigational for the diagnosis of genetic disorders for all other indications, except as described above due to the lack of clinical evidence demonstrating an impact on improved health outcomes.
Whole genome sequencing (WGS) is considered investigational for the diagnosis of genetic disorders.
WGS has been used as a tool to establish a diagnosis in individuals with exceptionally complex and severe phenotypes. WGS is most commonly performed in tertiary medical centers under the care of large multidisciplinary teams, with a large research component significantly contributing to the diagnosis and evaluation process. High-quality clinical trial data are lacking in the published peer reviewed medical literature to inform on the use and effectiveness of whole genome sequencing in routine clinical practice. At this time the clinical utility of this testing to impact clinical management and improve health outcomes has not been established.
Whole exome sequencing (WES) and whole genome sequencing (WGS) are considered investigational for screening asymptomatic individuals for genetic disorders. There is insufficient evidence to support a conclusion concerning the health outcomes or benefits associated with this testing for this indication.
Whole exome sequencing (WES) and whole genome sequencing (WGS) (i.e. NGS- next generation genome sequencing) for prenatal diagnosis or preimplantation testing of an embryo for the screening or diagnosis of genetic disorders is considered investigational.
Prenatal and preimplantation diagnosis and screening by genomics (i.e. next generation whole exome or whole genome) sequencing has significant limitations. Current technology does not support short turnaround times which is often expected in the prenatal setting. There are also false positive, false negative and variants of unknown clinical significance. The peer reviewed medical literature is lacking on the use of whole exome and whole genome sequence testing in the invasive prenatal and preimplantation setting. Further well conducted randomized clinical trials are needed to also include the diagnostic yield compared to standard clinical workup before conclusions can be drawn about the impact on the net health benefit. The evidence is insufficient to determine the effects of this testing on net health outcomes.
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when getting testing for inherited conditions is considered. The interpretation of results of genetic tests and 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.
A variety of genetics professionals provide these services: Board-Certified or Board-Eligible Medical Geneticists, and American Board of Medical Genetics or American Board of Genetic Counseling-certified Genetic Counselor, and genetic nurses credentialed as either a Geneteic Clinical Nurse (GCN) or an Advanced-Practice Nurse in Genetics (APGN) by either the Genetic Nursing Credentialing Commission (GCNN) or the American Nurses Credentialing Center (ANCC).
Analysis of the individual’s exome with comparative evaluation of the exons of two close relatives – typically both parents.
Is a precise genetic or acquired biological brain disorder or condition that is responsible for childhood onset brain dysfunction. It may result in developmental differences manifested as cognitive dysfunction, behavioral problems, and/or motor dysfunction.
Congenital disorder is also known as birth defects, congenital anomalies or congenital malformations. Congenital disorder can be defined as structural or functional anomalies that occur during intrauterine life and can be identified prenatally, at birth or sometimes may only be detected later in infancy.
Systematic program offered to a specified population of asymptomatic individuals to make a risk estimate regarding an inherited predisposition to disease, to detect an inherited disease at an early stage, or make a risk estimate regarding the possibility of transmitting a disease to offspring, for the purpose of disease prevention, early treatment or family planning.
Performed in symptomatic individuals and the genetic testing may be the method used to identify, confirm or rule out a condition in conjunction with clinical signs and symptoms. The confirmatory evidence should then assist with therapeutic interventions.
Allows for identification of very small deletions or duplications of chromosomes.
Is a technique that allows the detection of losses and gains of DNA copy number across the entire genome.
Is a laboratory technique that produces an image of an individual’s chromosomes. The karyotype is used to look for abnormal numbers or structures of chromosomes.
FISH is a test that maps the genetic material in human cells, including specific genes of portion of genes. FISH uses a protein, called a probe, to “stick” to known sequence of DNA (usually a known mutation). If that sequence is present in a patient’s sample, the probe will bind to it and light up under a fluorescent microscope. FISH also can be used to detect chromosome rearrangements, marker chromosomes (extra pieces of unidentified chromosomal material), and duplications or deletions of large pieces of DNA.
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