Coverage Policy Manual
Policy #: 2013035
Category: Medicine
Initiated: September 2013
Last Review: March 2018
  Genetic Test: Whole Exome and Whole Genome Sequencing

Description:
CLINICAL CONTEXT AND TEST PURPOSE
Whole exome sequencing (WES) is targeted 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 (NGS) 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. (Dixon-Salazar, 2012). The search for a diagnosis may thus become a time-consuming and expensive process. WES or WGS using NGS 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: 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 to WES, but requires greater data analytics. Technical aspects of WES and WGS are evolving, including 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 (Richards, 2015). Guidelines developed by this workgroup, published in 2015, describe criteria for classifying pathogenic and benign sequence variants based on types of data into 5 categories: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign.
 
AVAILABLE 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), 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.
 
The following labs offer WES sequencing Ambry Genetics (Aliso Viejo, CA), GeneDx (Gaithersburg, MD), Baylor College of Medicine (Houston, TX), Illumina (San Diego, CA), University of California Los Angeles Health System, EdgeBio (Gaithersburg, MD), Children’s Mercy Hospitals and Clinics (Kansas City, MO) and Emory Genetics Laboratory (Atlanta, GA).

Policy/
Coverage:
EFFECTIVE APRIL 2017
Whole exome and whole genome sequencing for all indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, whole exome and whole genome sequencing is considered investigational for all indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
EFFECTIVE PRIOR TO APRIL 2017
Whole exome sequencing for all indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, Whole exome sequencing is considered investigational for all indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
Analytic validity
Whole exome sequencing has not yet been well-standardized for the clinical laboratory and has not been fully characterized in publicly available documents with regard to the analytic validity for the various types of relevant mutations. The few existing professional guidelines give only high-level direction. Technical limitations include error rates due to uneven sequencing coverage and gaps in exon capture prior to sequencing, and the variability contributed by the different platforms and procedures used by different clinical laboratories offering exome sequencing as a clinical service is unknown.
 
Clinical utility
The clinical utility of exome sequencing lies in the influence of the results on medical decision-making and patient outcomes. There are several ways in which clinical utility can be demonstrated.
 
    • WES may detect additional mutations that are missed by other testing methods, thus leading to a definitive diagnosis.
        • If the establishment of a definitive diagnosis leads to management changes that improve outcomes, then clinical utility has been established.
        • If the establishment of a definitive diagnosis leads to avoidance of other tests that are unnecessary, then this is another example of clinical utility.
 
    • If WES is at least as accurate as other methods of sequencing, then an improvement in the efficiency of workup (diagnosis obtained more quickly and/or at less cost), then clinical utility has been established.
 
 WES in characterizing Mendelian disorders
Typically, when a phenotype/history suggests a genetic etiology, microdeletions/duplications should be excluded by chromosomal microarray analysis and, if clinically appropriate, other possible disorders like inborn errors of metabolism should also be excluded. If these tests are negative, the potential uses of WES include facilitating the accurate diagnosis of individuals with a suspected monogenic (Mendelian) disorder that presents with an atypical presentation or multiple congenital anomalies, is difficult to confirm with clinical or laboratory criteria alone (e.g. when disease characteristics are shared among multiple disorders, leading to potentially overlapping differential diagnoses [clinical heterogeneity]), and when there is a long list of possible candidate genes (Bamshad, 2011).
 
An additional potential use of WES is when a clinical presentation is suggestive of a specific genetic condition, but targeted testing is negative or unavailable. In this situation, the yield of a definitive diagnosis can be used to evaluate the clinical utility of WES, also considering whether management changes occur that improve outcomes.
 
Currently there are no published studies that systematically examine potential outcomes of interest such as changes in medical management (including revision of initial diagnoses), and changes in reproductive decision-making after a diagnosis of a Mendelian disorder by WES. A small number of studies of patient series, and a larger number of very small series or family studies report anecdotal examples of medical management and reproductive decision-making outcomes of exome sequencing in patients who were not diagnosed by traditional methods. These studies show that over and above traditional molecular and conventional diagnostic testing, exome sequencing can lead to a diagnosis that influences patient care and/or reproductive decisions, but give no indication of the proportion of patients for which this is true. The publication of a large number of small diagnostic studies with positive results but few with negative results, raise the possibility of publication bias—the impact of which is unknown.
 
Summary
Whole exome sequencing (WES) using next-generation sequencing has been recently introduced as a laboratory-developed diagnostic clinical laboratory test. A potential major indication for use is molecular diagnosis of patients with a phenotype that is suspicious for a genetic disorder or for patients with known genetic disorders that have a large degree of genetic heterogeneity involving substantial gene complexity. Such patients 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 patients, WES, after initial conventional testing has failed to make the diagnosis, may return a likely pathogenic variant.
 
However, at this time, there are many technical limitations to WES that prohibit its use in routine clinical care. The limited experience with WES on a population level leads to gaps in understanding and interpreting ancillary information and variants of uncertain significance. As a result, the risk/benefit ratio of WES testing is poorly defined.
 
Practice Guidelines and Position Statements
The American College of Medical Genetics (ACMG) states that diagnostic testing with WES (and whole genome sequencing [WGS]) should be considered In the clinical diagnostic assessment of a phenotypically affected individual when:
 
a. 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.
 
b. 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.
 
c. A patient presents with a likely genetic disorder but specific genetic tests available for that phenotype have failed to arrive at a diagnosis.
 
d. 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.
 
The ACMG states 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 states that WGS/WES should not be used at this time as an approach to prenatal screening, or as a first-tier approach for newborn screening.
 
 
In March 2013, an ACMG board finalized approval of their recommendations for reporting incidental findings in whole genome and whole exome sequencing (Green, 2013). 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. A full list of the specified conditions can be found at:
 
https://www.acmg.net/docs/ACMG_Releases_Highly- Anticipated_Recommendations_on_Incidental_Findings_in_Clinical_Exome_and_Genome_Sequencing.p df
 
2016 Update
A literature search conducted through February 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Analytic Validity
Whole Exome Sequencing
There is relatively little data specific to the analytic validity of whole exome sequencing (WES). The next-generation sequencing (NGS) techniques used for WES are generally expected to have high accuracy for mutation detection, NGS platforms differ in terms of the depth of sequence coverage, methods for base calling and read alignment, and other factors. These factors contribute to potential variability across the different platforms and procedures used by different clinical laboratories offering exome sequencing as a clinical service The American College of Medical Genetics has clinical laboratory standards for NGS, including WES (Rehm, 2013). 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 (CNVs), and structural chromosome rearrangements due to the short sequence read lengths (Rehm, 2013).
 
Whole Genome Sequencing
Whole genome sequencing (WGS) is subject to the same considerations related to potential variability in technical performance as WES.
 
With advances in sequencing capacity, novel sequence variants associated with genetic disorders are rapidly being described. Sequence variants detected on WES/WGS, or any form of NGS, must be classified on a spectrum from almost certainly pathogenic to almost certainly benign. In 2013, the ACMG, Association for Molecular Pathology, and College of American Pathologists convened a workgroup to develop standard terminology for describing sequence variants (Richards, 2015). Guidelines developed by this workgroup, published in 2015, describe criteria for classifying pathogenic and benign sequence variants based on a variety of population, computational and predictive, functional and data, segregation data into 5 categories: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign.
 
WES/WGS for Identifying Novel Mutations
Since publication of the 2013 TEC Special Report, studies continue to demonstrate that WES can be used to identify novel genetic mutations in a range of clinical conditions. In particular, WES/WGS has been evaluated for disorders associated with significant genetic heterogeneity (Greenway, 2014; Jiang, 2013; Kim, 2013; Zhou, 2014).
 
WES/WGS in Clinical Practice
Several studies have reported on the use of WES and, less frequently, WGS in clinical practice. Typically the populations included in these studies are those with suspected rare genetic disorders, although the specific patient populations varu.
 
In 2015, Lee and colleagues reported on a large (n=814) single-center cohort of patients with   undiagnosed, suspected genetic conditions who underwent WES (Lee, 2015). The investigators used a “trio-CES [clinical exome sequencing]” technique which involves sequencing of the proband and 2 family members, typically unaffected parents. For the first approximately 300 cases, all reported variants were confirmed by Sanger sequencing with more than 99% confirmation. After that, variants were evaluated with a QUAL score, a scaled probability of a variant existing at a given site, and only clinically significant mutations with a QUAL score lower than 500 were confirmed. Variants found were annotated to provide information about their effect on protein function, allele frequency in the general population, and prior evidence of disease causality and filtered to select likely pathogenic DNA variants. For variants in probands, with family member testing available, variants were categorized as de novo (usually heterozygous in the patient and potentially causing an autosomal dominant condition), homozygous, compound heterozygous, and inherited variants. Variants were evaluated in the context of a “primary gene list” which was determined based on phenotypic key words included in referring clinician notes. Of the 814 patients included, 520 patients (64%) were children, and 254 of those were younger than 5 years at testing. The most common clinical indication for testing was developmental delay in the entire population and in the childhood group (37% and 53%, respectively). In the adult group, ataxia was the most common indication for testing (26%). Overall, a molecular diagnosis with a causative variant in a well-established clinical gene was provided for 213/814 cases (26%; 95% CI 23 to 29%). Of the 264 variants reported in 213 cases, 188 were reported as “likely pathogenic” and 73 were reported as “pathogenic” variants..
 
In 2014, Yang and colleagues reported on a single-center observational study that included 2000 consecutive patients referred for clinical WES for a suspected genetic disorder (Yang, 2014). This report excluded 250 patients reported in an earlier publication. The majority of the samples were from pediatric patients, with 900 from children under 5 years (45.0%), 845 from children/adolescents aged 5 to 18 years (42.2%), 244 from adults (12.2%), and 11 fetal samples. The most common indications for testing were neurological disorders or developmental delay (87.8%). Molecular diagnoses were reported for 504 patients (25.2%, 95% CI 23.3% to 27.2%), with a total of 708 presumptive causative variants. Most of the identified disease-associated variants were novel (409/708; 57.8%). Overall, 95 medically-actionable incidental findings were reported in 92 patients (4.6%), most of which (n=59) were included in the American College of Medical Genetics list of 56 genes recommended to be disclosed to patients.
 
Tammimies and colleagues reported on the results of chromosomal microarray analysis (CMA) and WES in a sample of children with autism spectrum disorders (Tammimies, 2015). The patient cohort included 258 consecutively enrolled patients, stratified into three groups based on the presence of major congenital abnormalities and minor physical anomalies (n=168, 37, and 53 considered essential, equivocal, and complex, respectively). All probands underwent CMA testing. WES was performed for 95 proband-parent trios. Among the 95 patients undergoing WES, 8 children (9 mutations) were received an ASD-related molecular diagnosis (8.4%, 95% CI 3.7% to 15.9%). Incidental or medically-actionable findings were reported in 8/95 (8.4%) probands tested with WES, 6 of which were considered medically-actionable.
 
Other studies have reported the yield of WES/WGS testing in clinical populations, varying depending on the population. Taylor and colleagues report a yield of 21% for disease-causing variants with WES in a population of 217 patients with suspected genetic disorders with no pathogenic variants on prior screening (Taylor, 2015).  Among 11 subjects with cardiomyopathy, Golbus and colleagues reported a yield of 82% for pathogenic variants using WGS (Golbus, 2014).
 
Clinical Utility: Change in Patient Management with WES/WGS
Several studies have reported on potential benefits, in terms of medical management changes or avoidance of alternative testing, following WES/WGS. Soden and ciolleagues reported on the use of WGS and/or WES in parent-child trios for 119 children with neurodevelopmental disorders (Soden, 2014).  A definitive molecular diagnosis of an established genetic disorder was identified in 45 of the 100 families with children affected by neurodevelopmental disorders (53 of 119 affected children). Chart reviews and interviews with referring physicians were used to assess changes in short-term management following WES/WGS, and changed patient management and/or clinical impression was reported in 22/45 families (49%). In a retrospective study of 78 children with neurodevelopmental disorders with a prior unrevealing workup who underwent WES, Srivastava and colleagues reported a presumptive diagnostic testing rate of 41% (Srivastava, 2014). Results of WES changed patient management in all cases, most often related to reproductive planning (n=27), along with additional disease monitoring in 4 cases, further workup for systemic involvement in 6 cases, and 7 medication changes.
 
Iglesias et al reported on clinical changes that occurred after WES/WGS in a broader population of 115 patients with a genetically undefined disorder (Iglesias, 2014). The most common indications for WES evaluation were birth defects, developmental delay, and seizures, in 24.3%, 25.2%, and 14% of patients, respectively. A definitive diagnosis was made in 37 cases (32.2%). The clinical implications of testing are described qualitatively for patients with a genetic diagnosis. In 6 cases, it was noted that genetic information was used for reproductive planning; in 11 cases, patients were noted to have a change in medical management or surveillance or testing for related conditions.
 
With wider genome coverage in sequencing comes an increased likelihood that testing will identify potentially clinically-significant gene mutations that may be unrelated to the phenotype being evaluated. The ACMG issued recommendations in 2013 outlining 56 genes associated with 24 conditions that should be reported to patients when known or likely pathogenic variants are detected (Green. 2013). The risks and benefits of WES/WGS in terms of detection of clinically actionable incidental findings should be evaluated on an individual basis.
 
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed below:
 
Ongoing
(NCT01969370) NCGENES: North Carolina Clinical Genomic Evaluation by NextGen Exome Sequencing; planned enrollment 750; completion date December 2015.
 
(NCT02175264) Genetic Basis of Non Syndromic Congenital Diaphragmatic Hernia; planned enrollment 78; completion date July 2016
 
(NCT02067962) Identification of Genes Involved in Juvenile Idiopathic Arthritis by Whole Exome Sequencing; planned enrollment 30; completion date December 2017.
 
(NCT02077894) Whole Exome and Whole Genome Sequencing for Genotyping of Inherited and Congenital Eye Cond; planned enrollment 150; completion date September 2018.
 
(NCT01087320) Whole Genome Medical Sequencing for Gene Discovery; planned enrollment 400; completion No Date
 
(NCT00340626) Genetic Analysis of Hereditary Non-Syndromic Oral Clefts; planned enrollment 1000; completion No date
 
(NCT01952275) Assessment of the Enrichment of Rare Coding Genetic Variants in Patients Affected by Neutrophil-Mediated Inflammatory Dermatoses; planned enrollment 660; completion date January 2020.
 
(NCT01858285) Genetics of Epilepsy and Related Disorders; planned enrollment 500; completion date December 2020.
 
(NCT02014961) Worm Study: Identification of Modifier Genes in a Unique Founder Population With Sudden Cardiac Death; planned enrollment 223; completion date April 2025.
 
2017 Update
 
A literature search conducted using the MEDLINE database through March 2017 did not reveal any new information that would prompt a change in the coverage statement.
 
The following clinical trials are ongoing:
 
    • NCT02340871 Finding Genes With NGS Techniques in Whom Mutations Cause Neurological Diseases
    • NCT 02418377 Whole-exome Sequencing to Identify Genetic Variants Associated With Severe Childhood Obesity, and Tracking the Changing Prevalence of Obesity Related Complications
    • NCT02826694 North Carolina Newborn Exome Sequencing for Universal Screening
    • NCT02077894 Whole Exome and Whole Genome Sequencing for Genotyping of Inherited and Congenital Eye Cond
    • NCT01087320 Whole Genome Medical Sequencing for Gene Discovery
    • NCT01952275  Assessment of the Enrichment of Rare Coding Genetic Variants in Patients Affected by Neutrophil-Mediated Inflammatory Dermatoses
    • NCT 02769975 Evaluation of Children With Endocrine and Metabolic-Related Conditions
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
WHOLE EXOME SEQUENCING IN PATIENTS WITH MULTIPLE CONGENITAL ANOMALIES OR A NEURODEVELOPMENTAL DISORDER
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 (Rehm, 2013).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 (Rehm, 2013). WES may be less sensitive for the detection of copy number variants than high-resolution microarray testing (de Ligt, 2013). NGS also has poorer coverage for A/T-rich, G/C-rich, and pseudogene regions, as well as homopolymer stretches (Mu, 2016; Hamilton, 2016).
 
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 (Vissers, 2017).
 
WHOLE GENOME SEQUENCING IN PATIENTS WITH A SUSPECTED GENETIC DISORDER
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 (Carss, 2017). 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.
  
 

CPT/HCPCS:
0010UInfectious disease (bacterial), strain typing by whole genome sequencing, phylogenetic-based report of strain relatedness, per submitted isolate
0012UGermline disorders, gene rearrangement detection by whole genome next-generation sequencing, DNA, whole blood, report of specific gene rearrangement(s)
0013UOncology (solid organ neoplasia), gene rearrangement detection by whole genome next-generation sequencing, DNA, fresh or frozen tissue or cells, report of specific gene rearrangement(s)
0014UHematology (hematolymphoid neoplasia), gene rearrangement detection by whole genome next-generation sequencing, DNA, whole blood or bone marrow, report of specific gene rearrangement(s)
0036UExome (ie, somatic mutations), paired formalin-fixed paraffin-embedded tumor tissue and normal specimen, sequence analyses
0056UHematology (acute myelogenous leukemia), DNA, whole genome next-generation sequencing to detect gene rearrangement(s), blood or bone marrow, report of specific gene rearrangement(s)
81415Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis
81416Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator exome (eg, parents, siblings) (List separately in addition to code for primary procedure)
81417Exome (eg, unexplained constitutional or heritable disorder or syndrome); re-evaluation of previously obtained exome sequence (eg, updated knowledge or unrelated condition/syndrome)
81425Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis
81426Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator genome (eg, parents, siblings) (List separately in addition to code for primary procedure)
81427Genome (eg, unexplained constitutional or heritable disorder or syndrome); re-evaluation of previously obtained genome sequence (eg, updated knowledge or unrelated condition/syndrome)

References: Bamshad MJ, Ng SB, Bigham AW et al.(2011) Exome sequencing as a tool for Mendelian disease gene discovery. Nature reviews. Genetics 2011; 12(11):745-55.

Biesecker LG.(2012) Opportunities and challenges for the integration of massively parallel genomic sequencing into clinical practice: lessons from the ClinSeq project. Genetics in medicine : official journal of the American College of Medical Genetics 2012; 14(4):393-8.

Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Special Report: Exome Sequencing for Clinical Diagnosis of Patients with Suspected Genetic Disorders. Volume 28 T.

Dixon-Salazar TJ, Silhavy JL, Udpa N et al.(2012) Exome sequencing can improve diagnosis and alter patient management. Science translational medicine 2012; 4(138):138ra78.

Golbus JR, Puckelwartz MJ, Dellefave-Castillo L, et al.(2014) Targeted analysis of whole genome sequence data to diagnose genetic cardiomyopathy. Circ Cardiovasc Genet. Dec 2014;7(6):751-759. PMID 25179549

Green RC, Berg JS, Grody WW et al.(2013) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in medicine : official journal of the American College of Medical Genetics 2013; 15(7):565-74.

Green RC, Berg JS, Grody WW, et al.(2013) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. Jul 2013;15(7):565-574. PMID 23788249

Greenway SC, McLeod R, Hume S, et al.(2014) Exome sequencing identifies a novel variant in ACTC1 associated with familial atrial septal defect. Can J Cardiol. Feb 2014;30(2):181-187. PMID 24461919

Iglesias A, Anyane-Yeboa K, Wynn J, et al.(2014) The usefulness of whole-exome sequencing in routine clinical practice. Genet Med. Dec 2014;16(12):922-931. PMID 24901346

Jiang YH, Yuen RK, Jin X, et al.(2013) Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am J Hum Genet. Aug 8 2013;93(2):249-263. PMID 23849776

Kim HJ, Won HH, Park KJ, et al.(2013) SNP linkage analysis and whole exome sequencing identify a novel POU4F3 mutation in autosomal dominant late-onset nonsyndromic hearing loss (DFNA15). PLoS One. 2013;8(11):e79063. PMID 24260153

Lee H, Deignan JL, Dorrani N, et al.(2014) Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA. Nov 12 2014;312(18):1880-1887. PMID 25326637

McLaughlin HM, Ceyhan-Birsoy O, Christensen KD, et al.(2014) A systematic approach to the reporting of medically relevant findings from whole genome sequencing. BMC Med Genet. 2014;15:134. PMID 25714468

Rehm HL, Bale SJ, Bayrak-Toydemir P, et al.(2013) ACMG clinical laboratory standards for next-generation sequencing. Genet Med. Sep 2013;15(9):733-747. PMID 23887774

Richards S, Aziz N, Bale S, et al.(2015) 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

Soden SE, Saunders CJ, Willig LK, et al.(2014) Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of euro developmental disorders. Sci Transl Med. Dec 3 2014;6(265):265ra168. PMID 25473036

Srivastava S, Cohen JS, Vernon H, et al.(2014) Clinical whole exome sequencing in child neurology practice. Ann Neurol. Oct 2014;76(4):473-483. PMID 25131622

Tammimies K, Marshall CR, Walker S, et al.(2015) Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder JAMA. Sep 1 2015;314(9):895-903. PMID 26325558

Taylor JC, Martin HC, Lise S, et al.(2015) Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet. Jul 2015;47(7):717-726. PMID 25985138

Weeke P, Mosley JD, Hanna D, et al.(2014) Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome. J Am Coll Cardiol. Apr 15 2014;63(14):1430-1437. PMID 24561134

Yang Y, Muzny DM, Xia F, et al.(2014) Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. Nov 12 2014;312(18):1870-1879. PMID 25326635

Zhou Q, Yang D, Ombrello AK, et al.(2014) Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. Mar 6 2014;370(10):911-920. PMID 24552284


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2019 American Medical Association.