ModifiedUnitedHealthcarePolicy CS150NE.F

Whole Exome and Whole Genome Sequencing (Non-Oncology Conditions) (for Nebraska Only)

Policy governing outpatient and post-discharge coverage of whole exome sequencing (WES) and whole genome sequencing (WGS) for non-oncology indications in Nebraska, including criteria for comparator analysis, reanalysis, and prenatal WES; applies to ordering clinicians and documentation requirements.

Policy Summary

PayerUnitedHealthcare

PolicyWhole Exome and Whole Genome Sequencing (Non-Oncology Conditions) (for Nebraska Only)

Policy CodePolicy CS150NE.F

Change TypeCoverage criteria revised; codes updated

Effective DateApril 1, 2026

Next Review DateN/A

Key ActionOrder WES/WGS only when clinical criteria are met and ensure medical record documentation supports medical necessity; genetic counseling is strongly recommended prior to testing.

SourceLink

POLICY UPDATE CHANGES

Genetic counseling is strongly recommended prior to Whole Exome Sequencing or Whole Genome Sequencing.

Epigenetic signature analysis is considered unproven and not medically necessary for any indication.

Replaced wording to refer to optical genome mapping (OGM) as unproven and not medically necessary.

Clarified and revised multiple coverage criteria for WES/WGS (including removal of prior requirement that CMA or WES be previously performed before WGS).

Reanalysis of WES/WGS data is proven and medically necessary when listed criteria are met, including timing changes.

Applicable CPT/proprietary codes were added or updated in the policy's applicable codes list.

2026-04-01Effective date

NebraskaGeographic applicability

>=18 moReanalysis interval

SpecialistsOrdering clinicians

UnprovenEpisignature/OGM stance

RecommendedPre-test counseling

Coverage Criteria for WES/WGS (Non-Oncology)

WES/WGS initial testing

Covered when ALL of the following are met

General requirements: Affected individual displays signs or symptoms of an undiagnosed or unexplained disorder with a suspected genetic cause; test results are intended to directly impact medical management; clinical presentation does not fit a Well-Delineated Genetic Syndrome or a specific test/Targeted Panel is not available (if a specific syndrome is suspected, perform single-gene or Targeted Panel testing first); test ordered by a medical geneticist, neonatologist, neurologist, immunologist, or developmental pediatrician.

Clinical presentation group A: One or more of: multiple congenital anomalies affecting at least two different organ systems; intellectual disability (moderate, severe, or profound) diagnosed by 18 years of age; global developmental delay; epileptic encephalopathy with onset before three years of age.

Clinical presentation group B: Two or more of the following: congenital anomaly; significant hearing or visual impairment diagnosed by 18 years of age; laboratory abnormalities suggestive of an inborn error of metabolism; autism spectrum disorder; neuropsychiatric condition (e.g., bipolar disorder, schizophrenia, obsessive-compulsive disorder); hypotonia or hypertonia in infancy; dystonia, ataxia, hemiplegia, neuromuscular or movement disorder; unexplained developmental regression unrelated to ASD or epilepsy; growth abnormality (e.g., failure to thrive, short stature, microcephaly, macrocephaly, or overgrowth); persistent and severe immunologic or hematologic disorder; dysmorphic features; consanguinity; other first- or second-degree family member(s) with similar clinical diagnosis.

Non-concurrent Comparator Analysis

Non-concurrent Comparator Analysis is covered when BOTH are met

Comparator requirements: Affected individual meets the policy criteria for WES or WGS AND WES or WGS has been previously performed on the affected individual.

Reanalysis of WES/WGS

Reanalysis is covered when ALL of the following are met

Reanalysis timing and conditions: At least 18 months have passed since the initial WES or WGS was performed; the affected individual continues to meet criteria for WES/WGS; AND either (a) the individual experiences additional unexplained symptoms since initial testing, or (b) new data or family history emerges suggesting a link between symptoms and specific genes.>= 18 months

Prenatal WES

Prenatal WES is covered when ALL of the following are met

Prenatal WES prerequisites: Chromosome microarray analysis and/or karyotyping has been performed but was uninformative; WES is ordered by or in consultation with a medical geneticist or maternal-fetal medicine specialist (perinatologist); specimen obtained from amniotic fluid and/or chorionic villi or DNA extracted from fetal blood or tissue; and the fetus has one or more of: (1) multiple congenital anomalies affecting at least two different organ systems, (2) fetal hydrops of unknown etiology, or (3) a congenital anomaly affecting a single organ system with family history suggesting a genetic etiology.

Unproven / Not Medically Necessary

Not covered (unproven) indications

WES/WGS not medically necessary: Evaluation of fetal demise; prenatal testing via cell-free fetal DNA; preimplantation genetic testing (PGT) in embryos; routine prenatal WES/WGS when fetal phenotype is normal or criteria are not met; screening or evaluation when above criteria are not met.

Rapid sequencing and outpatient use: Use of rapid WES (rWES), rapid WGS (rWGS), or ultra-rapid WGS (urWGS) is unproven and not medically necessary for outpatient settings.

Emerging technologies considered unproven: Whole transcriptome sequencing, epigenetic signature analysis, and optical genome mapping (OGM) are considered unproven and not medically necessary for any indication due to insufficient evidence of efficacy.

Evidence summaries (informational — not prescriptive criteria)

Evidence-based findings and reported diagnostic yields

GS vs ES diagnostic yield: Systematic reviews/meta-analyses report GS can identify additional diagnoses after negative ES (pooled GS-specific yield ~7.0% in children) while ES reanalysis also yields additional diagnoses; pooled diagnostic yields for GS/ES across pediatric cohorts are in the 30–40% range depending on population and methods.

Examples: Albuquerque et al. (2025); Pandey et al. (2025); Srivastava et al. (2019).

Trio testing and combined approaches: Trio-based sequencing and combining WES with CNV analysis improves diagnostic yield (e.g., trio-WES + CNV-seq yielded ~61% in a GDD cohort).

See Zhang et al. (2024).

Reanalysis yield: ES reanalysis increases diagnostic rates in multiple studies and can approach or exceed incremental yield from GS in some analyses, supporting periodic re-evaluation of prior ES data.

See pooled ES reanalysis findings in Albuquerque and Chung reviews.

Evidence-supported indications (literature summaries)

Contexts in which ES/WGS has demonstrated substantial incremental diagnostic yield

Neurodevelopmental disorders/GDD/ID: ES shows higher diagnostic yield than CMA for unexplained neurodevelopmental disorders; pooled ES yield ~36% overall and higher in NDDs with associated conditions.36%

Srivastava et al. (2019)

Prenatal structural anomalies after nondiagnostic CMA/karyotype: Multiple meta-analyses report pooled incremental ES diagnostic yields around 31% overall, with phenotype-specific yields varying widely (e.g., skeletal ~60%, CNS ~32%).31%

Mellis 2022; Wang 2025; Blayney 2024

Specific high-yield prenatal subgroups: Higher yields observed in multisystem anomalies, skeletal dysplasias, agenesis of corpus callosum with extracranial anomalies, CAKUT BEKs, complex CHD/heterotaxy, and select pregnancy loss cohorts.

Coverage-relevant evidence summaries

Summarized coverage-relevant conclusions and contexts from evidence and society guidance

Prenatal testing after nondiagnostic standard testing: Prenatal ES/WGS can provide incremental diagnostic yield when fetal structural anomalies are present and CMA/karyotype are nondiagnostic; case selection and multidisciplinary review are recommended.after nondiagnostic CMA/karyotype

Supports testing in multisystem and selected single-system fetal anomalies

Rapid sequencing in critical care: Rapid and ultra-rapid sequencing demonstrate high diagnostic yields (~42% pooled) and are supported in critically ill inpatient infants, but evidence does not support outpatient use.critically ill inpatient infants

Xiao et al.; Kingsmore et al.

Reanalysis importance: Periodic reanalysis of ES/WGS data increases diagnostic yield and is recommended; some guidance and studies suggest intervals around 18 months or as clinical/family data change.

Guideline-supported indications

Covered when indications align with multiple professional society recommendations:

Pediatric congenital anomalies or DD/ID (ACMG): WES or WGS recommended as first- or second-tier testing for individuals with one or more congenital anomalies with onset prior to one year of age or for individuals with developmental delay/intellectual disability with onset prior to 18 years, per ACMG guidance.

ACMG practice guideline (Manickam et al., 2021)

Prenatal fetuses with anomalies (ISPD/ACOG): Prenatal WES/WGS may be considered when routine prenatal methods (karyotype/CMA) do not yield a diagnosis in a fetus with major single or multiple anomalies; CMA should be run before or in parallel in many cases per ISPD/ACOG statements.

ISPD 2022; ACOG Committee Opinion 682

Epilepsy with suspected genetic etiology (ILAE, NSGC, NICE): WES/WGS is recommended as first-line testing in many cases of suspected genetic epilepsy (severe childhood-onset, epilepsy with ID/ASD, progressive myoclonus epilepsies, familial non-acquired focal epilepsies); genetic counseling recommended.

ILAE 2022; NSGC 2023; NICE 2022

Covered when criteria are met (summary)

Policy revised; WES/WGS (with or without concurrent Comparator Analysis) is considered proven and medically necessary when the listed criteria are met

General: WES or WGS, with or without concurrent Comparator Analysis, is proven and medically necessary when the affected individual displays signs or symptoms of an undiagnosed or unexplained disorder with a suspected genetic cause and results are intended to directly impact medical management.

Policy revision clarifies wording and scope

Clinical presentation and test selection: Clinical presentation does not fit a Well-Delinated Genetic Syndrome or a disorder for which a specific test/Targeted Panel is available; when a specific syndrome is suspected, perform single-gene or Targeted Panel testing prior to WES/WGS.

Retains targeted-testing-first guidance

Prenatal congenital anomalies wording: Multiple congenital anomalies wording clarified to require anomalies affecting at least two different organ systems (applies to prenatal and other contexts where specified).

Revised phrasing in policy history

The policy clarifies that certain rapid or alternative sequencing technologies remain investigational or not supported for routine outpatient use. Specifically, the use of rapid Whole Exome Sequencing (rWES), rapid Whole Genome Sequencing (rWGS), and ultra-rapid Whole Genome Sequencing (urWGS) is unproven and not medically necessary when performed in outpatient settings due to insufficient evidence of clinical utility. Whole transcriptome (RNA) sequencing, epigenetic signature analysis (episignature testing), and optical genome mapping (OGM) are also considered unproven and not medically necessary for any indication in routine clinical practice at this time. These positions reflect the document's distinction between established inpatient/critical-care uses of rapid sequencing and the lack of peer-reviewed evidence supporting routine outpatient application.

Review summaries cited in the policy (e.g., Hayes evaluations) found insufficient evidence to support the routine clinical use of WES or WGS for some adult populations, including adults with suspected neuromuscular or movement disorders. The policy also emphasizes that genetic counseling is strongly recommended prior to WES/WGS to inform patients about test limitations and implications, and that testing should be ordered by qualified specialists as specified in the coverage criteria.

A systematic review examining prenatal exome sequencing in fetuses with an apparently normal phenotype and normal karyotype/CMA reported a pooled incremental diagnostic yield of only 1.6%. Based on these low yields and limitations of the current evidence, authors advise against routine prenatal ES in pregnancies without a medical indication or abnormal fetal phenotype.

The policy states that evidence is insufficient to support routine outpatient use of rapid/ultra-rapid sequencing and several emerging technologies. Specifically, routine outpatient use of rWES/rWGS/urWGS, whole transcriptome sequencing, epigenetic signature analysis, and optical genome mapping (OGM) is not supported because clinical utility has not been established for these contexts. Where limited or promising data exist (for example, OGM or episignature testing in research or select diagnostic settings), these technologies remain classified as investigational pending additional high-quality evidence.

Professional society guidance (ACOG, ISPD, ACMG) advises against routine use of WES/WGS in the prenatal setting when no fetal anomalies are present. The policy aligns with these recommendations and does not support routine prenatal WES/WGS for fetuses without structural anomalies; testing is recommended only when prenatal imaging or clinical assessment indicates a suspected genetic etiology and standard cytogenetic testing has been considered.

Epigenetic signature analysis (episignature testing) is described in the policy as an emerging modality under active study but, based on current evidence, is considered unproven and not medically necessary for routine diagnostic use. Although some case series report diagnostic yields in selected cohorts, the policy concludes that further validation and demonstration of clinical utility are required before routine coverage.

Optical genome mapping (OGM) is recognized as a promising technology for structural variant detection but is currently considered unproven and not medically necessary. The policy cites preliminary concordance and proof-of-principle studies but indicates that additional development and clinical utility studies are required prior to routine clinical adoption and coverage.

An operational note in the policy emphasizes that documentation demonstrating that a patient meets the listed clinical criteria does not guarantee coverage. Benefit determinations are subject to federal, state, and contractual requirements, and medical records documentation may be requested to assess whether the member meets clinical criteria, but submission of documentation alone does not ensure payment or coverage.

The policy history indicates that several definitions were removed or revised. Notably, the document records the removal of definitions such as Next Generation Sequencing (NGS) and Variant of Unknown Significance (VUS) as part of the revisions; these changes are noted in the policy history section.

Policy history entries included in the document provide revision and administrative information but do not explicitly list additional coverage exclusions in the cited segments. The history records updates to definitions, supporting information, and applicable CPT codes without adding new explicit exclusion conditions in these excerpts.

A related segment of the policy history reiterates administrative updates and section revisions; within the provided excerpts there are no explicit exclusion conditions added beyond the investigational/not medically necessary statements already present for specific technologies.

Technologies and indications that do not meet the policy's coverage criteria include: rapid/ultra-rapid sequencing in outpatient settings, whole transcriptome sequencing (RNAseq), epigenetic signature analysis (episignature testing), and optical genome mapping (OGM). The policy also identifies prenatal cfDNA testing, evaluation of fetal demise, and preimplantation genetic testing (PGT) as contexts where WES/WGS is not indicated when clinical criteria are not met.

Hayes evaluations and related systematic reviews identified insufficient evidence to support WES or WGS for certain adult populations — for example, adults with suspected neuromuscular or movement disorders — and concluded that larger prospective studies are needed to determine clinical utility in those contexts.

Summarizing the policy stance: routine outpatient use of rapid genomic sequencing, routine use of whole transcriptome sequencing, optical genome mapping, and episignature testing is not supported by current evidence and therefore not covered in routine outpatient practice per this policy.

Professional societies cited in the policy advise against routine prenatal WES/WGS when fetal anomalies are absent, and they do not support genome-wide sequencing for population screening of healthy children. The policy reflects these society positions by not recommending routine WES/WGS for prenatal cases without anomalies or for screening asymptomatic children.

The policy explicitly states that epigenetic signature analysis (episignature testing) is not medically necessary due to insufficient evidence of efficacy for routine clinical use. While certain series report diagnostic yields in select cohorts, the current evidence base is judged insufficient to support routine coverage.

Within the policy history excerpts provided, there are no new explicit 'not medically necessary' declarations beyond those already stated for specific technologies; the history focuses on updates to definitions, supporting information, and applicable codes rather than adding additional NMN statements in the cited segments.

This section of the policy history in the provided excerpts does not specify additional test-specific coverage details; it primarily documents administrative updates such as CPT code additions and supporting-information revisions and does not provide clinical decision-making criteria in these chunks.

Covered Indications and Clinical Contexts

Undiagnosed/unexplained disorder with suspected genetic cause where results will directly impact management

Undiagnosed or unexplained disorder with suspected genetic cause where results will directly impact management — clinical features listed

Eligibility and intended impact: Affected individual displays signs or symptoms of an undiagnosed or unexplained disorder with a suspected genetic cause and test results are intended to directly impact medical management.

Ordering providers: medical geneticist, neonatologist, neurologist, immunologist, or developmental pediatrician

Key single findings: One or more of: multiple congenital anomalies affecting at least two different organ systems; intellectual disability (moderate, severe, or profound) diagnosed by 18 years; global developmental delay; epileptic encephalopathy with onset before 3 years.

Additional supporting findings (need two or more): Two or more of: congenital anomaly; significant hearing or visual impairment by 18 years; laboratory abnormalities suggestive of inborn error of metabolism; autism spectrum disorder; neuropsychiatric condition; hypotonia/hypertonia in infancy; dystonia/ataxia/hemiplegia/neuromuscular or movement disorder; unexplained developmental regression not due to ASD or epilepsy; growth abnormality; persistent severe immunologic or hematologic disorder; dysmorphic features; consanguinity; other first- or second-degree family member(s) with similar diagnosis.

Applicable Procedure and CPT/PLA Codes

Applicable procedure codes (reference)mixed

0094U	Genome (e.g., unexplained constitutional or heritable disorder or syndrome), rapid sequence analysis.
0212U	Rare diseases (constitutional/heritable disorders), whole genome and mitochondrial DNA sequence analysis, proband.
0213U	Rare diseases (constitutional/heritable disorders), whole genome and mitochondrial DNA sequence analysis, each comparator genome (e.g., parent, sibling).
0214U	Rare diseases (constitutional/heritable disorders), whole exome and mitochondrial DNA sequence analysis, proband.
0215U	Rare diseases (constitutional/heritable disorders), whole exome and mitochondrial DNA sequence analysis, each comparator exome (e.g., parent, sibling).
0260U	Identification of copy number variations and structural variants by optical genome mapping.
0264U	Identification of copy number variations, inversions, insertions, translocations, and other structural variants by optical genome mapping.
0265U	Whole genome and mitochondrial DNA sequence analysis, identification of single nucleotide and copy number variants.
0266U	Tissue-specific gene expression by whole-transcriptome and next-generation sequencing.
0267U	Identification of copy number variations by optical genome mapping and whole genome sequencing.

1–10 of 28

1/3

No CPT/HCPCS/ICD codes listed in this excerptmixed

No codes listed

Applicable/Added CPT CodesCPTCovered

0318U	added to applicable CPT codes (as listed in policy history)
0582U	added to applicable CPT codes (as listed in policy history)
0583U	added to applicable CPT codes (as listed in policy history)
81354	added to applicable CPT codes (*annual edit)

Updated applicable CPT/PLA codesCPT

0318U
0582U
0583U
81354

Applicable CPT/Proprietary Codes (added)mixed

0318U	listed as newly added applicable code
0582U	listed as newly added applicable code
0583U	listed as newly added applicable code
81354	listed as newly added applicable code (appears with '*annual edit' in some entries)

Updated Applicable CPT CodesCPT

0318U	0318U (as listed in applicable CPT codes update)
0582U	0582U (as listed in applicable CPT codes update)
0583U	0583U (as listed in applicable CPT codes update)
81354	81354 (as listed in applicable CPT codes update)

Updated applicable CPT codesCPT

0318U	CPT code added (description not provided in these chunks)
0582U	CPT code added (description not provided in these chunks)
0583U	CPT code added (description not provided in these chunks)
81354	CPT code added (description not provided in these chunks)

Updated Applicable CPT CodesCPT

0318U	Added to applicable CPT codes (as listed in policy history)
0582U	Added to applicable CPT codes (as listed in policy history)
0583U	Added to applicable CPT codes (as listed in policy history)
81354	Added to applicable CPT codes (annual edit)

Reanalysis interval (coding context)

Minimum reanalysis interval>= 18 months

Condition for reanalysis timingAt least 18 months must have passed since the initial WES or WGS was performed

Reanalysis contextReanalysis applies when the individual still meets criteria for WES/WGS and new symptoms or new data/family history emerge

Reanalysis interval (explicit wording)

Explicit reanalysis wordingReanalysis is covered when at least 18 months have passed since the initial WES or WGS was performed

Provider Actions, Documentation, and Billing Guidance

Note

Prior testing expectation

Prior testing expectation: When a Well‑Delineated Genetic Syndrome is suspected, perform single‑gene testing or a Targeted Panel prior to WES/WGS. Many prenatal and pediatric sequencing studies perform ES/WES after non‑diagnostic karyotype and CMA; evidence and society guidance support a tiered approach where targeted tests and CMA/karyotype are performed before genome‑wide sequencing unless the clinical presentation indicates otherwise.

Perform targeted/single‑gene or targeted panel testing first when a specific syndrome is suspected.
Many ES/WES studies occur after non‑diagnostic CMA/karyotype; literature supports using ES after standard testing fails to diagnose.

Note

Prenatal testing sequencing pathway

Prenatal testing sequencing pathway: In prenatal cases with fetal anomalies, standard cytogenetic testing such as CMA and karyotype should be considered first; if non‑diagnostic, fetal WES or WGS may be considered. Reanalysis of prior ES results may be considered before proceeding to GS in selected postnatal workflows.

Investigational, Unproven, and Not Medically Necessary

The 'Not Covered' list in the policy includes outpatient/ambulatory use of rapid and ultra-rapid sequencing, whole transcriptome sequencing, epigenetic signature analysis, and optical genome mapping. The policy frames these as investigational or unproven modalities for routine outpatient practice and therefore not covered for those indications.

OGM and epigenetic signature analysis are described in the policy as technologies currently under study. Because available evidence does not yet demonstrate clinical utility for routine indications, the policy classifies both OGM and episignature testing as investigational or not medically necessary for routine coverage.

The policy does not support routine prenatal exome sequencing for fetuses with an apparently normal phenotype and normal CMA/karyotype, citing a very low pooled incremental diagnostic yield (~1.6%) and concluding that prenatal ES is not indicated in pregnancies without an imaging or clinical indication.

The policy explicitly states that the routine outpatient use of rapid genomic sequencing, the routine clinical application of whole transcriptome sequencing, and routine clinical use of OGM and episignature testing are not supported due to insufficient evidence of clinical utility and are therefore not covered in those contexts.

Professional societies such as ACOG and ISPD advise against routine prenatal WES/WGS without fetal anomalies; the policy cites society guidance to support its position that routine prenatal WES/WGS without anomalies and use of WES/WGS for screening healthy children are not recommended.

Both epigenetic signature analysis and optical genome mapping are described in the policy as unproven with insufficient evidence to support routine clinical use; the policy therefore considers them not medically necessary for standard indications.

Definitions and Background

WES sequences the protein-coding regions of the genome (the exome), which represent approximately 1–2% of the genome and where most known disease-causing variants are located. WGS sequences the entire genome and can detect single-nucleotide variants, copy number variants, structural variants, repeat expansions, and some noncoding variants; both approaches can return variants of uncertain significance and rely on laboratory interpretation and databases for clinical classification.

Comparator Analysis definition

DefinitionGenetic evaluation of an individual's close relative(s) to aid interpretation of the individual's test results (typically child plus biological parents).

Common nameAlso known as trio testing

PurposeUsed to clarify inheritance and help interpret variant pathogenicity in the proband

Well-Delineated Genetic Syndrome definition

Eligibility Requirements and Ordering Constraints

Summary: WES/WGS and related services are considered medically necessary when the documented clinical criteria are met; see the detailed criteria group blocks for precise eligibility requirements. Coverage decisions may require medical record documentation and testing must be ordered by specified specialists. Reanalysis is covered under stated timing and condition thresholds. Refer to the full policy for complete criterion language and code lists.

The policy references evidence and reanalysis discussions to support eligibility rules: reanalysis is considered proven and medically necessary when at least 18 months have passed since the initial WES/WGS and the member meets coverage criteria, and providers may be asked to supply medical record documentation to determine whether criteria are met. Providers should also follow society guidance regarding sequencing pathway and prior testing when applicable.

The policy clarifies reanalysis timing: reanalysis of prior WES/WGS data is considered medically necessary when listed criteria are met and at least 18 months have passed since the initial WES or WGS was performed. This aligns with society guidance that periodic reevaluation can yield additional diagnoses as knowledge and phenotype evolve.

In prenatal contexts, the policy and cited literature commonly expect that standard cytogenetic testing (karyotype and/or CMA) be performed and uninformative prior to prenatal ES/WGS in many cases. Studies emphasize detailed prenatal phenotyping and multidisciplinary review to prioritize cases likely to have monogenic etiologies.

Society guidance (ACMG, ACOG, ISPD) informs eligibility framing: WES/WGS are recommended as first- or second-tier in specified pediatric indications per ACMG, while ISPD and ACOG recommend selective prenatal use after standard testing and multidisciplinary review rather than routine prenatal application.

Background, Evidence, and Supporting Information

WES targets protein-coding exons (~1–2% of the genome) where many pathogenic variants reside, while WGS surveys the entire genome and can detect broader variant types including CNVs and structural variants. Both tests require specialized laboratory interpretation and benefit from family comparator samples and detailed phenotype information to improve diagnostic yield.

Evidence summaries (background — diagnostic yields and findings)

Evidence summaries (repeated background context — diagnostic yields and study findings)

Reanalysis interval and rationale: Reanalysis of ES/WGS increases diagnostic yield; policy requires at least 18 months since initial testing before reanalysis unless new symptoms or family data emerge earlier.>= 18 months

See chunk 6 and policy history

Trio advantage: Trio testing and inclusion of parental samples consistently improve interpretation and diagnostic yield across multiple studies and prenatal cohorts.

Evidence summaries and cohort studies

Policy Revision History and Summary of Changes

04/01/2026summary_of_changesLatest

Summary of Changes entries added referencing Covered indications: Congenital Anomaly, Epileptic Encephalopathy, Targeted Panel, and Well-Delineated Genetic Syndrome.

Summary of material changes: The policy now strongly recommends genetic counseling prior to WES/WGS, classifies epigenetic signature analysis and OGM as unproven/not medically necessary, updates reanalysis timing to >= 18 months, and removes the prior requirement that CMA must precede WGS. Definitions and applicable CPT codes were also updated.

2026-04-01coding_update

Applicable CPT codes list updated to add 0318U, 0582U, 0583U, and 81354 (noted in policy history; some entries marked as annual edit).

Policy Summary

PayerUnitedHealthcare

PolicyWhole Exome and Whole Genome Sequencing (Non-Oncology Conditions) (for Nebraska Only)

Policy CodePolicy CS150NE.F

Change TypeCoverage criteria revised; codes updated

Effective DateApril 1, 2026

Next Review DateN/A

Key ActionOrder WES/WGS only when clinical criteria are met and ensure medical record documentation supports medical necessity; genetic counseling is strongly recommended prior to testing.

SourceLink

On This Page

Multiple systematic reviews and cohorts

See ACMG statements and policy reanalysis criterion

Emerging technologies not yet routine: OGM, whole transcriptome sequencing, and epigenetic episignature analysis currently lack sufficient evidence for routine clinical use and are considered investigational/unproven for general coverage.insufficient evidence

Policy stance: not medically necessary

Laboratory and accreditation: Diagnostic WGS and related testing should be performed in accredited laboratories with validated tests; research results should be confirmed in diagnostic labs prior to clinical reporting.

Society-level expectations

Reanalysis summary: Reanalysis of prior WES/WGS data is proven and medically necessary when listed criteria are met and at least 18 months have passed since the initial WES or WGS was performed; applies if the individual has additional unexplained symptoms or new family/data information.>= 18 months since initial testing

Timing criterion revised in summary

Prenatal WES for fetal multiple congenital anomalies, fetal hydrops, or single-system anomaly + family history

Prenatal WES for fetal multiple congenital anomalies, fetal hydrops of unknown etiology, or single-system congenital anomaly with suggestive family history when CMA/karyotype uninformative and ordered by appropriate specialists

Prenatal prerequisites: Chromosome microarray analysis and/or karyotyping performed but uninformative; WES ordered by or in consultation with a medical geneticist or maternal-fetal medicine specialist; specimen from amniotic fluid/chorionic villi or DNA from fetal blood/tissue.

Fetal phenotype qualifying criteria: Fetus has: (a) multiple congenital anomalies affecting at least two different organ systems, OR (b) fetal hydrops of unknown etiology, OR (c) a congenital anomaly affecting a single organ system with family history suggesting a genetic etiology.

ISPD/ACOG recommend CMA before or in parallel in many cases

Evaluation of neurodevelopmental disorders (NDDs), GDD, ID, and related pediatric phenotypes

Evaluation of neurodevelopmental disorders (NDDs), GDD, ID, and related pediatric phenotypes — literature supports high diagnostic yields for trio-WES/GS

Trio-based sequencing yields: Trio-based ES/WGS demonstrates high diagnostic yields in children with unexplained severe NDDs, GDD, and ID (examples: 48.9% in severe NDD cohort; combined trio-WES + CNV-seq yielded ~61% in young children with GDD).

Wayhelova et al. (2024); Zhang et al. (2024)

Clinical utility implications: High diagnostic yields enable genetic counseling, influence management, and support trio testing and CNV analysis to maximize diagnostic return.

See policy evidence summaries

Evaluation of NDDs where prior testing non-diagnostic

Unexplained NDDs (GDD, ID, ASD) where prior testing is non-diagnostic — ES recommended as first-tier in some reviews

ES as first-tier: Systematic reviews report ES outperforms CMA for unexplained NDDs (overall ES yield ~36%); ES is recommended as a first-tier diagnostic test in selected neurodevelopmental presentations.36%

Srivastava et al.; Pandey et al.

Testing sequence: CMA may remain first-tier in some settings, but ES (especially trio-based) is supported as first- or second-tier depending on presentation and society guidance.

ACMG recommendations

Prenatal structural anomalies after non-diagnostic karyotype/CMA

Prenatal structural anomalies after non-diagnostic karyotype/CMA — higher priority for multisystem anomalies and certain phenotype subgroups

Incremental yield after CMA/karyotype: Multiple meta-analyses report pooled incremental ES diagnostic yields around 31% overall after nondiagnostic CMA/karyotype, with higher yields in specific phenotypes such as skeletal (~60%) and CNS anomalies (~32%).31%

Mellis 2022; Wang 2025; Blayney 2024

Prioritization for testing: Higher priority for multisystem anomalies (>=2 organ systems), skeletal dysplasia, ACC with extracranial anomalies, BEKs, complex CHD/heterotaxy, and recurrent fetal anomalies; multidisciplinary review and selection for suspected monogenic etiologies recommended.

Society and evidence recommendations

Pregnancy loss or termination due to fetal structural anomalies

Pregnancy loss or termination due to fetal structural anomalies — detection rates and retrospective series summarized

Pregnancy loss detection rates: Retrospective series report overall detection rates around 32% when including aneuploidy, CNVs, and SNVs/indels in cohorts of pregnancy loss or termination for fetal structural anomalies.32%

Xiang et al. (2024)

Highest-yield subgroups: Increased nuchal translucency and skeletal anomalies show particularly high detection rates; quad WES in recurrent losses increased yield in some series.varies

Study-level findings

Congenital anomalies, DD/ID with onset in childhood

Congenital anomalies, DD/ID with onset in childhood — ACMG supports WES/WGS as first- or second-tier

ACMG recommendation: ACMG recommends WES or WGS as first- or second-tier testing for individuals with congenital anomalies with onset prior to one year or for DD/ID with onset before 18 years, based on evidence of clinical utility.

ACMG practice guideline (Manickam et al., 2021)

Clinical application: Apply WES/WGS in appropriate pediatric presentations with qualified ordering providers and genetic counseling.

Fetal structural anomalies after nondiagnostic CMA and karyotype

Fetal structural anomalies after nondiagnostic CMA and karyotype — ES/WGS can provide incremental diagnostic yield; consider multidisciplinary review

Incremental diagnostic yield: ES/WGS provides incremental diagnostic yield after nondiagnostic CMA/karyotype; pooled yields vary by phenotype and case selection (overall pooled ~31%).31%

Mellis et al. (2022)

Case selection: Multidisciplinary review and selection for suspected monogenic etiologies improves diagnostic yield and is recommended prior to prenatal ES/WGS.

Policy and society guidance

Critically ill hospitalized infants

Critically ill hospitalized infants — rWES/rWGS/urWGS supported for diagnostic evaluation in inpatient critical care settings

Support for rapid sequencing in ICU: rWES, rWGS, and urWGS have substantial pooled diagnostic yields (~42%) in critically ill infants and are supported for inpatient critical care diagnostic evaluation; evidence does not support outpatient use.42%

Xiao et al. (2022); Kingsmore et al. (2019)

Consolidated covered indications

Covered indications overview: WES/WGS is covered for: congenital anomalies with early onset; developmental delay/intellectual disability; fetuses with major single or multiple anomalies when prior standard testing (karyotype/CMA) is nondiagnostic; unexplained epilepsy with suspected genetic etiology; and other presentations meeting the policy's clinical criteria and ordered by qualified specialists.

See society-specific nuances (ACMG, ISPD, ACOG, ILAE)

Undiagnosed disorder where results will directly impact management (including prenatal multisystem anomalies)

Undiagnosed or unexplained disorder where results are intended to directly impact management — includes prenatal indications with multiple congenital anomalies affecting >=2 organ systems

Core eligibility: Affected individual displays signs/symptoms of an undiagnosed or unexplained disorder with suspected genetic cause; results intended to directly impact management; test ordered by qualified specialist; clinical presentation meets the policy's listed features (including prenatal multisystem anomalies affecting at least two organ systems).

Policy summary and revised prenatal wording

Fetus with multiple congenital anomalies (>=2 organ systems)

Fetus with multiple congenital anomalies affecting at least two different organ systems (revised wording)

Definition and application: For prenatal coverage, 'multiple congenital anomalies' is defined as anomalies affecting at least two different organ systems; such presentations meet the prenatal WES criteria when CMA/karyotype are nondiagnostic and other policy prerequisites are met.>= 2 organ systems

Revised policy wording

Fetus with single-organ-system congenital anomaly + suggestive family history

Fetus with a congenital anomaly affecting a single organ system plus family history suggesting a genetic etiology

Single-system fetal anomaly plus family history: A fetus with a congenital anomaly affecting a single organ system may qualify for prenatal WES when family history suggests a genetic etiology, CMA/karyotype are nondiagnostic, and WES is ordered by/with consultation from appropriate specialists.

Standardized wording in revisions

Congenital Anomaly (summary of changes reference)

Summary of changes examples: Covered indications listed in Summary of Changes include: Congenital Anomaly; Epileptic Encephalopathy; Targeted Panel; Well-Delineated Genetic Syndrome — referenced for record but detailed criteria located in primary sections.

Summary of Changes entries

Epileptic Encephalopathy (summary)

Epileptic Encephalopathy (summary): Epileptic encephalopathy is included among covered indications; severe childhood-onset epilepsies and related presentations are supported by ILAE and other society guidance for genome-wide testing.

See ILAE recommendations and policy summary

Targeted Panel (role relative to WES/WGS)

Targeted Panel role: When a Well-Delineated Genetic Syndrome is suspected, targeted single-gene or multi-gene panel testing should be performed prior to WES/WGS; WES/WGS is indicated when phenotype is nonspecific or panels are uninformative.

Policy and guidance

Well-Delineated Genetic Syndrome (operational note)

Well-Delineated Genetic Syndrome note: If clinical presentation fits a Well-Delineated Genetic Syndrome for which a specific test/panel exists, perform that test first; WES/WGS is not the first choice in such cases.

Policy statement

Summary of Changes (definitions updated)

Summary of Changes and definitional updates (referenced)

Definitions updated: Policy updated definitions for Comparator Analysis, Global Developmental Delay, Intellectual Disability, and Preimplantation Genetic Testing (PGT); see policy definitions for details.

Policy history entries

Additional reanalysis conditionsAffected individual must meet WES/WGS criteria and have new unexplained symptoms or new data/family history suggesting a gene link

Policy intentReanalysis of prior WES/WGS data is considered proven and medically necessary when listed criteria are met

ACMG recommends CMA and karyotype be considered before fetal WES/WGS in the prenatal setting.
ES reanalysis may yield additional diagnoses and can be considered prior to GS in some cases.

Note

Prenatal CMA before/with WES/WGS

Prenatal CMA before/with WES/WGS: ISPD notes that when multiple anomalies strongly suggest a single‑gene disorder, CMA should be performed before or in parallel with prenatal WES. Prenatal WES coverage criteria in this policy require prior CMA and/or karyotype to have been performed and uninformative unless other criteria for testing are met.

ISPD: run CMA before or in parallel with prenatal WES when multiple anomalies suggest single‑gene etiology.
Policy prenatal WES criteria include CMA and/or karyotype performed but uninformative.

Documentation Required

Coverage criteria and documentation

Coverage criteria and documentation: WES/WGS (with or without Comparator Analysis) is covered when specified clinical criteria are met (suspected genetic cause, results intended to impact medical management, presentation not fitting a Well‑Delineated Genetic Syndrome, ordering by specified specialists, and defined clinical presentation elements). Medical records documentation that supports medical necessity — including relevant history, exam, phenotype, prior test results (e.g., CMA/karyotype), and family history — may be required for review and must be made available on request. Lack of sufficient documentation may result in denial; documentation requirement does not guarantee coverage.

WES/WGS coverage requires meeting the policy criteria (see Coverage Rationale).
Medical record must contain legible documentation of history, exam, pertinent tests, phenotype, and prior testing; providers may be asked to supply these records.
Insufficient documentation can lead to claim denial; documentation requests do not assure coverage.

Billing Rule

Applicable CPT codes updated

Applicable CPT codes updated: Policy history notes that applicable CPT/proprietary codes were updated and the following codes were added in the revision cycle: 0318U, 0582U, 0583U, and 81354. Claims and prior‑authorization processes that reference code lists may be affected; ensure current code lists are used when submitting claims.

Added applicable codes: 0318U, 0582U, 0583U, 81354 (per policy history).
Claims may be impacted if outdated CPT lists are used; verify current applicable codes before billing.

Note

Applicable Codes Updated

Applicable Codes Updated / Applicable CPT code updates (revision history): The Revision History repeatedly documents updates to the list of applicable CPT codes and supporting information sections (Description of Services, Clinical Evidence, References). This section of the policy contains revision‑history entries noting code additions and supporting updates; no new clinical coverage criteria were introduced in these code‑update entries.

Policy history entries repeatedly record addition of CPT codes 0318U, 0582U, 0583U, and 81354.
Supporting sections (Description of Services, Clinical Evidence, References) were updated to reflect current evidence.

Prior Authorization

Prior authorization not specified in segment

Prior authorization and authorization triggers: This revision‑history excerpt does not specify explicit prior‑authorization requirements or step‑therapy rules for WES/WGS. If prior authorization is required by the payer or product, providers should follow the payer’s prior‑authorization process; the policy history does not itself establish new authorization triggers.

No explicit prior authorization codes or requirements are stated in the provided policy history excerpts.
Providers should check payer/practice‑specific authorization channels for any authorization needed.

Note

None explicit in these chunks

Not present/None explicit in these chunks: The provided revision‑history excerpts are largely administrative (code list and supporting‑section updates) and do not include explicit operational authorization, denial trigger lists, or step‑therapy requirements relevant to clinical decision making.

This section contains policy history only; no new explicit denial triggers or step‑therapy requirements were described in the excerpt.
No additional operational documentation requirements beyond standard medical record requests were added in these chunks.

Documentation Required

Provider laboratory collaboration

Provider laboratory collaboration: Consistent with ACMG/AMP guidance, the ordering clinician is expected to collaborate with the testing laboratory by providing detailed phenotype, prior test results, family history, and other relevant clinical information to support variant interpretation. Parental samples should be pursued when feasible to improve diagnostic yield (trio testing preferred when possible).

Provide labs with comprehensive phenotype, prior testing, and family history information.
Pursue parental samples/trio testing when feasible — diagnostic yield is higher with trio analysis.

Denial Risk

Documentation‑related denial risk

Documentation‑related denial risk: Medical record documentation must fully support medical necessity. Failure to provide legible, complete documentation of history, exam, phenotype, and prior diagnostic testing may result in denial or inability to determine coverage. Documentation requests do not guarantee authorization or payment.

Maintain legible records of relevant history, physical exam, prior tests (CMA/karyotype, targeted panels), and rationale for WES/WGS.
Incomplete or missing documentation may lead to claim denial.

Note

This section contains policy history only

Policy history and supporting information updates: The section contains multiple policy history entries noting updates to coverage language (including recommendation for genetic counseling prior to WES/WGS), additions/removals of language, and updates to Description of Services, Clinical Evidence, and References to reflect recent literature. These entries are administrative and summarize changes rather than introduce new procedural requirements in the excerpt.

Policy history added recommendation: genetic counseling is strongly recommended prior to WES/WGS.
Supporting sections (Description of Services, Clinical Evidence, References) were updated to reflect new evidence and revisions.

Documentation Required

Documentation alignment

Documentation alignment and clinical workflow notes: Providers should ensure their clinical documentation and test‑ordering workflows align with current evidence and policy expectations — including the tiered testing approach, prenatal sequencing considerations, and reanalysis recommendations. Reanalysis of WES/WGS data is described as proven and medically necessary when criteria are met, with a timing threshold of at least 18 months since initial testing in many policy revisions.

Ensure documentation aligns with coverage criteria and reflects prior testing, phenotype, and intended impact on management.
Consider ES reanalysis workflows before GS where clinically appropriate; policy revisions reference reanalysis timing (e.g., ≥18 months since initial testing when criteria met).

The policy history contains multiple administrative updates and notes the removal or revision of several definitions; however, the provided excerpts do not include a separate 'tests excluded' section beyond the investigational/not medically necessary language, and therefore do not present explicit extra tests as excluded in these segments.

A syndrome characterized by a collection of recognizable traits or abnormalities that tend to occur together and are associated with a specific disease.

IdentificationDistinguishing features (e.g., facial features), laboratory tests, or family history can be used to identify a Well‑Delineated Genetic Syndrome.

Implication for testingIf a specific syndrome is suspected, a single gene or Targeted Panel should be performed prior to WES/WGS.

Whole Exome Sequencing (WES) definition

DefinitionSequencing of the exome — the protein‑coding portions (exons) of the genome — which comprise approximately 1–2% of the genome.

Clinical rationaleMost known disease‑causing variants are found in exons; WES yields many variants and depends on laboratory interpretation capacity.

Alternative testingUsed when targeted single‑gene or panel testing is not appropriate or nondiagnostic.

Whole Genome Sequencing (WGS) definition

DefinitionSequencing of the entire genome — determining the order of all nucleotides in an individual's DNA — enabling detection of variants across the genome.

Variant types detectedCan detect single nucleotide variants, copy number variants (CNVs), structural variants (SVs), repeat expansions, and noncoding/regulatory variants.

Comparative noteWGS may offer modest incremental yield over WES in some settings and can require less DNA or enable faster turnaround in specific contexts.

Whole transcriptome sequencing definition

DefinitionSequencing of all RNA transcripts (the transcriptome) present in a tissue to identify coding and noncoding RNA reads.

Clinical useCan provide additional or different information from DNA‑based sequencing and has been proposed for rare genetic diseases and oncology; evidence for routine constitutional use is insufficient.

Distinct from WES/WGSAnalyzes RNA expression/readouts rather than DNA sequence, potentially informing splicing and expression effects.

Optical genome mapping (OGM) definition

DefinitionAn imaging‑based method that constructs long‑range genome 'maps' from single, labeled DNA molecules to identify structural variants.

DetectsUsed to detect insertions, deletions, duplications, inversions, translocations, and small balanced structural variants not easily seen by standard cytogenetics.

Policy stanceOGM is currently being studied and is considered unproven and not medically necessary for routine clinical use.

Incremental diagnostic yield

DefinitionProportion of additional cases in which pathogenic or likely pathogenic variants are identified by ES/WGS beyond those detected by prior standard testing (e.g., CMA/karyotype).

UseOften reported as 'incremental diagnostic yield' of ES/WGS over CMA/karyotype in prenatal and postnatal cohorts.

ImplicationHelps quantify added value of genome‑wide sequencing versus prior targeted/standard tests.

rWES/rWGS/urWGS — rapid sequencing definition

DefinitionRapid sequencing refers to abbreviated‑turnaround whole exome or whole genome sequencing (rWES, rWGS) and ultra‑rapid WGS (urWGS) developed for urgent inpatient evaluation.

Setting limitationSupported evidence exists for use in critically ill inpatient infants, but evidence is insufficient to support routine outpatient use.

Typical yieldPooled diagnostic yield in critically ill infants ~42% per meta‑analyses cited.

Epigenetic signature analysis definition

DefinitionAnalysis of DNA methylation profiles (episignatures) to identify diagnostic methylation patterns associated with specific disorders.

EvidenceSome case series report diagnostic yields (e.g., EpiSign cohorts), but overall evidence is currently insufficient to support routine clinical use for constitutional disorders.

Policy stanceEpigenetic signature analysis is considered unproven and not medically necessary for any indication per the policy revisions.

Reanalysis / reevaluation

DefinitionPeriodic variant and case‑level review of previously obtained sequencing data because phenotype and variant knowledge change over time, potentially altering diagnostic interpretation.

Recommended practiceReanalysis is recommended and can increase diagnostic yield; many sources and policy language support reanalysis considering evolving evidence.

Triggering eventsReanalysis may be indicated when new symptoms emerge, new family history appears, or after a specified time interval (policy: >=18 months).

Comparator Analysis (non-concurrent) definition referenced in revisions

DefinitionNon‑concurrent Comparator Analysis: Genetic testing of family member(s) performed at a different time than the proband's WES/WGS to aid interpretation.

Use caseCovered when the affected individual meets WES/WGS criteria and prior WES/WGS has been performed on the affected individual.

SynonymIncludes testing of parental or other close‑relative samples to resolve variant significance after initial testing.

Multiple congenital anomalies — revised wording

Definition updateMultiple congenital anomalies now specified as anomalies affecting at least two different organ systems.

ScopeApplies to prenatal and non‑prenatal contexts where policy lists multiple congenital anomalies as a covered presentation.

ImplicationClarifies prior wording to require involvement of >=2 organ systems rather than vague 'different organ systems'.

Single-organ-system congenital anomaly with family history — clarified phrasing

Clarified phrasingFor a fetus with a congenital anomaly affecting a single organ system, coverage consideration requires family history that suggests a genetic etiology.

ApplicationUsed in prenatal WES criteria to allow single‑system anomalies to qualify when supported by suggestive family history.

Relation to targeted testingIf a specific syndrome is suspected based on family history, targeted single‑gene or panel testing should be considered first.

Policy definition changes

Definition changes summaryPolicy history notes removal and updates of several definitions (e.g., removal of NGS and VUS; updates to Comparator Analysis, GDD, ID, PGT).

Removed itemsRemoved definitions include Next Generation Sequencing (NGS) and Variant of Unknown Significance (VUS).

Updated itemsComparator Analysis, Global Developmental Delay, Intellectual Disability, and Preimplantation Genetic Testing (PGT) definitions were updated.

Specific updated definitions

Specific updated definitionsDefinitions explicitly updated include Comparator Analysis; Global Developmental Delay; Intellectual Disability; and Preimplantation Genetic Testing (PGT).

Purpose of updatesClarifies terminology used in coverage criteria and aligns definitions with current references and policy wording.

DocumentationThese updates are recorded in the policy history Summary of Changes entries.

The policy requires that the patient's medical record contain documentation that fully supports the medical necessity for the requested services, and it notes that documentation may be requested to assess whether the member meets clinical criteria. Documentation alone does not guarantee coverage.

For prenatal WES, coverage eligibility includes cases where a fetus has a congenital anomaly affecting a single organ system together with a family history suggesting a genetic etiology; the policy reiterates that CMA/karyotype should have been uninformative prior to prenatal WES in many covered scenarios.

Fallback summary: WES/WGS must be ordered by the specified clinicians and the clinical presentation must meet the policy's defined features; if a specific syndrome is suspected, targeted testing should be performed before proceeding to WES/WGS.

Evidence cited in the policy supports that ES/WGS reanalysis can identify additional diagnoses and that reanalysis may be considered prior to pursuing other tests in certain diagnostic pathways. The policy uses these evidence summaries to justify coverage of reanalysis under defined timing conditions.

Prenatal studies and society guidance commonly required or recommended prior non-diagnostic karyotype and CMA before considering WES/WGS; these expectations are reflected in the policy's prenatal coverage criteria and prior-testing guidance.

ACMG and ACOG guidance contextualize ordering and sequencing choices: test selection should be phenotype-driven, and WES/WGS may be considered after standard testing in prenatal cases or as first/second tier in certain pediatric presentations.

Society guidance referenced in the policy supports periodic reanalysis of genomic data because phenotypes and variant knowledge evolve; the policy incorporates this rationale into its reanalysis criteria and timing threshold.

Additional note: the policy's coverage criteria and related requirement summaries are detailed in the criteria group blocks; this summary block directs providers to those sections for specific eligibility language and thresholds.

The policy references major guideline years and sources that informed coverage nuance: ACMG practice guidance (2021), ISPD position statement (2022), and other society documents (NICE 2022; NSGC 2023) which inform the policy's indication- and sequencing-pathway decisions.

04/01/2026coding_updateLatest

CPT/proprietary codes 0318U, 0582U, 0583U, and 81354 appended to the policy's applicable codes list (entries reference annual edit for 81354 in some history notes).