Medical Policy: 02.04.50
Original Effective Date: April 2015
Reviewed: March 2018
Revised: March 2018
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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.
Whole exome sequencing (WES) sequences the portion of the genome that contains protein-coding DNA. 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 disease or disabilities that have not been explained by standard clinical work-up.
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.
Given the variety of disorders and management approaches, there are a variety of potential health outcomes from a definitive diagnosis. In general, the outcomes of a molecular genetic diagnosis include 1) impacting the search for diagnosis, 2) informing follow-up that can benefit a child by reducing morbidity, and 3) affecting reproductive planning for parents and potentially the affected patient.
The standard diagnostic work-up for patients with suspected Mendelian (genetic disease which follows simple mendelian patterns of inheritance) may include combinations of radiographic, electrophysiologic, biochemical, biopsy, and targeted genetic evaluations. The search for a diagnosis may become a time consuming and expensive process.
Whole genome sequencing (WGS), also known as full genome sequencing, 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 98% of the genome that does not generally contain protein coding genes. 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.
WES or WGS using next-generation sequencing technology can facilitate obtaining a genetic diagnosis in patients. WES is limited to most of the protein-coding sequence of an individual (85%), is composed of about 20,000 genes and 180,000 exons (protein-coding segments of a gene), and constitutes approximately 1% of the genome. It is believed that the exome contains about 85% of heritable disease-causing mutations. WES has the advantage of speed and efficiency relative to Sanger sequencing of multiple genes. WES shares some limitations with Sanger sequencing. For example, it will not identify the following: intronic sequences or gene regulatory regions; chromosomal changes; large deletions; duplications; or rearrangements within genes, nucleotide repeats, or epigenetic changes. WGS uses techniques similar to WES, but includes noncoding regions. WGS has greater ability to detect large deletions or duplications in protein-coding regions compared with WES, but requires greater data analytics. Technical aspects of WES and WGS are evolving, including the development of databases such as the National Institutes of Health’s ClinVar database to catalog variants, uneven sequencing coverage, gaps in exon capture before sequencing, and difficulties with narrowing the large initial number of variants to manageable numbers without losing likely candidate mutations. The variability contributed by the different platforms and procedures used by different clinical laboratories offering exome sequencing as a clinical service is unknown.
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 whole exome and whole 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.
The purpose of whole exome sequencing (WES) in patients who have multiple unexplained congenital anomalies or a neurodevelopmental disorder is to establish a molecular diagnosis. The criteria under which diagnostic testing for a genetic or heritable disorder may be considered clinically useful are as follows:
There are relatively few data specific to the analytic validity of WES. Next generation sequencing (NGS) techniques used for WES are expected to have high accuracy for mutation detection. However, NGS platforms differ regarding the depth of sequence coverage, methods for base calling and read alignment, and other factors. These factors contribute to potential variability across the platforms and procedures used by different clinical laboratories offering exome sequencing as a clinical service. The American College of Medical Genetics and Genomics has clinical laboratory standards for NGS, including WES. The guidelines outline the documentation of test performance measures that should be evaluated for NGS platforms, and note that typical definitions of analytic sensitivity and specificity do not apply for NGS.
Depending on the platform and variant call method used, WES may not accurately detect large insertions and deletions, large copy number variants, and structural chromosome rearrangements due to the short sequence read lengths.
A number of studies have reported on the use of WES in clinical practice. Typically, the populations included in these studies have suspected rare genetic disorders, although the specific populations vary.
Series have been reported with as many as 2000 patients. The largest reason for referral to a tertiary care center was an unexplained neurodevelopmental disorder. Many patients had been through standard clinical workup and testing without identification of a genetic variant to explain their condition. Diagnostic yield in these studies, defined as the proportion of tested patients with clinically relevant genomic abnormalities, ranged from 25% to as many as 48%. Because there is no reference standard for the diagnosis of patients who have exhausted alternative testing strategies, clinical confirmation may be the only method for determining false-positive and false-negative rates. No reports were identified of incorrect diagnoses, and how often they might occur is unclear.
When used as a first-line test in infants with multiple congenital abnormalities and dysmorphic features, diagnostic yield may be as high as 58%. Testing parent-child trios has been reported to increase diagnostic yield, to identify an inherited variant from an unaffected parent and be considered benign, or to identify a de novo variant not present in an unaffected parent. First-line trio testing for children with complex neurologic disorders was shown to increase the diagnostic yield (29%, plus a possible diagnostic finding in 27%) compared with a standard clinical pathway (7%) performed in parallel in the same patients.
Cohort studies following children from presentation to outcomes have not been reported. There are considerable challenges conducting studies of sufficient size given the underlying genetic heterogeneity, and including follow-up adequate to observe final health outcomes. Studies addressing clinical utility have reported mainly diagnostic yield and management changes. Thus, it is difficult to quantify lower or upper bounds for any potential improvement in the net health outcome owing in part to the heterogeneity of disorders, rarity, and outcome importance that may differ according to identified pathogenic variants. Actionable items following testing in the reviewed studies included family planning, change in management, change or avoidance of additional testing, surveillance for associated morbidities, prognosis, and ending the diagnostic odyssey.
The evidence reviewed supports a perspective that identifying a pathogenic variant can (1) impact the search for a diagnosis, (2) inform follow-up that can benefit a child by reducing morbidity and rarely potential mortality, and (3) affect reproductive planning for parents and later potentially the affected child. When recurrence risk can be estimated for an identified variant (e.g. by including parent testing), future reproductive decisions can be affected. Early use of WES can reduce the time to diagnosis and reduce the financial and psychological burdens associated with prolonged investigation.
For individuals who have multiple unexplained congenital anomalies or a neurodevelopment phenotype who receive whole exome sequencing (WES), the evidence includes case series. 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 (chromosomal microarray analysis, chromosomal karyotype, fluorescence in situ hybridization (FISH), metabolic testing, imaging, single gene tests, referrals to other specialists), may be left without a clinical diagnosis of their disorder, despite a lengthy clinical workup. These case series have reported diagnostic yields of WES ranging from 25% to 60%, depending on the individual’s age, phenotype, and previous workup. Comparative studies have reported an increase in diagnostic yield compared with standard testing strategies. Thus, for individuals who have a suspected genetic etiology but for whom the specific genetic alteration is unclear or unidentified by standard clinical work-up, WES may return a likely pathogenic variant. A genetic diagnosis for these patients is reported to change 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.
Most of the literature on WES is on neurodevelopmental disorders in children; however, other potential indications for WES have been reported. These include limb-girdle muscular dystrophy, inherited retinal disease, and other disorders including mitochondrial, endocrine, and immunologic disorders. The yield for unexplained limb-girdle muscular dystrophy and retinal disease is high, but a limited number of patients have been studied to date.
The purpose of WES in patients who have a suspected genetic disorder other than multiple unexplained congenital anomalies, a neurodevelopmental disorder or epilepsy/seizure disorders is to establish a molecular diagnosis. The criteria under which diagnostic testing for a genetic or heritable disorder may be considered clinically useful are as above.
As described above for use of WES in patients with multiple congenital anomalies or a neurodevelopmental disorder.
Studies have assessed WES for a broad spectrum of disorders. Some studies used a virtual gene panel that is restricted to genes that are associated with the phenotype, while others have examined the whole exome, either initially or sequentially. An advantage of WES over individual gene or gene panel testing is that the stored data allows reanalysis as new genes are linked to the patient phenotype. WES has also been reported to be beneficial in patients with atypical presentations.
A genetic diagnosis for an unexplained disorder can alter management in several ways: such a diagnosis may lead to including genetic counseling and ending the diagnostic odyssey, and may affect reproductive decision making.
For individuals who have a suspected genetic disorder other than multiple congenital anomalies, neurodevelopmental disorders or epilepsy/seizure disorders, who receive whole exome sequencing (WES), the evidence includes small case series and prospective research studies. There are increasing reports of use of WES to identify a molecular basis for disorders other than multiple congenital anomalies, neurodevelopmental disorders or epilepsy/seizure disorders. The diagnostic yield in these studies range from as low as 3% to 60%. One concern with WES is the possibility of incidental findings. Some studies reported on the use of a virtual gene panel with restricted analysis of disease-associated genes, and the authors noted that WES data allows reanalysis as new genes are linked to the patient phenotype. Overall, there are a limited number of patients that have been studied for any specific disorder, and clinical use of WES in these disorders is at an early stage. The evidence is insufficient to determine the effects of the technology on net health outcomes.
The purpose of whole genome sequencing (WGS) in patients who have a suspected genetic disorder is to establish a molecular diagnosis from either the coding or noncoding regions of the genome. The criteria under which diagnostic testing for a genetic or heritable disorder may be considered clinically useful are as above.
WGS can detect structural variants and variants in regulatory regions. However, it is subject to many of the same considerations for potential variability in technical performance as WES. In 2014, Dewey et. al. reported the coverage and concordance of clinically relevant genetic variations provided by WGS technologies in 12 healthy adult volunteers. All subjects underwent WGS with the Illumina platform; 9 subjects also underwent WGS by the Complete Genomics (Mountain View, CA) platform to evaluate the reproducibility of sequence data. Genome sequences were compared with several reference standards. Depending on the sequencing platform, a median of 10% (Illumina; range, 5%-34%) to 19% (Complete Genomics; range, 18%-21%) of genes associated with inherited disease and a median of 9% (Illumina; range, 2%-27%) to 17% (Complete Genomics; range, 17%-19%) of American College of Medical Genetics and Genomics reportable genes were not covered at a minimum threshold for genetic variant discovery. The genotype concordance between sequencing platforms was high for common genetic variants, for single-nucleotide variants in protein-coding regions of the genome, and among candidate variants for inherited disease risk. However, genotype concordance between sequencing platforms for small insertion or deletion variants was moderate overall (median, 57%; range, 53%-59%) and in protein-coding regions of the genome (median, 66%; range, 64%-70%), but was substantially lower among genetic variants that were candidates for inherited disease risk (median, 33%; range, 10%-75%).
Studies have shown that WGS can detect more pathogenic variants than WES, due to an improvement in detecting copy number variants, insertions and deletions, intronic single-nucleotide variants, and exonic single-nucleotide variants in regions with poor coverage on WES. In some studies the genes examined were those that had previously been associated with the phenotype, while other studies were research-based and conducted more exploratory analysis. It has been noted that genomes that have been sequenced with WGS are available for future review when new variants associated with clinical diseases are discovered.
The effect on health outcomes based on WGS results are the same as those with WES, with a possible change in surveillance, management and/or reproductive planning. A reduction in invasive testing and an end of the diagnostic odyssey are also considered to be significant health outcomes.
WGS has increased coverage and diagnostic yield compared with WES, but the technology is limited by the amount of data generated and greater need for storage and analytic capability. One of the limitations of this testing is the lengthy turnaround times for the production and analysis of whole genome data, which hampers its clinical application. Several authors have proposed that, as WGS becomes feasible on a larger scale, it may in the future become the standard first-tier diagnostic test. At present there is limited data on the clinical use of WGS. Further studies are needed to evaluate clinical utility. The evidence is insufficient to determine the effects of the technology on net health outcomes.
Cancer is a complex biological process. Historically, cancers have been classified according to their anatomic site of origin (e.g. lung, breast, liver, colon), but within these groupings there are multiple subtypes with differences in response to treatment and overall behavior. Currently there are a number of DNA sequence based tests that are used in cancer medicine, ranging from single gene tests for mutations to more expensive panels which might include hundreds of defined cancer genes and mutations “hot spots”. Technologic advances have now brought the possibility of more extensive interrogation of the genome through whole exome and whole genome sequencing for cancer.
Cancers are caused by the accumulation of genetic alterations that may lead to the dysfunction of regulation cell growth, resulting in the development of tumors. In recent years, whole exome sequencing (WES), which allows detection of 85% of disease causing variants, has been used to compare tumor and normal DNA to allow the identification of variants specific to the tumor. Genetic changes in cancer are increasingly used for diagnosis and may guide treatment decisions. In 2014, Malhotra et. al. explored whether there is evidence that WES improves outcomes for patients with cancer. The published evidence was evaluated using a methodology that combines the analytic validity, clinical validity, clinical utility, and ethical, legal and social implications (ACCE) model for genetic test evaluations and internationally accepted health technology assessment methodology. Conclusions were based on peer reviewed published studies of > 10 patients, with ≥ 3 studies for a given phenotype. WES has been conducted most extensively (seven studies to date) in breast cancer patients, with fewer studies of other types of cancers (e.g. leukemia, prostate cancer, and ovarian cancer). Studies evaluating somatic alterations showed high intratumor and intertumor heterogeneity. In addition, both novel and previously implicated variants were identified. However, only three studies with > 10 individuals have shown potential for clinical utility of WES; whereby, variants identified through WES may determine response to drug treatment. The authors concluded despite evidence for clinical validity of WES in cancers, clinical utility is very limited and needs to be further evaluated in larger clinical studies.
In 2015, Laskin et. al. reviewed the findings of a Personalized OncoGenomics (POG) study. This study sought to establish a process to integrate data from whole genome sequencing (WGS) into routine cancer care. In this POG program study, medical oncologists recruited patients from their general oncology clinics with the intention of sampling a variety of cancer histologies, Between June 2012 and August 2014, 100 adult patients with incurable cancers consented to participate. Fresh tumor and blood samples were obtained and used for whole genome and RNA sequencing. Computational approaches were used to identify candidate driver mutations, genes, and pathways. Diagnostic and drug information were then sought based on these candidate “drivers.” Reports were generated and discussed weekly in a multidisciplinary team setting. Other multidisciplinary working groups were assembled to establish guidelines on the interpretation, communication, and integration of individual genomic findings into patient care. Of 78 patients for whom WGS was possible, results were considered actionable in 55 cases. In 23 of these 55 cases, the patients received treatments motivated by WGS. The authors indicated that a multidisciplinary team of clinicians and scientists can implement a paradigm in which WGA is integrated into the care of late stage cancer patients to inform systemic therapy decisions. In this study it was noted that a limitation of using whole genome sequencing is the lengthy turnaround times for the production and analysis of whole genome data, which hampers its clinical application in cancer where rapid treatment decisions are frequently required.
Oncologists are becoming rapidly educated about the range of genomic platforms that exist in the treatment of cancer, and technologic advances have brought the possibility of more extensive interrogation of the genome through whole exome sequencing (WES) and whole genome sequencing (WGS) where the variants identified may determine response to drug treatment and improve outcomes for patients with cancer. One of the limitations of this testing is the lengthy turnaround times for the production and analysis of whole genome data, which hampers its clinical application in cancer, where rapid treatment decisions are frequently required. While studies may show promising results, at present, there is limited data on the clinical use of WES and WGS in the treatment of cancer. The clinical utility is very limited and needs to be further evaluated in large clinical studies to include larger patient populations in a variety of cancer histologies. The evidence is insufficient to determine the effects of the technology on net health outcomes.
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 net 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:
In 2007, the American Society for Reproductive Medicine (ASRM) issued a practice committee opinion that concluded that available evidence did not support the use of preimplantation genetic screening (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 2016, the American College of Obstetricians and Gynecologists issued a joint committee opinion (Number 682) with the Society for Maternal-Fetal Medicine, regarding microarrays and next-generation sequencing technology: the use of advanced genetic diagnostic tools in obstetrics and gynecology that states: Routine use of whole genome or whole exome sequencing for prenatal diagnosis in not recommended outside the context of clinical trials until sufficient peer reviewed data and validation studies are published.
Prenatal and preimplantation for screening or 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 impacts prenatal diagnosis and reproductive decision making. There are high false positive, false negative, and variants of unknown clinical significance rates (incidental findings that may cause anxiety). Based on the peer reviewed medical literature the evidence is insufficient in proving the clinical utility of this technology in the use of prenatal and preimplantation genetics. Further validation studies are needed regarding the clinical utility and therefore, the evidence is insufficient to determine the effects of the technology on net health outcomes.
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”.
“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.”
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.
See also medical policy 02.04.38 Noninvasive Prenatal Screening for Fetal Aneuploidies Using Cell - Free Fetal DNA in Maternal Plasma
Whole exome sequencing (WES) may be considered medically necessary for the evaluation of unexplained neurodevelopmental disorders, 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 all other indications including but not limited to the following:
Based on review of the peer reviewed medical literature there is insufficient evidence to support a conclusion concerning the net health outcomes or benefits associated with this testing. Further studies are needed to evaluate the clinical utility of whole exome sequencing (WES) for all other indications.
Whole genome sequencing (WGS) is considered investigational for all indications.
WGS has increased coverage and diagnostic yield compared with WES, but the technology is limited by the amount of data generated and greater need for storage and analytic capability. One of the limitations of this testing is the lengthy turnaround times for the production and analysis of whole genome data, which hampers its clinical application. Several authors have proposed that as WGS becomes feasible on a larger scale, it may in the future become the standard first-tier diagnostic test. At present there is limited data on the clinical use of WGS. Further studies are needed to evaluate the clinical utility. The evidence is insufficient to determine the effects of the technology on net health outcomes.
Whole exome sequencing (WES) and whole genome sequencing (WGS) is considered investigational for screening asymptomatic individuals for genetic disorders. There is insufficient evidence to support a conclusion concerning the net 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. The current technology does not support short turnaround times which impacts prenatal diagnosis and reproductive decision making. There are also false positive, false negative and variants of unknown clinical significance (incidental findings that may cause anxiety). Based on the peer reviewed medical literature the evidence is insufficient in proving the clinical utility of this technology in the use of prenatal and preimplantation genetics. Further validation studies are needed regarding the clinical utility and therefore, the evidence is insufficient to determine the effects of the technology 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 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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