ModifiedUnitedHealthcarePolicy CS150LA.O

Whole Exome and Whole Genome Sequencing (Non‑Oncology) — Louisiana

State-specific UnitedHealthcare Community Plan medical policy governing coverage of whole exome and whole genome sequencing (non-oncology) for Louisiana Medicaid members, including prenatal testing, reanalysis, and comparator testing.

Policy Summary

PayerUnitedHealthcare

PolicyWhole Exome and Whole Genome Sequencing (Non‑Oncology) — Louisiana

Policy CodePolicy CS150LA.O

Change TypeAdministrative code update

Effective Date02/01/2026

Next Review DateN/A

Key ActionDocument genetic counseling (pre- and post-test), include structured family history and ordering specialist when submitting for coverage.

SourceLink

POLICY UPDATE CHANGES

Updated list of applicable CPT codes to reflect annual edits and added CPT code 81354.

Louisiana-onlyGeographic application

Genetic counseling requiredCounseling requirement

≥18 monthsReanalysis interval

Specialist-onlyOrdering provider

81354

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Coverage Criteria — WES / WGS

WES Initial testing criteria

WES is covered when ALL of the following are met:

WES general conditions: Results expected to directly influence medical management and clinical outcomes

Clinical presentation is nonspecific and does not fit a well‑defined syndrome for which a specific or targeted gene test is available; if a specific genetic syndrome is suspected, single gene or targeted gene panel testing should be performed prior to WES

Ordering provider: WES must be ordered by a medical geneticist, neonatologist, neurologist, immunologist, or developmental pediatrician

Supporting clinical features (one of): Clinical history strongly suggests a genetic cause and one or more of the following features is present: multiple congenital anomalies affecting different organ systems; moderate, severe, or profound intellectual disability diagnosed by 18 years of age (additional features addressed in alternate criteria)

WES alternate criteria (two-or-more features)

Alternatively, WES is covered when ALL general conditions are met and BOTH of the following feature requirements are satisfied:

WES alternate feature set: Clinical history strongly suggests a genetic cause and two or more of the following features are present: congenital anomaly; significant hearing or visual impairment diagnosed by 18 years; laboratory abnormalities suggestive of an inborn error of metabolism; autism spectrum disorder; neuropsychiatric condition (e.g., bipolar disorder, schizophrenia, OCD); hypotonia or hypertonia in infancy; dystonia/ataxia/hemiplegia/neuromuscular or other movement disorder; unexplained developmental regression (not due to autism or epilepsy); growth abnormality (failure to thrive, short stature, microcephaly, macrocephaly, or overgrowth); persistent/severe immunologic or hematologic disorder; dysmorphic features; consanguinity; or another first‑ or second‑degree family member with similar clinical features

WES comparator and reanalysis

Additional covered WES scenarios:

Comparator testing: Comparator (e.g., parents or siblings) WES is covered when performed concurrently or previously on the individual and the initial WES clinical criteria have been met

Reanalysis of previously obtained WES is covered after at least 18 months when initial WES criteria were met and either the individual develops additional unexplained symptoms or new data/family history emerges that suggests a link to specific genes>=18 months

WGS Initial testing criteria

WGS is covered when ALL of the following are met:

WGS general conditions: Results expected to directly influence medical management and clinical outcomes; neither chromosomal microarray analysis (CMA) nor WES have been performed or CMA/WES were nondiagnostic

Ordering provider: WGS must be ordered by a medical geneticist, neonatologist, neurologist, immunologist, or developmental pediatrician

Supporting clinical features (one of): Clinical history strongly suggests a genetic cause and one or more of the following features is present: multiple congenital anomalies affecting different organ systems; moderate, severe, or profound intellectual disability diagnosed by 18 years of age; global developmental delay; or epileptic encephalopathy with onset before three years of age (additional features addressed in alternate criteria)

WGS alternate criteria (two-or-more features)

Alternatively, WGS is covered when ALL general conditions are met and two or more of the listed features are present:

WGS alternate feature set: Clinical history strongly suggests a genetic cause and two or more of the following features are present: congenital anomaly; significant hearing or visual impairment diagnosed by 18 years; laboratory abnormalities suggestive of an inborn error of metabolism; autism spectrum disorder; neuropsychiatric condition; hypotonia or hypertonia in infancy; dystonia/ataxia/hemiplegia/neuromuscular or other movement disorder; unexplained developmental regression (not due to autism or epilepsy); growth abnormality (failure to thrive, short stature, microcephaly, macrocephaly, or overgrowth); persistent and severe immunologic or hematologic disorder; dysmorphic features; consanguinity; or another first‑ or second‑degree family member with similar clinical features

WGS comparator and reanalysis

Additional covered WGS scenarios:

Comparator testing: Comparator (e.g., parents or siblings) WGS is covered when performed concurrently or previously and the initial WGS clinical criteria have been met

Reanalysis of previously obtained WGS is covered after at least 18 months when initial WGS criteria were met and either the individual develops additional unexplained symptoms or new data/family history emerges that suggests a link to specific genes>=18 months

Prenatal WES

Prenatal WES coverage (ALL must be met):

Prior testing: Chromosomal microarray analysis (CMA) and/or karyotyping have been performed but were uninformative

Ordering/consultation: WES is ordered by or in consultation with a medical geneticist or maternal‑fetal medicine specialist (perinatologist)

Sample source: Sample obtained from amniotic fluid and/or chorionic villi, cultured cells from amniotic fluid/CVS, or DNA extracted from fetal blood or tissue

Fetal findings: Fetus has one or more of: multiple congenital anomalies affecting different organ systems; fetal hydrops of unknown etiology; or a congenital anomaly affecting a single organ system with family history that suggests a genetic etiology

Evidence-supported coverage contexts

Evidence-supported scenarios where WES/WGS or rapid sequencing demonstrate diagnostic utility:

Prenatal ES/WES/WGS after abnormal ultrasound: Prenatal sequencing (trio when available) identifies pathogenic/likely pathogenic variants in a proportion of fetuses with ultrasound anomalies and normal CMA; pooled incremental yield over CMA/karyotyping reported (for example, 14% in one cohort and pooled incremental ~31% in meta-analysis).varies by phenotype; pooled incremental yield ~31%

Yield higher with multisystem anomalies and when cases are preselected for monogenic etiology

Prenatal ES/WGS as adjunct or standalone: Some studies report WES/WGS yields higher diagnostic rates than CMA and suggest it may be considered as standalone testing in selected prenatal cases, though further evidence and expert review are recommended.

Authors recommend multidisciplinary review

Reanalysis after nondiagnostic ES: Systematic reanalysis or resequencing of prior ES/WES data yields additional diagnoses (examples range 10%–31%); GS can identify diagnoses not found on prior ES; reanalysis at intervals (e.g., ~18–34 months) or when new knowledge emerges is supported.

Supported indications and evidentiary context

Summary of scenarios where sequencing/testing is supported by evidence or guidelines

Inpatient/critically ill infants/children: rWGS, rWES and urWGS show diagnostic yield and clinical utility in critically ill neonatal and pediatric ICU populations; urWGS yields faster turnaround and higher yield in some studies; consider as first‑tier in ICU setting per trials and meta‑analyses.

Generalizability to outpatient setting is limited

Older children/PICU: Rapid sequencing produced diagnostic yields (~30–50%) in some PICU cohorts and changed management in a subset; evidence limited for older/pediatric ICU populations outside neonatal settings.

Whole transcriptome sequencing: RNAseq may incrementally increase diagnostic yield when combined with WES/WGS for selected undiagnosed cases (e.g., ~15% incremental in a specialized cohort), but evidence is limited and routine clinical utility is not established.

Specialized referral centers primarily

Prenatal sequencing - ISPD recommended indications

ISPD indicates prenatal genome‑wide sequencing may be beneficial in the following situations:

ISPD prenatal indications - current pregnancy: Current pregnancy where fetus has a major single anomaly or multiple organ system anomalies and no genetic diagnosis found after CMA and a genetic expert considers the phenotype suggestive of genetic etiology; CMA should be run before or in parallel with prenatal exome sequencing when multiple anomaly pattern strongly suggests a single‑gene disorder.

ISPD prenatal indications - prior history: Personal history of a prior undiagnosed fetus or child with a major single or multiple anomalies (recurrence in current pregnancy) when prior karyotype or CMA was nondiagnostic; consider parental sequencing for shared autosomal recessive carrier status if proband sample unavailable; tissue from previously affected fetus/child preferable.

ISPD exceptional cases: In special circumstances (strong family history of recurrent childhood‑onset severe genetic conditions), testing may be considered after multidisciplinary expert review, preferably in research context.

Genetic testing for unexplained epilepsy

Guidance for consideration of WGS/ES in individuals with unexplained epilepsy:

Age-based criteria: Onset of epilepsy before 2 years of age, or 2–3 years if a specialty multidisciplinary team recommends testing

NICE guidance

Phenotype-based criteria: Clinical features suggesting a specific genetic epilepsy syndrome (e.g., Dravet) or features such as learning disability, ASD, structural abnormality, or unexplained cognitive decline

NICE guidance

Testing approach: Genetic testing with ES/GS and/or multigene panels (>25 genes) is strongly recommended as first‑tier for unexplained epilepsy, followed by chromosomal microarray; ES/GS conditionally recommended over multigene panel—testing should be selected, ordered and interpreted by a qualified provider with appropriate pre/post‑test counseling

NSGC recommendation

WES/WGS and related modalities are considered unproven and not medically necessary for several uses identified in the policy excerpt. Examples specifically listed include evaluation of fetal demise, prenatal testing via cell-free fetal DNA (cfDNA), and preimplantation genetic testing (PGT) of embryos. The policy also states these technologies are not supported when applied outside the stated clinical criteria (i.e., for screening or evaluation when the coverage criteria are not met) and for outpatient rapid/ultra-rapid sequencing applications unless the clinical scenarios described in the policy (e.g., critically ill inpatient infants) are present.

Administrative note: several procedure codes in the policy's applicable code lists are marked with an asterisk indicating they are not on the State of Louisiana Medicaid Fee Schedule. These starred codes therefore may not be covered by the State of Louisiana Medicaid Program; providers should confirm state fee-schedule coverage and any prior authorization requirements before billing.

Meta-analyses cited in the evidence summary have methodologic limitations that affect generalizability. Limitations include heterogeneous study methods, variable sample and data collection approaches, inconsistent use of ACMG variant classification across studies, and geographic gaps (no studies from Africa, India, or Latin America were included), all of which may reduce applicability of pooled estimates to a global population.

The policy supports use of rapid and ultra-rapid sequencing only in critically ill infants in inpatient/ICU settings and explicitly notes that the use of rapid/ultra-rapid WES/WGS in outpatient settings is not supported. Ordering outpatient rapid sequencing may therefore be considered unsupported or not medically necessary.

Whole transcriptome sequencing (RNAseq) and whole genome optical mapping (OGM) are described as having insufficient evidence for routine clinical diagnostic use. The policy states these modalities are considered unproven and not medically necessary for indications covered by this excerpt until further validation and clinical utility data are available.

Per the ISPD position referenced in the policy, routine sequencing of fetal tissues obtained from invasive prenatal procedures (amniocentesis or chorionic villus sampling) is not supported when no fetal anomalies are present. For fetal tissue testing to be considered, the fetus must have anomalies or other qualifying indications per ISPD guidance.

This policy excerpt provides clinical guidance and evidence summaries but does not itself override federal, state, or contractual benefit plan terms. Coverage determinations remain subject to the member's applicable benefit plan; in the event of a conflict, federal, state, or contractual requirements govern.

Summary: outpatient rapid WES/WGS (rWES/rWGS/urWGS), whole transcriptome sequencing (RNAseq), and whole genome optical mapping (OGM) are considered investigational or not supported for routine outpatient diagnostic use in this policy excerpt. Rapid/ultra-rapid sequencing retains demonstrated utility in inpatient critically ill neonatal/pediatric settings only; RNAseq and OGM lack sufficient evidence for routine clinical implementation.

WES/WGS are not indicated for screening healthy children. Professional guidance cited in the policy emphasizes that genomic sequencing should be targeted to individuals with clinical indications rather than used for population screening of asymptomatic children.

The ISPD position referenced states that prenatal genome-wide sequencing is not supported in the absence of fetal structural anomalies. Prenatal exome/genome sequencing should be reserved for pregnancies with major anomalies, multiple organ system anomalies, or recurrent undiagnosed anomalies, and CMA/karyotype considerations apply as outlined by ISPD.

The excerpt does not contain explicit, standalone nomenclature declaring particular tests universally 'not medically necessary' beyond the evidence-based exclusions and investigational statements it lists; final coverage and formal exclusion language are determined by the member's benefit plan and applicable federal/state contractual terms.

Covered Indications and Clinical Contexts

Core diagnostic criteria

Diagnosing or evaluating a suspected genetic disorder when results are expected to directly influence medical management and clinical outcomes; coverage requires specified clinical criteria:

Core diagnostic requirement: Results are expected to directly influence medical management and clinical outcomes

Nonspecific presentation: Clinical presentation is nonspecific and does not fit a well‑defined syndrome for which targeted testing is available; if a specific syndrome is suspected, perform single gene or targeted panel testing first

Ordering provider: Test must be ordered by a medical geneticist, neonatologist, neurologist, immunologist, or developmental pediatrician

Supporting clinical features:

Eligibility Requirements and Preconditions

Family history of similar features in first- or second-degree relatives can satisfy or contribute to the clinical feature requirements for coverage when assessing eligibility. In prenatal contexts, a family history of a prior undiagnosed affected fetus or child or recurrent anomalies strengthens consideration for sequencing and may justify parental or targeted testing per ISPD guidance.

As noted elsewhere in the policy, a documented family history of similar clinical features may count toward meeting the clinical feature thresholds for coverage. For prenatal indications, family history of a previously affected fetus or child supports consideration of prenatal sequencing where indicated.

Family history can be leveraged to meet feature-based eligibility criteria for WES/WGS. In prenatal scenarios, recurrence of similar anomalies or an affected prior pregnancy increases the rationale for sequencing and for parental testing when a proband sample is unavailable.

For WGS coverage, the policy specifies that either neither CMA nor WES has been performed or that those tests were nondiagnostic before proceeding to WGS. For prenatal WES, chromosome microarray (CMA) and/or karyotype should have been performed and found uninformative prior to prenatal exome sequencing, consistent with ISPD recommendations.

WGS should generally follow a prior nondiagnostic evaluation (including CMA or WES) or be justified as first-tier per the clinical scenario; prenatal WES requires prior or concurrent CMA/karyotype as indicated by ISPD and the policy's prenatal criteria.

Restating prior-testing expectations: for WGS coverage the policy requires that CMA and WES have not already produced a diagnosis (or were not previously performed), and for prenatal exome sequencing CMA and/or karyotype should be performed prior to or in parallel with pES when indicated.

Applicable Procedure and CPT/HCPCS Codes

Applicable procedure codes (reference list)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, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, proband.
0213U	Rare diseases (constitutional/heritable disorders), whole genome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, each comparator genome (e.g., parent, sibling).
0214U	Rare diseases (constitutional/heritable disorders), whole exome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, proband.
0215U	Rare diseases (constitutional/heritable disorders), whole exome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, each comparator exome (e.g., parent, sibling).
0260U	Rare diseases (constitutional/heritable disorders), identification of copy number variations, inversions, insertions, translocations, and other structural variants by optical genome mapping.
0264U	Inversions, insertions, translocations, and other structural variants by optical genome mapping.
0265U	Rare constitutional and other heritable disorders, whole genome and mitochondrial DNA sequence analysis, blood, frozen and formalin-fixed paraffin-embedded (FFPE) tissue, saliva, buccal swabs or cell lines, identification of single nucleotide and copy number variants.
0266U	Unexplained constitutional or other heritable disorders or syndromes, tissue-specific gene expression by whole-transcriptome and next-generation sequencing, blood, formalin-fixed paraffin- embedded (FFPE) tissue or fresh frozen tissue, reported as presence or absence of splicing or expression change.
0267U	Rare constitutional and other heritable disorders, identification of copy number variations, inversions, insertions, translocations, and other structural variants by optical genome mapping and whole genome sequencing.

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Applicable proprietary and CPT codes (OGM, WGS, WES-related)mixed

0454U	Rare diseases (constitutional/heritable disorders), identification of copy number variations, inversions, insertions, translocations, and other structural variants by optical genome mapping.
0469U	Rare diseases (constitutional/heritable disorders), whole genome sequence analysis for chromosomal abnormalities, copy number variants, duplications/deletions, inversions, UPD, aneuploidy; fetal sample; identification and categorization of genetic variants; diagnostic report based on phenotype with maternal/paternal comparators.
0532U	Rare diseases (constitutional/hereditary disorders), rapid whole genome and mitochondrial DNA sequencing for SNVs, indels, CNVs; various sample types; results reported positive or negative.
0567U	Rare diseases (constitutional/heritable disorders), whole-genome sequence analysis combination of short and long reads for SNVs, indels, intronic variants, CNVs, mobile element insertions, ROH, aneuploidy, inversions, mitochondrial DNA, STR genes, methylation of selected regions.
81354	Cytogenomic (genome-wide) analysis for constitutional chromosomal abnormalities; interrogation of structural and copy number variants, optical genome mapping (OGM).

Covered CPT Codes for exome and genome sequencingCPTCovered

81415	Exome (e.g., unexplained constitutional or heritable disorder or syndrome); sequence analysis.
81416	Exome; sequence analysis, each comparator exome (e.g., parents, siblings).
81417	Exome; re-evaluation of previously obtained exome sequence.
81425	Genome (e.g., unexplained constitutional or heritable disorder or syndrome); sequence analysis.
81426	Genome; sequence analysis, each comparator genome (e.g., parents, siblings).
81427	Genome; re-evaluation of previously obtained genome sequence.

Applicable CPT Codes (updates)CPT

81354

CPT code added (as listed in policy history)

WES/WGS reanalysis interval

Reanalysis interval>= 18 months from initial WES/WGS

Triggering conditions for reanalysisIndividual develops new unexplained symptoms after initial testing or new data/family history emerges linking phenotype to specific genes

Applies when initial criteria metReanalysis permitted when initial WES/WGS coverage criteria were satisfied at time of original test

Comparator testing noteComparator (parents or siblings) testing may be performed concurrently or previously and does not change reanalysis interval requirement

Provider Actions, Documentation & Prior Authorization

Billing Rule

Applicable codes listed and state-specific coverage note

Applicable CPT/HCPCS and proprietary codes related to WES, WGS, rapid sequencing, OGM, and related procedures are listed for reference. Inclusion of a code does not guarantee coverage under a member's benefit plan; verify benefit plan terms. Codes marked with an asterisk (*) are not on the State of Louisiana Medicaid Fee Schedule and may not be covered by Louisiana Medicaid.

Reference code lists are for billing/administrative use only; inclusion is not an admission of coverage.
Codes with * may not be covered by Louisiana Medicaid — check state fee schedule.

Documentation Required

Genetic counseling and consent documentation required

Genetic counseling is required before and after genetic testing and informed consent must be documented. Counseling must include a structured family genetic history, genetic risk assessment, and counseling about diagnosis, prognosis, and treatment. Documentation of counseling and informed consent should be present in the medical record prior to testing.

Not Covered / Investigational

Not covered/Investigator findings summary: the policy identifies evaluation of fetal demise, prenatal cfDNA testing, preimplantation genetic testing, outpatient rapid/ultra-rapid sequencing, whole transcriptome sequencing (RNAseq), and whole genome optical mapping (OGM) as uses that are unproven or not medically necessary in the contexts described. Providers should reference benefit plan terms and state fee-schedule details for definitive coverage decisions.

Certain procedure codes in the applicable code lists are administratively excluded from Louisiana Medicaid coverage because they are not included on the State of Louisiana Medicaid Fee Schedule (these are indicated with an asterisk in the policy). This is an administrative limitation separate from the clinical coverage stance and may affect claims payment.

The policy's evidence review highlights methodological limitations in some meta-analyses, including heterogeneous methods and lack of standardized variant classification. These limitations may affect interpretation of pooled diagnostic yield estimates and should be considered when applying results to clinical decision-making.

The evidence presented does not support outpatient use of rapid or ultra-rapid genomic sequencing; such rapid sequencing approaches are supported only for critically ill inpatients and may be denied if requested for outpatient management.

Whole transcriptome sequencing and whole genome optical mapping are described as investigational with insufficient evidence to support routine clinical diagnostic use across indications; these tests are therefore not supported for routine coverage in this policy excerpt.

Per ISPD guidance cited in the policy, routine prenatal sequencing of fetal tissues obtained via invasive procedures is not supported in the absence of fetal anomalies; ordering such tests without qualifying anomalies may lead to non-coverage.

Background and Definitions

Background: Whole Exome Sequencing (WES) targets the protein-coding exons, which represent approximately 1% of the genome, whereas Whole Genome Sequencing (WGS) sequences the entire genome including coding and noncoding regions. These tests are intended for diagnosing constitutional/heritable disorders when results are expected to directly influence medical management; rapid sequencing and other emergent modalities are limited to specific settings per the policy.

Revision History & Policy Changes

2026-02-01administrative_updateLatest

Updated applicable CPT code list to reflect annual edits and added CPT 81354; previous policy version CS150LA.N was archived (superseded).

Note

Policy Summary

PayerUnitedHealthcare

PolicyWhole Exome and Whole Genome Sequencing (Non‑Oncology) — Louisiana

Policy CodePolicy CS150LA.O

Change TypeAdministrative code update

Effective Date02/01/2026

Next Review DateN/A

Key ActionDocument genetic counseling (pre- and post-test), include structured family history and ordering specialist when submitting for coverage.

SourceLink

On This Page

Reanalysis methods include updated pipelines, CNV calling, additional sequencing, trio testing

Rapid/ultra‑rapid sequencing in critically ill infants: Rapid and ultra‑rapid genomic sequencing have diagnostic and clinical utility for critically ill infants in inpatient settings, with pooled diagnostic rates and demonstrated management impact; outpatient rapid/ultra‑rapid sequencing is not supported.

urWGS may yield higher diagnostic percent and shorter turnaround time

Whole genome optical mapping: OGM shows proof‑of‑principle concordance with standard cytogenetics for certain structural variants but insufficient evidence exists to support broad clinical use at this time.

Further validation required

Prenatal sequencing: Professional societies (ISPD, ACOG) advise against routine prenatal exome/genome sequencing in absence of fetal anomalies; consider pES/pGS when fetus has major anomalies and prior testing (CMA/karyotype) is negative or phenotype suggests single‑gene disorder; CMA recommended before or in parallel when indicated.

Multidisciplinary expert review recommended

Hearing loss: ACMG advises genetics evaluation and, if no known syndrome, a tiered testing approach (hearing loss panel then ES/GS if negative); ordering providers should understand panel gene content and performance.

Clinical history strongly suggests a genetic cause; supporting indications with evidence of diagnostic yield include: global developmental delay/intellectual disability, multiple congenital anomalies, neurodevelopmental disorders, cerebral palsy, rare undiagnosed diseases, and critically ill infants in ICU—see evidence summaries for yield estimates by indication

Prenatal WES for fetus with congenital anomalies or fetal hydrops when CMA/karyotype uninformative and ordered by/consult with genetics or MFM

Prenatal WES is covered when ALL of the following are met:

Prior testing: Chromosomal microarray analysis (CMA) and/or karyotype have been performed and were uninformative

Specialist ordering/consultation: WES is ordered by or in consultation with a medical geneticist or maternal‑fetal medicine specialist

Appropriate fetal sample: Sample obtained from amniotic fluid and/or chorionic villi, cultured cells from amniotic fluid/CVS, or DNA from fetal blood or tissue

Fetal anomalies or hydrops: Fetus has one or more of: multiple congenital anomalies affecting different organ systems; fetal hydrops of unknown etiology; or a congenital anomaly affecting a single organ system with family history suggesting genetic etiology

Evaluation of rare genetic disorders, GDD, ID, NDD, ASD, epilepsy, short stature, cerebral palsy, and fetal structural anomalies when genetic etiology suspected

Evaluation of the following clinical presentations when a genetic etiology is suspected:

Neurodevelopmental disorders and developmental delay: Global developmental delay (GDD), intellectual disability (ID), autism spectrum disorder (ASD) — evidence shows higher diagnostic yield for ES/GS compared with CMA and supports ES/GS utility

See Srivastava et al. meta-analysis and cohort studies

Rare genetic disorders and undiagnosed disease: Undiagnosed individuals with suspected rare monogenic disease—GS and reanalysis can yield additional diagnoses after prior nondiagnostic testing

Multisystem congenital anomalies and fetal structural anomalies: Fetuses or children with multiple congenital anomalies or structural anomalies on ultrasound—ES/GS increases diagnostic yield over CMA

Short stature, cerebral palsy, and other selected phenotypes: Selected indications such as short stature and cerebral palsy have demonstrated diagnostic yields supporting consideration of ES/GS in evaluation when genetic cause suspected

Suspected genetic etiology contexts — fetal anomalies, NDD, cerebral palsy, critically ill infants, undiagnosed rare diseases

Suspected genetic‑etiology contexts supported by evidence:

Fetal anomalies and prenatal suspicion: Fetuses with structural anomalies on ultrasound, especially multisystem anomalies, when CMA/karyotype are uninformative—prenatal ES/WGS demonstrates incremental diagnostic yield

Neurodevelopmental disorders and cerebral palsy: Individuals with NDD/GDD/ID or cerebral palsy of suspected genetic origin—ES/GS shows substantial diagnostic yield (meta‑analyses and cohort studies) and may alter management

Critically ill infants and undiagnosed rare diseases: Critically ill infants in ICU with suspected genetic disease and undiagnosed rare disease cases—rapid and ultra‑rapid sequencing demonstrate diagnostic and clinical utility in inpatient settings

Fetuses with structural anomalies on ultrasound and normal CMA/karyotype — consider ES/WGS

Fetuses with structural anomalies on ultrasound and normal CMA/karyotype:

Incremental diagnostic yield: Multiple studies and meta‑analyses report incremental diagnostic yield of ES/WGS in fetuses with structural anomalies after normal CMA/karyotype; pooled incremental yield of ES over CMA reported ~31% with variation by phenotypepooled incremental yield ~31% (varies by phenotype)

Yield higher for multisystem anomalies and preselected cases

Testing considerations: Trio testing when available increases diagnostic yield; expert multidisciplinary review and targeted gene set/exome analysis recommended for interpretation

Critically ill infants in inpatient/ICU settings — rapid and ultra-rapid sequencing supported

Critically ill infants in inpatient/ICU settings — rapid/ultra‑rapid sequencing:

Setting requirement: Rapid and ultra‑rapid genomic sequencing (rWES, rWGS, urWGS) are supported for critically ill infants in inpatient/ICU settings only; outpatient rapid/ultra‑rapid sequencing is not supported

Evidence of utility: Systematic reviews and randomized/controlled trials report pooled diagnostic yields and management impact (diagnostic yields and perceived clinical utility range from ~37% to >70% in some urWGS cohorts), supporting use in ICU when rapid results affect immediate management

Undiagnosed individuals after prior nondiagnostic genetic testing — reanalysis or GS utility

Undiagnosed individuals after prior nondiagnostic genetic testing:

Reanalysis and GS utility: Reanalysis of prior ES/WES or performance of GS can yield additional diagnoses after prior nondiagnostic testing; studies report diagnostic gains from reanalysis and GS in selected cohorts

Reanalysis often fruitful after ~18 months or when new knowledge emerges

When to consider GS: GS may be considered when prior ES/WES/CMA were nondiagnostic or when detection of CNVs, noncoding variants, or structural variants is suspected; GS can be first‑tier in some rare disease contexts but is not universally required

Critically ill infants and children in ICU/PICU with disease of unknown etiology

Critically ill infants and children in ICU/PICU with unknown etiology — sequencing implications:

Diagnostic yield and utility: Multiple studies report meaningful diagnostic yield and clinical utility for rWGS/rWES/urWGS in ICU/PICU settings; urWGS particularly useful when ultra‑rapid turnaround affects immediate management

Implementation note: Trio testing and rapid comparator analysis may increase yield; specialized clinical genetics involvement is recommended for interpretation and downstream management

Individuals with early-onset epilepsy without known cause (per NICE) — consider WGS/ES

Individuals with early‑onset epilepsy without known cause (per NICE):

Age and phenotype considerations: Consider WGS/ES for onset <2 years of age, or 2–3 years if recommended by a specialty multidisciplinary team; evaluate features suggesting genetic epilepsy

NICE guidance

Testing recommendations: Genetic testing with ES/GS and/or multigene panels (>25 genes) is recommended as first‑tier for unexplained epilepsy, followed by chromosomal microarray; testing should be ordered and interpreted by qualified providers with genetic counseling

NSGC and NICE recommendations

Prenatal cases with major fetal anomalies or recurrent undiagnosed anomaly when CMA/karyotype negative or phenotype suggests single-gene disorder

Prenatal cases with major fetal anomalies or recurrent undiagnosed anomaly where CMA/karyotype negative or phenotype suggests single‑gene disorder:

ISPD-supported prenatal scenarios: Consider prenatal exome/genome sequencing for current pregnancy with a major single anomaly or multiple organ system anomalies, or for recurrence/prior undiagnosed affected fetus/child when CMA/karyotype is nondiagnostic; CMA should be performed before or in parallel when indicated and expert review recommended when CMA is nondiagnostic

ISPD 2022 position statement

Prenatal exome/genome sequencing for current pregnancy with major single anomaly or multiple organ system anomalies, or for recurrence when CMA/karyotype nondiagnostic

Prenatal exome/genome sequencing considerations:

Current pregnancy indications: Prenatal ES/GS may be considered when fetus has a major single anomaly or multiple organ system anomalies, especially when CMA is negative and phenotype suggests monogenic disease

CMA before or in parallel when multiple anomaly pattern suggests single‑gene disorder

Recurrence or prior undiagnosed case: Consider pES/pGS for recurrence or prior undiagnosed affected fetus/child; expert review and appropriate sample selection (preferably tissue from previously affected fetus/child) recommended

ES/GS and/or multigene panels (>25 genes) for unexplained epilepsy

ES/GS and/or multigene panels for unexplained epilepsy:

Testing options: ES/GS and multigene panels (>25 genes) are acceptable testing strategies for unexplained epilepsy; NSGC strongly recommends these as first‑tier testing with CMA to follow

Testing should be ordered and interpreted by a qualified provider with pre/post‑test counseling

When to use panels vs ES/GS: Multigene panels may be used first if phenotype suggests a limited gene set; ES/GS preferred when panel is unrevealing or phenotype is broad

NSGC guidance

References supporting clinical utility of exome/genome sequencing

References supporting clinical utility of exome/genome sequencing across multiple settings are cited; notable examples include:

Rare disease and neurometabolic management: Exome sequencing has been shown to inform management of neurometabolic disorders and rare diseases (e.g., Tarailo‑Graovac et al., 2016; Wojcik et al., 2024)

Rapid sequencing evidence: Systematic reviews and trials support use of rapid/ultra‑rapid sequencing in critically ill infants with demonstrated diagnostic yield and management impact (e.g., Xiao et al., 2022; NSIGHT studies)

Prior testing prerequisites: WGS is generally considered after nondiagnostic CMA/WES unless clinical circumstances support first-line WGS; for prenatal WES, CMA/karyotype is expected before or concurrently when indicated by fetal phenotype.

Documented pre-test genetic counseling including family history and risk assessment is required.
Documented post-test counseling and explanation of results should be included in the record.

Prior Authorization

Prior authorization and setting-based limitation for rapid sequencing

Rapid (rWES/rWGS) and ultra-rapid (urWGS) sequencing are supported only for critically ill infants in an inpatient setting. Prior authorization may be required per the member's benefit plan and state Medicaid rules; outpatient use of rapid/ultra-rapid sequencing is not supported.

Rapid/ultra-rapid sequencing: inpatient, critically ill infants only — outpatient use not supported.
Check benefit plan and obtain prior authorization when required; state rules may vary.

Note

Prior/parallel testing expectations for prenatal sequencing (CMA/karyotype)

When considering prenatal exome/genome sequencing (pES/pGS), chromosomal microarray (CMA) and karyotype should have been performed and been nondiagnostic, or CMA should be performed before or in parallel with prenatal exome sequencing when indicated by phenotype. ISPD guidance supports genome-wide prenatal sequencing only when fetal anomalies are present and after appropriate prior testing.

CMA and/or karyotype should be performed prior to or in parallel with prenatal exome sequencing when fetal anomalies are present.
Prenatal exome/genome sequencing is not recommended in the absence of fetal anomalies.

Prior Authorization

Check benefit plan for prior authorization and coverage requirements

Ordering providers must check the member's applicable benefit plan, federal/state, or contractual requirements for prior authorization and coverage. Plan-specific terms govern when there is a conflict between this policy and the member's benefit plan.

Benefit plan terms and state Medicaid rules may impose additional prior authorization or coverage conditions.
In the event of conflict, federal/state/contractual requirements govern and may lead to claim denial.

Denial Risk

WES/WGS for indications not meeting criteria — excluded uses

WES and WGS are considered not medically necessary for indications that do not meet clinical criteria in this policy, including evaluation of fetal demise, prenatal testing via cell-free fetal DNA, preimplantation genetic testing (PGT), routine genome-wide sequencing of fetal tissues without anomalies, and rapid/ultra-rapid sequencing in outpatient settings.

Do not order WES/WGS for fetal tissues without anomalies or for routine prenatal screening.
Outpatient rapid/ultra-rapid sequencing is not supported — may be denied.

Denial Risk

Insurance coverage can block testing — verify prior authorization

Insurance coverage limitations can prevent testing. Lack of coverage or failure to obtain required prior authorization may result in tests being declined or denied. Ordering providers and facilities should confirm coverage and obtain necessary approvals prior to testing.

Verify insurance coverage and prior authorization prior to sample submission to avoid denials.
Document attempts to obtain authorization and coverage decisions in the medical record.

Documentation Required

Required documentation and provider responsibilities

Required clinical documentation must accompany orders for WES/WGS. Ordering providers are responsible for providing the individual's phenotype, prior test results, family history, and relevant clinical evaluations. Genetic counseling documentation and informed consent must be included.

Include detailed phenotype, age at onset, clinical features, prior testing (CMA, karyotype, panels), and three-generation pedigree where applicable.
Document genetic counseling, informed consent, and any discussion of potential VUS and reanalysis policies.

Documentation Required

Parental testing and documentation expectations

Parental and comparator testing (trio or family member sequencing) is often necessary to interpret results, reduce variants of uncertain significance, and improve diagnostic yield. Document parental testing when performed or when declined.

Trio testing is recommended when feasible to improve interpretation and diagnostic yield.
If parental/comparator samples are unavailable, document reasons and any alternative interpretive strategies.

Documentation Required

Typical documentation expected with testing

Typical documentation expected with WES/WGS orders includes prior negative or normal tests (e.g., CMA, karyotype, targeted panels), exclusion of maternal cell contamination for prenatal samples, and statement of whether trio testing is planned or performed.

Attach reports of prior CMA, karyotype, targeted gene panels, or other relevant testing.
Document sample source, maternal cell contamination checks for prenatal tissues, and comparator samples used.

Documentation Required

Clinical documentation and specialist involvement expectations

Clinical documentation for specialized indications (e.g., epilepsy, neurodevelopmental disorders, hearing loss) should include age at onset, features suggesting a genetic etiology, multidisciplinary evaluations, and justification for why genome-wide testing is indicated versus targeted testing.

For epilepsy: document onset age, developmental status, dysmorphic features, and prior neurologic workup.
For hearing loss: document comprehensive genetics evaluation and whether syndromic features are present.

Step Therapy

Step testing before WES/WGS and when to escalate testing

When a specific genetic syndrome is suspected, perform single-gene testing or a targeted gene panel before WES/WGS. A tiered testing approach is appropriate in many settings; escalate to WES or WGS when targeted testing is negative or when broader detection (CNVs, non-coding variants) is needed.

Order single-gene or targeted MGP testing first if clinical presentation fits a well-defined syndrome.
Escalate to WGS when prior WES or targeted testing is negative and broader variant detection is needed.

Note

Typical testing sequence and recommended sequencing escalation

Typical testing sequences: many studies performed WES or WGS after CMA was negative; some guidelines and evidence support WES/WGS as first- or second-tier testing depending on phenotype (e.g., NDD, DD/ID). Use clinical judgment and guideline recommendations to select sequencing order.

For unexplained NDD/DD/ID, ES/GS may be considered first-tier per some professional guidance; CMA may be included depending on clinical context.
For prenatal anomalies, CMA/karyotype typically precede or run in parallel with pES.

Denial Risk

Conflict with plan terms may cause denial — verify and document

When conflicts exist between this medical policy and a member's federal, state, or contractual benefit plan terms, the benefit plan terms control and may result in denial even if policy criteria are met. Always verify and document plan-specific requirements.

Document verification of plan-specific requirements and any obtained authorizations.
Be aware that state Medicaid rules may impose different coverage or coding limitations.

Note

No additional explicit prior-authorization steps specified in this excerpt — follow plan rules

No explicit provider pre- or post-test counseling procedural prerequisites (beyond documentation requirements) or specialty-only ordering restrictions are specified in this excerpt; however, ordering providers are expected to be qualified (geneticist, neonatologist, neurologist, immunologist, or developmental pediatrician) for many indications per the policy and to collaborate with genetics professionals as needed.

Although the excerpt does not list formal preauthorization steps beyond checking benefit plan, follow local plan rules and employer/facility procedures.
Ordering provider specialty recommendations should be followed where stated in the policy.

Although the excerpt lists clinical exclusions and investigational statements, it does not itself enumerate a comprehensive set of explicit test exclusions applicable to all benefit plans; providers must consult the member's federal, state, or contractual plan terms to determine definitive coverage.