CAM 204102

Whole Exome and Whole Genome Sequencing for Diagnosis of Patients With Suspected Genetic Disorders

Category:Laboratory   Last Reviewed:July 2018
Department(s):Medical Affairs   Next Review:July 2019
Original Date:October 2013    

Description 
Whole exome sequencing (WES) sequences the portion of the genome that contains protein-coding DNA, while whole genome sequencing (WGS) sequences both coding and noncoding regions of the genome. WES and WGS have been proposed for use in patients presenting with disorders and anomalies that have not been explained by standard clinical workup. Potential candidates for WES and WGS include patients who present with a broad spectrum of suspected genetic conditions.

For individuals who have multiple unexplained congenital anomalies or a neurodevelopmental disorder who receive WES, the evidence includes large case series and within-subject comparisons. Relevant outcomes are test accuracy and validity, functional outcomes, changes in reproductive decision making, and resource utilization. Patients who have multiple congenital anomalies or a developmental disorder with a suspected genetic etiology, but whose specific genetic alteration is unclear or unidentified by standard clinical workup, may be left without a clinical diagnosis of their disorder, despite a lengthy diagnostic workup. For a substantial proportion 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 the technology results in a meaningful improvement in the net health outcome.

For individuals who have a suspected genetic disorder other than multiple congenital anomalies or a neurodevelopmental disorder who receive WES, the evidence includes small case series and prospective research studies. Relevant outcomes are test accuracy and validity, functional outcomes, changes in reproductive decision-making, and resource utilization. There are increasing reports of use of WES to identify a molecular basis for disorders other than multiple congenital anomalies or neurodevelopmental disorders. The diagnostic yields in these studies range from as low as 3% to 60%. One concern with WES is the possibility of incidental findings. Some studies have reported on the use of a virtual gene panel with restricted analysis of disease-associated genes, and WES data allows reanalysis as new genes are linked to the patient phenotype. Overall, there are a limited number of patients who have been studied for any specific disorder, and clinical use of WES for these disorders is at an early stage. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with a suspected genetic disorder who receive WGS, the evidence includes case series. Relevant outcomes are test accuracy and validity, functional outcomes, changes in reproductive decision making, and resource utilization. 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. 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. The evidence is insufficient to determine the effects of the technology on health outcomes.   

Background 
WHOLE EXOME SEQUENCING AND WHOLE GENOME SEQUENCING
Whole exome sequencing (WES) is targeted next-generation sequencing of the subset of the human genome that contains functionally important sequences of protein-coding DNA, while whole genome sequencing (WGS) uses next-generation sequencing techniques to sequence both coding and noncoding regions of the genome. WES and WGS have been proposed for use in patients presenting with disorders and anomalies not explained by standard clinical workup. Potential candidates for WES and WGS include patients who present with a broad spectrum of suspected genetic conditions.

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 a 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 workup for patients with suspected Mendelian disorders may include combinations of radiographic, electrophysiologic, biochemical, biopsy, and targeted genetic evaluations.1 The search for a diagnosis may thus become a time-consuming and expensive process.  

WES and WGS Technology
WES or WGS using next-generation sequencing technology can facilitate obtaining a genetic diagnosis in patients efficiently. 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 (http://www.ncbi.nlm.nih.gov/clinvar/) 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.

In 2013, the American College of Medical Genetics and Genomics, Association for Molecular Pathology, and College of American Pathologists convened a workgroup to develop standard terminology for describing sequence variants. Guidelines developed by this workgroup, published in 2015, describe criteria for classifying pathogenic and benign sequence variants based on 5 categories of data: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign.2 

WES and WGS Testing Services
Several laboratories offer WES and WGS as a clinical service. Illumina offers 3 TruGenome tests: the TruGenome Undiagnosed Disease Test (indicated to find the underlying genetic cause of an undiagnosed rare genetic disease of single-gene etiology), the TruGenome™Predisposition Screen (indicated for healthy patients interested in learning about their carrier status and genetic predisposition toward adult-onset conditions), and the TruGenome™Technical Sequence Data (WGS for labs and physicians who will make their own clinical interpretations). Ambry Genetics offers 2 WGS tests, the ExomeNext and ExomeNext-Rapid, which sequence both the nuclear and the mitochondrial genomes. GeneDx offers WES with its XomeDx™ test. Medical centers may also offer WES and WGS as a clinical service.

Examples of laboratories offering WES as a clinical service and their indications for testing are summarized in Table 1.

Table 1: Examples of Laboratories Offering Whole Exome Sequencing as a Clinical Service

Laboratory Laboratory Indications for Testing
Ambry Genetics, (Aliso Viejo, CA)    

 "The patient's clinical presentation is unclear/atypical disease and there are multiple genetic conditions in the defferential diagnosis."

GeneDx, (Gaithersburg, MD) "a patient with a diagnosis that suggests the involvement of one or more of many different genes, which would, if even available and sequenced individually, be prohibitively expensive'
Baylor Collge of Medicine, (Houston TX)  "used when a patient's medical history and physical exam findings strongly suggest that there is an underlying genetic etiology. In some cases, the patient may have had an extensive evaluation consisting of multiple genetic test, without identifying an etiology."
University of California Los Angeles Health System "This test is intended for use in conjunction with the clinical presentation and other markers of disease progession for the management of patients with rare genetic disorders."
EdgeBio, (Gaithersburg, MD) Recommended "In situations where there has been a diagnostic failure with no discernible path. In situations where there are currently no available tests to determine the status of a potential genetic disease. In situations with atypical findings indicative of multiple disease(s)."
Children's Mercy Hospitals and Clinics, (Kansas City, MO) Provided as a service to families with children who have had an extensive negative work-up for a genetic disease; also used to identify novel disease genes.
Emory Genetics Laboratory, (Atlanta, GA) "Indicated when there is a suspicion of a genetic etiology contributing to the proband's manifestations."

Note that this evidence review does not address the use of WES and WGS for preimplantation genetic diagnosis or screening, prenatal (fetal) testing, or for testing of cancer cells.

Regulatory Status  
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Whole exome or genome sequencing tests as a clinical service are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.  

Policy 

  1. Whole exome sequencing is considered MEDICALLY NECESSARY  for the evaluation unexplained congenital or neurodevelopmental disorder in children when all the following criteria are met:
    • The patient has been evaluated by a board-certified clinician with expertise in clinical genetics and counseled about the potential risks of genetic testing
    • WES results will directly impact patient management and clinical outcome for the individual being tested
    • A genetic etiology is the most likely explanation for the phenotype
    • No other causative circumstances (e.g. environmental exposures, injury, infection) can explain the symptoms
    • Clinical presentation does not fit a well-described syndrome for which single-gene or targeted panel testing (e.g., comparative genomic hybridization/chromosomal microarray analysis) is available
    • The differential diagnosis list and/or phenotype warrant testing of multiple genes and ONE of the following:
      •  WES is more practical than the separate single gene tests or panels that would be recommended based on the differential diagnosis
      • WES results may preclude the need for multiple and/or invasive procedures, follow-up, or screening that would be recommended in the absence of testing
  2. If whole exome sequencing has been previously performed, further genetic tests involving only exome analyses is INVESTIGATIONAL
  3. Whole exome sequencing is INVESTIGATIONAL for all other indications, including but not limited to, tumor sequencing.
  4. Whole genome sequencing is considered INVESTIGATIONAL for all indications.

Policy Guidelines
Beginning in 2015, there will be specific codes for this testing:

81415 Exome (e.g., unexplained constitutional or heritable disorder or syndrome); sequence analysis

81416 sequence analysis, each comparator exome (e.g., parents, siblings) (List separately in addition to code for primary procedure)

81417 re-evaluation of previously obtained exome sequence (e.g., updated knowledge or unrelated condition/syndrome)

81425 Genome (e.g., unexplained constitutional or heritable disorder or syndrome); sequence analysis

81426 sequence analysis, each comparator genome (e.g., parents, siblings) (List separately in addition to code for primary procedure)

81427 re-evaluation of previously obtained genome sequence (e.g., updated knowledge or unrelated condition/syndrome)

Prior to 2015, there are no specific CPT codes for whole exome sequencing. It would likely be reported with the unlisted molecular pathology code 81479.

Benefit Application
Blue Card®/National Account Issues
No applicable information.

Rationale
Validation of the clinical use of any genetic test focuses on 3 main principles: (1) analytic validity, which refers to the technical accuracy of the test in detecting a variant that is present or in excluding a variant that is absent; (2) clinical validity, which refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease; and (3) clinical utility (i.e., how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes). 

WHOLE EXOME SEQUENCING IN PATIENTS WITH MULTIPLE CONGENITAL ANOMALIES OR A NEURODEVELOPMENTAL DISORDER
Clinical Context and Test Purpose
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:

  • A definitive diagnosis cannot be made based on history, physical examination, pedigree analysis, and/or standard diagnostic studies or tests;
  • The clinical utility of a diagnosis has been established (e.g., by demonstrating that a definitive diagnosis will lead to changes in clinical management of the condition, changes in surveillance, or changes in reproductive decision making, and these changes will lead to improved health outcomes); and
  • Establishing the diagnosis by genetic testing will end the clinical workup for other disorders.

The question addressed in this evidence review is: Does WES improve health outcomes when used for the diagnosis of patients with multiple unexplained congenital anomalies or a neurodevelopmental disorder?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is patients presenting with multiple unexplained congenital anomalies or a neurodevelopmental disorder that is suspected to have a genetic basis but are not explained by standard clinical workup.

Intervention
The relevant intervention of interest is WES.

Comparators
The relevant comparator of interest is standard clinical workup without WES.

Outcomes
The general outcomes of interest are the accuracy of next-generation sequencing (NGS) compared with Sanger sequencing, the sensitivity and specificity and positive and negative predictive value for the clinical condition, and improvement in health outcomes. Health outcomes include a reduction in morbidity due to appropriate treatment and surveillance, the end of the diagnostic odyssey, and effects on reproductive planning for parents and potentially the affected patient.

False-positive test results can lead to misdiagnosis and inappropriate clinical management. False-negative test results can lead to a lack of a genetic diagnosis and continuation of the diagnostic odyssey. 

Timing
These tests are performed when standard clinical workup has failed to arrive at a diagnosis.

Setting
These tests are offered commercially through various manufacturers.

Analytic Validity
There are relatively few data specific to the analytic validity of WES. 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.4 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.4 WES may be less sensitive for the detection of copy number variants than high-resolution microarray testing.5 NGS also has poorer coverage for A/T-rich, G/C-rich, and pseudogene regions, as well as homopolymer stretches.6,7

Clinical Validity
A number of studies have reported on the use of WES in clinical practice (see Table 2). 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 2,000 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.8

Clinical Utility
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 (see Table 2) 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 here reflects the accompanying uncertainty, but 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 (eg, 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. 

Table 2. Diagnostic Yields of WES for Congenital Anomalies or a Neurodevelopmental Disorder

(Year)

Patient Population

                  N                     

Design

Yield, n (%)

Additional Information

Yang et al. (2013)9 

Suspected genetic disorder (80% neurologic)  

250 (1% fetus; 50% <5 y;38% 5-18 y; 11% adults) 

Consecutive patients at single center

62 (25) 

Identification of atypical phenotypes of known genetic diseases and blended phenotypes  

Yang et al. (2014)10 

Suspected genetic disorder (88% neurologic or  developmental)

2,000 (45% <5 y; 42% 5-18 y; 12% adults)

Consecutive patients at single center

504 (25)

Identification of novel variants. End of the diagnostic odyssey and change in management

Lee et al. (2014)11

Suspected rare Mendelian disorders (57% of children had developmental delay; 26% of adults had ataxia)

814 (49% <5 y; 15% 5-18 y; 36% adults)

Consecutive patients at single center

213 (26)

Trio (31% yield) vs proband only (22% yield)

Iglesias et al. (2014)12

Birth defects (24%); developmental delay (25%); seizures (32%)

115 (79% children)

Single-center tertiary clinic

37 (32)

Discontinuation of planned testing, changed medical management, and family planning

Soden et al. (2014)13

Children with unexplained neurodevelopmental disorders

119 (100 families)

 

Single-center databasea

53 (45)

 

Change in clinical care or impression in 49% of families

Srivastava et al. (2014)14

Children with unexplained neurodevelopmental disorders

78

Pediatric neurogenetics clinic

32 (41)

Changed medical management, prognostication, and family planning

Farwell et al. (2015)1

Unexplained neurologic disorders (65% pediatric)

500

WES laboratory

152 (30)

Trio (37.5% yield) vs proband only (20.6% yield); 31 (7.5% de novo)

Nolan and Carlson (2016)16

Children with unexplained neurodevelopmental disorders

50

Pediatric neurology clinic

41 (48)

Changed medication, systemic investigation, and family planning

Allen et al. (2016)17

Patients with unexplained early-onset epileptic encephalopathy

50 (95% <1 y)

Single center

11 (22)

2 VUS for follow-up, 11 variants identified as de novo

Stark et al. (2016)18

Infants (≤2 y) with suspected monogenic disorders with multiple congenital abnormalities and dysmorphic features

80

Prospective comparative study at a tertiary center

46 (58)

First-line WES increased yield by 44%, changed clinical management and family planning

Vissers et al. (2017)8

Children with complex neurologic disorders of suspected genetic origin

150

Prospective comparative study at a tertiary center

  • 44 (29) conclusive
  • 41 (27) possible

First-line WES had 29% yield vs 7% yield for standard diagnostic workupb

VUS: variants of uncertain significance; WES: whole exome sequencing.
a Included both WES and whole genome sequencing.
b Standard diagnostic workup included an average of 23.3 physician-patient contacts, imaging studies, muscle biopsies or lumbar punctures, other laboratory tests, and an average of 5.4 sequential gene by gene tests.

Section Summary: Whole Exome Sequencing in Patients With Multiple Congenital Anomalies or a Neurodevelopmental Disorder
The evidence on WES in patients who have multiple congenital anomalies or a developmental disorder with a suspected genetic etiology includes case series. These series have reported diagnostic yields of WES ranging from 22% to 58%, 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 workup, 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.

WES IN PATIENTS WITH A SUSPECTED GENETIC DISORDER OTHER THAN MULTIPLE CONGENITAL ANOMALIES OR A NEURODEVELOPMENTAL DISORDER

Clinical Context and Test Purpose
Most of the literature on WES is on neurodevelopmental disorders in children; however, other potential indications for WES have been reported (see Table 3). 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 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 above.

The question addressed in this evidence review is: Does WES improve health outcomes when used for the diagnosis of a suspected genetic condition?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is patients presenting with a disorder other than multiple unexplained congenital anomalies or a neurodevelopmental disorder that is suspected to have a genetic basis but is not explained by standard clinical workup.

Intervention
The relevant intervention of interest is WES.

Comparators
The relevant comparator of interest is standard clinical workup without WES.

Outcomes
The general outcomes of interest are the accuracy of NGS compared with Sanger sequencing, the sensitivity and specificity and positive and negative predictive value for the clinical condition, and clinical health outcomes. Health outcomes include a reduction in morbidity due to appropriate treatment and surveillance, the end of the diagnostic odyssey, and effects on reproductive planning for parents and potentially the affected patient.

Timing
The test is performed when standard clinical workup has failed to arrive at a diagnosis.

Setting
These tests are offered commercially through various manufacturers.

Analytic Validity
As described above for use of WES in patients with multiple congenital anomalies or a neurodevelopmental disorder.

Clinical Validity
Studies have assessed WES for a broad spectrum of disorders. The diagnostic yield in patient populations restricted to specific phenotypes ranges from 3% for colorectal cancer to 60% for unexplained limb-girdle muscular dystrophy. 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.

Table 3. Diagnostic Yields of WES for Conditions Other Than Multiple Congenital Anomalies or a Neurodevelopmental Disorder

Study (Year)

Patient Population

N

Design

Yield, n (%)

Additional Actions

Neveling et al. (2013)19  

Unexplained disorders: blindness, deafness, movement disorders, mitochondrial disorders, hereditary cancer 

 186

Outpatient genetic clinic; post hoc comparison with Sanger sequencing  

3%-52% 

WES increased yield vs Sanger sequencing. Highest yield for blindness and deafness  

Ghaoui et al. (2015)20  

Unexplained limb-girdle muscular dystrophy 

60 families 

Prospective study of patients identified from a specimen bank 

27 (60) 

Trio (60% yield) vs proband only (40% yield)  

Valencia et al. (2015)21

Unexplained disorders: congenital anomalies (30%), neurologic (22%), mitochondrial (25%), endocrine (3%), immunodeficiencies (17%)

40 (<17 y)

Consecutive patients in a single center

12 (30)

Altered management including genetic counseling and ending diagnostic odyssey

Wortmann et al. (2015)22

Suspected mitochondrial disorder

 

109

 

Patients referred to a single center

 

42 (39)

 

57% yield in patients with high suspicion of mitochondrial disorder

Posey et al. (2016)23

Adults (overlap of 272 patients reported by Yang et al., 2014),10 includes neurodevelopmental and other phenotypes

486 (53% 18-30 y; 47% >30 y)

 

Review of lab findings in adults

 

85 (18)

 

Yield in patients 18-30 y (24%) vs those >30 y (10.4%)

 

Walsh et al. (2017)24

Peripheral neuropathy in patients ranging from 2-68 y

  • 23 children
  • 27 adults

Research study at tertiary pediatric and adult centers

19 (38)

Initial targeted analysis with virtual gene panel, followed by WES

Miller et al. (2017)25

Craniosynostosis in patients who tested negative on targeted genetic testing

40

Research study of referred patientsa

15 (38)

Altered management and reproductive decision making

WES: whole exome sequencing.
a Included both WES and whole genome sequencing.   

Clinical Utility
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.

Section Summary: WES in Patients with a Suspected Genetic Disorder Other Than Multiple Congenital Anomalies or a Neurodevelopmental Disorder
There are increasing reports of WES being used to identify a molecular basis for disorders other than multiple congenital anomalies or neurodevelopmental disorders. The diagnostic yields in these studies ranged from 3% for colorectal cancer to 60% for trio (parents and child) analysis of limb-girdle muscular dystrophy. One concern with WES is the possibility of incidental findings. Some studies report 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 study of WES in these disorders is at an early stage.

WHOLE GENOME SEQUENCING IN PATIENTS WITH A SUSPECTED GENETIC DISORDER
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.

The question addressed in this evidence review is: Does WGS improve health outcomes when used for the diagnosis of a suspected genetic disorder?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is patients presenting with any of a variety of disorders and anomalies that are suspected to have a genetic basis but are not explained by standard clinical workup.

Intervention
The relevant intervention of interest is WGS.

Comparators
The relevant comparator of interest is standard clinical workup without WGS.

Outcomes
As described above for use of WES in patients with multiple congenital anomalies or a neurodevelopmental disorder.

Timing
As described above for use of WES in patients with multiple congenital anomalies or a neurodevelopmental disorder.

Setting
As described above for use of WES in patients with multiple congenital anomalies or a neurodevelopmental disorder.

Analytic Validity
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.26 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%).

WGS may have improved coverage compared with WES, particularly in GC-rich regions, structural variants, and intronic variants. 

Clinical Validity
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 (see Table 4).27 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.  

Table 4. Diagnostic Yields With WGS

Study (Year)

Patient Population

N

Design

Yield, n (%)

Additional Actions

Taylor et al. (2015)28

Broad spectrum of suspected genetic disorders

 

217

 

Multicenter series

 

46 (21 

34% yield in Mendelian disorders; 57% yield in trios

Ellingford et al. (2016)29

Unexplained inherited retinal disease

46

 

WGS in patients referred to a single center

24 (52)

 

Estimated 29% increase in yield vs NGS

Carss et al. (2017)30

Unexplained inherited retinal disease

 

605 

NIHR-BioResource Rare Diseases Consortium

 

331 (55 

Compared with a detection rate of 50% with WES (n=117)

Lionel et al. (2017)27

Well-characterized but genetically heterogeneous cohort that had undergone targeted gene sequencing

10 

Trio test for patients recruited from pediatric nongenetic subspecialists

 

42 (41)

 

Compared with a yield of 24% with standard diagnostic testing and a 25% increase in yield from WES

 NGS: next-generation sequencing; NIHR: National Institute for Health Research; WGS: whole genome sequencing; WES: whole exome sequencing 

Clinical Utility
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.

Section Summary: Whole Exome Sequencing in Patients With a Suspected Genetic Disorder
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. 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.

SUMMARY OF EVIDENCE
For individuals who have multiple unexplained congenital anomalies or a neurodevelopmental disorder who receive WES, the evidence includes large case series and within-subject comparisons. Relevant outcomes are test accuracy and validity, functional outcomes, changes in reproductive decision making, and resource utilization. Patients who have multiple congenital anomalies or a developmental disorder with a suspected genetic etiology, but whose specific genetic alteration is unclear or unidentified by standard clinical workup, may be left without a clinical diagnosis of their disorder, despite a lengthy diagnostic workup. For a substantial proportion 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 the technology results in a meaningful improvement in the net health outcome.

For individuals who have a suspected genetic disorder other than multiple congenital anomalies or a neurodevelopmental disorder who receive WES, the evidence includes small case series and prospective research studies. Relevant outcomes are test accuracy and validity, functional outcomes, changes in reproductive decision making, and resource utilization. There are increasing reports of use of WES to identify a molecular basis for disorders other than multiple congenital anomalies or neurodevelopmental disorders. The diagnostic yields in these studies range from as low as 3% to 60%. One concern with WES is the possibility of incidental findings. Some studies have reported on the use of a virtual gene panel with restricted analysis of disease-associated genes, and WES data allows reanalysis as new genes are linked to the patient phenotype. Overall, there are a limited number of patients who have been studied for any specific disorder, and clinical use of WES for these disorders is at an early stage. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with a suspected genetic disorder who receive WGS, the evidence includes case series. Relevant outcomes are test accuracy and validity, functional outcomes, changes in reproductive decision making, and resource utilization. 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. 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. The evidence is insufficient to determine the effects of the technology on health outcomes

PRACTICE GUIDELINES AND POSITION STATEMENTS
American College of Medical Genetics and Genomics
The American College of Medical Genetics and Genomics (ACMG) has recommended that diagnostic testing with whole exome sequencing (WES) and whole genome sequencing (WGS) should be considered in the clinical diagnostic assessment of a phenotypically affected individual when31

  • "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. "

ACMG has recommended that for screening purposes:

WGS/WES may be considered in preconception carrier screening, using a strategy to focus on genetic variants known to be associated with significant phenotypes in homozygous or hemizygous progeny.

ACMG has also recommended that WGS and WES should not be used at this time as an approach to prenatal screening or as a first-tier approach for newborn screening.

In 2013, ACMG finalized its recommendations for reporting incidental findings in WGS and WES.32 ACMG determined that reporting some incidental findings would likely have medical benefit for the patients and families of patients undergoing clinical sequencing, recommending 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.

American Academy of Neurology et al.
In 2014, the American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine issued evidence-based guidelines on the diagnosis and treatment of limb-girdle and distal dystrophies, which made the following recommendations (see Table 5).33

Table 5. Guidelines on Limb-Girdle Muscular Dystrophy

Recommendation

LOE

Diagnosis

  • For patients with suspected muscular dystrophy, clinicians should use a clinical approach to guide genetic diagnosis based on the clinical phenotype, including the pattern of muscle involvement, inheritance pattern, age at onset, and associated manifestations (e.g., early contractures, cardiac or respiratory involvement).

B

 

  • In patients with suspected muscular dystrophy in whom initial clinically directed genetic testing does not provide a diagnosis, clinicians may obtain genetic consultation or perform parallel sequencing of targeted exomes, whole-exome sequencing, whole-genome screening, or next-generation sequencing to identify the genetic abnormality.

C

 

Management of cardiac complications

  • Clinicians should refer newly diagnosed patients with (1) limb-girdle muscular dystrophy (LGMD)1A, LGMD1B, LGMD1D, LGMD1E, LGMD2C–K, LGMD2M–P, …or (2) muscular dystrophy without a specific genetic diagnosis for cardiology evaluation, including electrocardiogram (ECG) and structural evaluation (echocardiography or cardiac magnetic resonance imaging [MRI]), even if they are asymptomatic from a cardiac standpoint, to guide appropriate management.

B

 

  • If ECG or structural cardiac evaluation (e.g., echocardiography) has abnormal results, or if the patient has episodes of syncope, near-syncope, or palpitations, clinicians should order rhythm evaluation (e.g., Holter monitor or event monitor) to guide appropriate management.

B

 

  • Clinicians should refer muscular dystrophy patients with palpitations, symptomatic or asymptomatic tachycardia or arrhythmias, or signs and symptoms of cardiac failure for cardiology evaluation

B

 

  • It is not obligatory for clinicians to refer patients with LGMD2A, LGMD2B, and LGMD2L for cardiac evaluation unless they develop overt cardiac signs or symptoms.

B

 

Management of pulmonary complications

  • Clinicians should order pulmonary function testing (spirometry and maximal inspiratory/expiratory force in the upright and, if normal, supine positions) or refer for pulmonary evaluation (to identify and treat respiratory insufficiency) in muscular dystrophy patients at the time of diagnosis, or if they develop pulmonary symptoms later in their course.

B

 

  • In patients with a known high risk of respiratory failure (e.g., those with LGMD2I …), clinicians should obtain periodic pulmonary function testing (spirometry and maximal inspiratory/expiratory force in the upright position and, if normal, in the supine position) or evaluation by a pulmonologist to identify and treat respiratory insufficiency 

  • It is not obligatory for clinicians to refer patients with LGMD2B and LGMD2L for pulmonary evaluation unless they are symptomatic.

C

  • Clinicians should refer muscular dystrophy patients with excessive daytime somnolence, nonrestorative sleep (e.g., frequent nocturnal arousals, morning headaches, excessive daytime fatigue), or respiratory insufficiency based on pulmonary function tests for pulmonary or sleep medicine consultation for consideration of noninvasive ventilation to improve quality of life.

LOE: level of evidence; LGMD: limb-girdle muscular dystrophy ECG: electrocardiogram.

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable. 

ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed in Table 6.

Table 6. Summary of Key Trials

NCT No. Trial Name Planned Enrollment Completion Date
Ongoing
NCT02380729

Mutation Exploration in Non-acquired, Genetic Disorders and Its Impact on Health Economy and Life Quality

200 Dec 2017
NCT02826694 North Carolina Newborn Exome Sequencing for Universal Screening 400 Augl 2016
NCT02699190 LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies 50 Apr 2020

NCT:  national clinical trial. 

References  

  1. Dixon-Salazar TJ, Silhavy JL, Udpa N, et al. Exome sequencing can improve diagnosis and alter patient management Sci Transl Med. Jun 13 2012;4(138):138ra178. PMID 22700954
  2. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. May 2015;17(5):405-424. PMID 25741868
  3. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Special Report: Exome Sequencing for Clinical Diagnosis of Patients with Suspected Genetic Disorders. TEC Assessments. 2013;Volume 28:Tab 3. PMID
  4. Rehm HL, Bale SJ, Bayrak-Toydemir P, et al. ACMG clinical laboratory standards for next-generation sequencing. Genet Med. Sep 2013;15(9):733-747. PMID 23887774
  5. de Ligt J, Boone PM, Pfundt R, et al. Detection of clinically relevant copy number variants with whole-exome sequencing. Hum Mutat. Oct 2013;34(10):1439-1448. PMID 23893877
  6. Mu W, Lu HM, Chen J, et al. Sanger Confirmation Is Required to Achieve Optimal Sensitivity and Specificity in Next-Generation Sequencing Panel Testing. J Mol Diagn. Nov 2016;18(6):923-932. PMID 27720647
  7. Hamilton A, Tetreault M, Dyment DA, et al. Concordance between whole-exome sequencing and clinical Sanger sequencing: implications for patient care. Mol Genet Genomic Med. Sep 2016;4(5):504-512. PMID 27652278
  8. Vissers L, van Nimwegen KJM, Schieving JH, et al. A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med. Sep 2017;19(9):1055-1063. PMID 28333917
  9. Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med. Oct 17 2013;369(16):1502-1511. PMID 24088041
  10. Yang Y, Muzny DM, Xia F, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. Nov 12 2014;312(18):1870-1879. PMID 25326635  
  11. Lee H, Deignan JL, Dorrani N, et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA. Nov 12 2014;312(18):1880-1887. PMID 25326637
  12. Iglesias A, Anyane-Yeboa K, Wynn J, et al. The usefulness of whole-exome sequencing in routine clinical practice. Genet Med. Dec 2014;16(12):922-931. PMID 24901346
  13. Soden SE, Saunders CJ, Willig LK, et al. Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med. Dec 3 2014;6(265):265ra168. PMID 25473036
  14. Srivastava S, Cohen JS, Vernon H, et al. Clinical whole exome sequencing in child neurology practice. Ann Neurol. Oct 2014;76(4):473-483. PMID 25131622
  15. Farwell KD, Shahmirzadi L, El-Khechen D, et al. Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med. Jul 2015;17(7):578-586. PMID 25356970
  16. Nolan D, Carlson M. Whole exome sequencing in pediatric neurology patients: clinical implications and estimated cost analysis. J Child Neurol. Jun 2016;31(7):887-894. PMID 26863999
  17. Allen NM, Conroy J, Shahwan A, et al. Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion. Epilepsia. Jan 2016;57(1):e12-17. PMID 26648591
  18. Stark Z, Tan TY, Chong B, et al. A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders. Genet Med. Nov 2016;18(11):1090-1096. PMID 26938784
  19. Neveling K, Feenstra I, Gilissen C, et al. A post-hoc comparison of the utility of sanger sequencing and exome sequencing for the diagnosis of heterogeneous diseases. Hum Mutat. Dec 2013;34(12):1721-1726. PMID 24123792
  20. Ghaoui R, Cooper ST, Lek M, et al. Use of whole-exome sequencing for diagnosis of limb-girdle muscular dystrophy: outcomes and lessons learned. JAMA Neurol. Dec 2015;72(12):1424-1432. PMID 26436962
  21. Valencia CA, Husami A, Holle J, et al. Clinical impact and cost-effectiveness of whole exome sequencing as a diagnostic tool: a pediatric center's experience.Front Pediatr. Aug 2015;3:67. PMID 26284228
  22. Wortmann SB, Koolen DA, Smeitink JA, et al. Whole exome sequencing of suspected mitochondrial patients in clinical practice. J Inherit Metab Dis. May 2015;38(3):437-443. PMID 25735936
  23. Posey JE, Rosenfeld JA, James RA, et al. Molecular diagnostic experience of whole-exome sequencing in adult patients. Genet Med. Jul 2016;18(7):678-685. PMID 26633545
  24. Walsh M, Bell KM, Chong B, et al. Diagnostic and cost utility of whole exome sequencing in peripheral neuropathy. Ann Clin Transl Neurol. May 2017;4(5):318-325. PMID 28491899
  25. Miller KA, Twigg SR, McGowan SJ, et al. Diagnostic value of exome and whole genome sequencing in craniosynostosis. J Med Genet. Apr 2017;54(4):260-268. PMID 27884935
  26. Dewey FE, Grove ME, Pan C, et al. Clinical interpretation and implications of whole-genome sequencing. JAMA. Mar 12 2014;311(10):1035-1045. PMID 24618965
  27. Lionel AC, Costain G, Monfared N, et al. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Genet Med. Aug 03 2017. PMID 28771251
  28. Taylor JC, Martin HC, Lise S, et al. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet. Jul 2015;47(7):717-726. PMID 25985138
  29. Ellingford JM, Barton S, Bhaskar S, et al. Whole genome sequencing increases molecular diagnostic yield compared with current diagnostic testing for inherited retinal disease. Ophthalmology. May 2016;123(5):1143-1150. PMID 26872967
  30. Carss KJ, Arno G, Erwood M, et al. Comprehensive rare variant analysis via whole-genome sequencing to determine the molecular pathology of inherited retinal disease. Am J Hum Genet. Jan 05 2017;100(1):75-90. PMID 28041643
  31. American College of Medical Genetics and Genomics (ACMG). Policy statement: Points to consider in the clinical application of genomic sequencing. 2012; http://www.acmg.net/ACMG/Publications/Policy_Statements/ACMG/Publications/Policy_Statements.aspx?hkey=6b7572b3-d01c-42a5-b59e-c0593347751c. Accessed October 11, 2017.
  32. Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. Jul 2013;15(7):565-574. PMID 23788249
  33. Narayanaswami P, Weiss M, Selcen D, et al. Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies: report of the guideline development subcommittee of the American Academy of Neurology and the practice issues review panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. Oct 14 2014;83(16):1453-1463. PMID 25313375

Coding Section

Codes Number Description
CPT   See Policy Guidelines.
  81412 (effective 1/1/2016) Ashkenzai Jewish associated idsorders (e.g., 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 
  81432 (effective 1/1/2016) Hereditary breast cancer-related disorders (e.g., hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); genomic dequence analysis panel, must include sequencing of at least 14 genes, including ATM, BRCA1, BRCA2, BRIP1, CDH1, MLH1, MSH2, MSH6, NBN, PALB2, PTEN, RAD51C, STK11 and TP53 
  81433 (effective 1/1/2016)  Hereditary breast cancer-related disorders (e.g., hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); duplication/deletion analysis panel, must include analyses for BRCA1, BRCA2, MLH1, MSH2 and STK11 
  81434 (effective 1/1/2016)  Hereditary retinal disorders (e.g., retinitis pigmentosa, Leber congenital amaurosis, cone-rod dystrophy), genomic dequence analysis panel, must include sequencing of at least 15 genes, including ABCA4, CNGA1, CRB1, EYS, PDE6A, PDE6B, PRPF31, PRPH2, RDH12, RHO, RP1, RP2, RPE65, RPGR and USH2A 
  81437 (effective 1/1/2016)   Hereditary neuroendocrine tumor disorders (e.g., medullary thyroid carcinoma, parathyroid carcinoma, malignant pheochromocytoma or paraganglioma); genomic sequence analysis panel, must include dequencing of at least 6 genes, including MAX, SDHB, SDHC, SDHD, TMEM127 and VHL
  81438 (effective 1/1/2016) Hereditary neuroendocrine tumor disorders (e.g., medullary thyroid carcinoma, parathyroid carcinoma, malignant pheochromocytoma or paraganglioma); duplication/deletion analysis panel, must include analyses for SDHB, SDHC, SDHD and VHL 
  81442 (effective 1/1/2016) Noonan spectrum disorders (e.g., Noonan syndrome, cardio-facio-cutaneous syndrome, Costello syndrome, LEOPARD syndrome, Noonan-like syndrome), genomic sequence analysis panel, must include sequencing of at least 12 genes, including BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, RIT1, SHOC2 and SOS1 
ICD-9-CM Diagnosis    Investigational for all indications
ICD-10-CM (effective 10/01/15)   Investigational for all indications
ICD-10-PCS (effective 10/01/15)   Not applicable. ICD-10-PCS codes are only used for inpatients services. There are no ICD procedure codes for laboratory tests.
Type of Service    
Place of Service    

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2013 Forward     

07/18/2018 Annual review, no change to policy intent. 
11/01/2017  Interim review, updating policy verbiage with medical necessity criteria for services previously considered investigational for all indications. Also updating background, description, regulatory status, rationale and references. 
07/19/2017  Annual review, no change to policy intent. 
04/25/2017  Updated category to Laboratory. No other changes. 
10/11/2016  Annual review, no change to policy intent. 
12/1/2016  Update CPT codes with 2016 codes. No change in policy intent. 
10/27/2015  Annual review, no change to policy intent. Updating background, description, rationale and references. 
10/20/2014  Annual review, extensive revision, as policy now addresses whole genome sequencing, as well as whole exome sequencing. Added coding & policy guidelines. Updated entire policy. 
03/6/2014 Corrected Last Reviewed Date
10/16/2013 NEW POLICY  

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