CurrentUnitedHealthcarePolicy CS150KY.14

Whole Exome Sequencing and Whole Genome Sequencing (Non-Oncology) - Kentucky

Defines medical necessity criteria, allowable indications, exclusions, applicable procedure codes, and documentation expectations for outpatient or discharge-based WES/WGS and related analyses for UnitedHealthcare Kentucky members.

Policy Summary

PayerUnitedHealthcare

PolicyWhole Exome Sequencing and Whole Genome Sequencing (Non-Oncology) - Kentucky

Policy CodePolicy CS150KY.14

Change TypeCodes updated (81354 added); prior version archived

Effective DateMay 1, 2026

Next Review Date

Key ActionEnsure medical records document medical necessity and order WES/WGS only when criteria are met and by an approved specialist; use updated CPT list (81354 added) when billing.

POLICY UPDATE CHANGES

Applicable CPT codes: added 81354 to reflect annual edits.

Archived previous policy version CS150KY.13.

MultipleKey covered indications

SeveralNot medically necessary

~40Applicable procedure codes

48%Highest meta-analysis yield (GS)

42%Rapid sequencing yield (critically ill)

1CPT codes added in revision

Coverage Summary

Policy Number CS150KY.14; Effective Date May 1, 2026. Scope: applies only to Kentucky members and to testing performed in the outpatient setting or upon discharge from an inpatient stay.

This policy defines when Whole Exome Sequencing (WES/ES), Whole Genome Sequencing (WGS/GS), comparator (family/trio) analyses, and related services are considered medically necessary with criteria, lists unproven/not medically necessary uses, and specifies documentation and billing expectations including an updated CPT code list (81354 added).

Concise summary: WES/WGS (with or without comparator analysis) is covered with criteria for individuals with suspected genetic disorders when testing will directly affect medical management and when the presentation is not consistent with a well-delineated genetic syndrome or when targeted testing is inappropriate. Key covered indications include multiple congenital anomalies (≥2 organ systems), moderate–profound intellectual disability by age 18, global developmental delay, and epileptic encephalopathy with onset before age 3, or the presence of two or more other listed features (e.g., congenital anomaly, significant sensory impairment, laboratory findings suggesting inborn errors of metabolism, hypotonia, movement disorders, growth abnormalities, persistent severe immunologic or hematologic disorder, dysmorphic features, consanguinity, or affected first-/second-degree relatives). Notable exclusions include routine prenatal cfDNA, preimplantation genetic testing, evaluation of fetal demise, outpatient use of rapid/ultra-rapid sequencing, and routine clinical use of whole transcriptome sequencing, optical genome mapping (OGM), and episignature (epigenetic) testing.

Key policy facts

Policy NumberCS150KY.14

Effective DateMay 1, 2026

StatusCURRENT

PayerUnitedHealthcare

ScopeOutpatient or upon discharge testing for Kentucky members; defines medical necessity criteria, allowed indications, exclusions, codes, and documentation expectations

Applicable reference procedure codes listed~40 codes (includes CPT/HCPCS codes and many U-codes such as 0094U–0583U, 81415–81427, added 81354)

CPT codes added in this revision81354

Medical-Necessity Criteria

WES/WGS Medical Necessity

Whole Exome Sequencing (WES) or Whole Genome Sequencing (WGS), with or without concurrent Comparator Analysis, is proven and medically necessary when the following are met:

ALL of the following

The affected individual displays signs or symptoms of an undiagnosed or unexplained disorder with a suspected genetic cause.
Test results are intended to directly impact the individual's medical management.
The clinical presentation does not fit a Well-Delineated Genetic Syndrome or disorder for which a specific test or a Targeted Panel test is available (if a specific genetic syndrome is suspected, a single gene or Targeted Panel should be performed prior to determining if WES or WGS is necessary).
The test is ordered by a medical geneticist, neonatologist, neurologist, immunologist, or developmental pediatrician.

Not Medically Necessary / Unproven Indications

Policy-level stance: rapid and ultra-rapid sequencing modalities (rWES, rWGS, urWGS) have demonstrated diagnostic utility and faster turnaround in critically ill, hospitalized infants (e.g., pooled rapid sequencing diagnostic yield ~42%; urWGS diagnostic rate reported at 46% in Kingsmore et al. 2019) but the policy states their use is not supported in outpatient settings.

Reanalysis / resequencing: periodic systematic reanalysis of prior ES/GS data and selective resequencing are supported when criteria are met (reanalysis intervals in literature commonly recommended at least 18 months and may increase diagnostic yield; combining reanalysis with repeat sequencing/trio testing and CNV detection increases yield).

Whole transcriptome sequencing (RNAseq/TS): evidence is insufficient to support routine clinical use; it may increase diagnostic yield in selected unresolved cases (example: RNAseq added ~15% diagnostic yield among WGS-negative cases in a referral cohort) but limitations include tissue-specific expression and small studies.

Optical genome mapping (OGM): current evidence is proof-of-principle with high concordance in small studies but insufficient to support routine clinical use for any indication at this time.

Epigenetic signature (episignature) testing: studies report diagnostic yields in selected cohorts, but the policy considers episignature testing insufficient for routine clinical use and highlights limitations (restricted biomarkers, potential false positives, need for standardized interpretation).

Professional Society Recommendations & Evidence Summary

Professional Society Recommendations (selection)

Guideline-aligned recommendations for test selection and use:

ANY of the following

ACMG: WES/WGS supported for congenital anomalies and DD/ID; consider trio testing where feasible; reanalysis recommended
AAP: CMA and WES as first-tier for GDD/ID; if WGS performed, CMA may be deferred; reanalysis every 1-2 years if negative
AAN/AANEM: consider WES/WGS in selected congenital muscular dystrophy where standard testing is negative (Evidence Level C)
ILAE / NSGC / NICE: recommend WES/WGS (often as first-line) for many unexplained epilepsies and advise genetic counseling and periodic reevaluation

Coding

Applicable (reference) Procedure Codes listedmixed

0094U	Genome (e.g., unexplained constitutional or heritable disorder or syndrome), rapid sequence analysis
0212U	Whole genome and mitochondrial DNA sequence analysis, proband
0213U	Whole genome and mitochondrial DNA sequence analysis, each comparator genome
0214U	Whole exome and mitochondrial DNA sequence analysis, proband
0215U	Whole exome and mitochondrial DNA sequence analysis, each comparator exome
0260U	Identification of copy number variations and structural variants by optical genome mapping
0264U	Identification of copy number variations by optical genome mapping
0265U	Whole genome and mitochondrial DNA sequence analysis, various sample types
0266U	Tissue-specific gene expression by whole-transcriptome sequencing
0267U	OGM and WGS combined identification of structural variants

1–10 of 28

1/3

Applicable CPT codes (updated)CPT

81354

Code added to list of applicable CPT codes (added effective 05/01/2026)

Provider Actions

Documentation Required

Medical record documentation required

The patient's medical record must contain documentation that fully supports the medical necessity for the requested services. Documentation includes relevant medical history, physical examination, and results of pertinent diagnostic tests or procedures. Records must be legible, maintained in the patient's medical record, and made available upon request.

Records must be available upon request.

Prior Authorization

Ordering provider requirement

WES or WGS must be ordered by an appropriate specialist to support medical necessity determination.

Required ordering provider specialties: medical geneticist, neonatologist, neurologist, immunologist, developmental pediatrician

Definitions

Comparator Analysis: Genetic evaluation of an individual's close relative(s) to aid interpretation of the individual's test results; typically involves the child (proband) and both biological parents (trio testing).

Well-Delineated Genetic Syndrome: A syndrome with recognizable traits associated with a specific disease where single gene or targeted panel testing is indicated first.

Global Developmental Delay: Failure to meet expected developmental milestones in several areas in an individual younger than 5 years of age.

ES (WES): Whole Exome Sequencing — sequencing of the protein-coding regions (exons) of the genome.

GS/WGS: Whole Genome Sequencing — sequencing of an individual's entire DNA, including coding and non-coding regions.

Trio sequencing: Sequencing that includes the proband and both biological parents.

CMA / CGH: Chromosomal microarray analysis / comparative genomic hybridization.

rWES/rWGS/urWGS: Rapid or ultra-rapid whole exome/genome sequencing with shortened turnaround times for clinical decision making in critically ill patients.

Whole Transcriptome Sequencing (TS/RNAseq): Sequencing of RNA to evaluate gene expression and splicing to aid interpretation of genomic variants.

Optical Genome Mapping (OGM): A technology for detecting structural chromosomal variants using ultra-high-molecular-weight DNA and optical mapping.

Episignature testing: DNA methylation-based clinical assays that detect disease-specific methylation signatures for certain genetic disorders.

Thresholds & Recommended Intervals

Thresholds / Reanalysis

nuchal translucency threshold>= 5 mm

Reanalysis intervalAt least 18-22 months (recommendation: >=18 months); policy requires >=18 months before reanalysis is proven medically necessary

Revision History

2026-05-01material_changeLatest

Updated list of applicable CPT codes; supports billing for genomic sequencing where applicable. Applicable CPT codes: added 81354 to reflect annual edits.

2026-05-01archival

Previous policy version archived as part of revision history: Archived previous policy version CS150KY.13.

Policy Summary

PayerUnitedHealthcare

PolicyWhole Exome Sequencing and Whole Genome Sequencing (Non-Oncology) - Kentucky

Policy CodePolicy CS150KY.14

Change TypeCodes updated (81354 added); prior version archived

Effective DateMay 1, 2026

Next Review Date

Key ActionEnsure medical records document medical necessity and order WES/WGS only when criteria are met and by an approved specialist; use updated CPT list (81354 added) when billing.

On This Page

Clinical presentation must include

Either ONE of the following
- Multiple Congenital Anomalies (affecting at least two different organ systems).
- Intellectual Disability characterized as moderate, severe, or profound, diagnosed by 18 years of age.
- Global Developmental Delay.
- Epileptic Encephalopathy with onset before three years of age.
Or 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 disorder, movement disorder, or other serious neurologic abnormality.
- Unexplained developmental regression, unrelated to Autism Spectrum Disorder 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 for WES or WGS is proven and medically necessary when both of the following criteria are met:

ALL of the following

The affected individual meets the above criteria for WES or WGS.
WES or WGS has been previously performed on the affected individual.

Reanalysis of WES/WGS

Reanalysis of previously generated WES or WGS data is proven and medically necessary when the following are met:

ALL of the following

At least 18 months have passed since the initial WES or WGS was performed.At least 18 months
The affected individual meets the above criteria for WES or WGS.
AND either of the following occurs
- The affected individual experiences additional symptoms after initial WES or WGS that cannot be explained by the results of the initial testing.
- New data or new family history emerges which suggests a link between the individual's symptoms and specific genes.

Prenatal WES

Prenatal WES is proven and medically necessary for diagnosing or evaluating a genetic disorder when all of the following criteria are met:

ALL of the following

Chromosome microarray analysis (CMA) 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).
The specimen is obtained from amniotic fluid and/or chorionic villi, or DNA is extracted from fetal blood or tissue.
Fetal criteria (one or more)
- Multiple Congenital Anomalies affecting at least two different organ systems.
- Fetal hydrops of unknown etiology.
- A Congenital Anomaly affecting a single organ system and family history that suggests a genetic etiology.

ACOG: do not recommend routine WES/WGS for prenatal diagnosis outside trials; WES may be reasonable when standard testing is negative in fetuses with anomalies

ESHG: recommend WGS introduction when it improves quality/diagnostic yield and testing be performed in accredited labs

Study / Source	Key result
Kingsmore et al. (NSIGHT2 randomized trial)
urWGS diagnostic rate 46%; rWES/rWGS diagnostic yields ~19-20%; urWGS faster turnaround
Xiao et al. (2022) meta-analysis of rapid sequencing in critically ill infants
Pooled diagnostic yield 42% for rapid sequencing; rWES 50%, rWGS 37%
Lee et al. (2020) RNAseq study
RNAseq added 15% diagnostic yield among WGS-negative cases (overall yield increased to 38%)
Albuquerque et al. (2025) systematic review/meta-analysis
GS-specific diagnostic yield after negative ES 7.0%; total GS diagnostic yield 24.1% in cohort with ES reanalysis data
Pandey et al. (2025) meta-analysis
Pooled diagnostic yield 34.2% for GS/ES vs 18.1% for non-GWS; ~2.4x higher odds of diagnosis
Chung et al. (2023) meta-analysis
Diagnostic yields: ES 38% vs GS 34% (no significant difference overall)
Sheidley et al. (2022) epilepsy meta-analysis
Compared yields across test types: GS 48%; ES 24%; multi-gene panels 19%; CMA 9% (overall 17%)

Prior Authorization

Rapid/ultra-rapid sequencing use limited to critically ill inpatients

Rapid (rWES/rWGS) and ultra-rapid (urWGS) sequencing are limited to critically ill inpatients. Outpatient use of rapid or ultra-rapid sequencing is unproven and not supported by this policy.

Outpatient use is not supported; prior authorization should reflect an inpatient critical illness indication.

Billing Rule

Comparator tests and reanalysis

Comparator (proband-relative) tests and routine reanalysis billing rules.

Affected CPT/PLA/other codes to consider: 0213U, 0215U, 0425U, 0583U, 81416, 81426, 81417, 81427
Reanalysis is considered medically necessary when at least 18 months have passed since the initial WES/WGS; earlier reanalysis may be appropriate if new symptoms or new family history/data emerge that could change interpretation.

Billing Rule

Use updated CPT code list

Use the policy's updated CPT/PLA code list for claims and prior authorization.

Added code 81354
Effective revision date: 05/01/2026

Documentation Required

Genetic counseling requirement

Genetic counseling is strongly recommended to ensure informed decision-making and interpretation of results.

Recommend pre-test genetic counseling prior to WES/WGS; post-test counseling recommended to discuss results and implications.
Document counseling in the medical record.

Documentation Required

Consider trio samples when feasible

When feasible, include parental (trio) samples to improve diagnostic yield and interpretation of variants.

Consider trio samples (proband + both biological parents) when feasible to aid variant interpretation.
If trio is not possible, document rationale and any alternative comparator testing performed.

Documentation Required

Periodic reanalysis guidance

Negative or uncertain WES/WGS results should be periodically reassessed given evolving knowledge and variant databases.

Periodic reanalysis of negative or uncertain genomic test results is recommended; consider reanalysis at or after 18 months if clinical status is unchanged.
Earlier reanalysis may be appropriate if new symptoms or new family history/data emerge.

Documentation Required

Follow federal/state/contractual plan terms

Follow federal, state, and contractual plan terms when determining coverage and benefit applicability.

Benefit coverage is determined by applicable federal, state, and contractual requirements and laws.
Medical record documentation may be required to assess whether the member meets clinical criteria for coverage.

Note

Use InterQual when applicable

Use InterQual or other plan-specified clinical criteria tools as directed for utilization review and prior authorization decisions.

Follow InterQual criteria when required by the plan for authorization or continued stay review.
Document use of InterQual determinations in the medical record where applicable.