CurrentCentenePolicy N/A

V1.2024 Concert Genetics Genetic Testing Exome and Genome Sequencing for the Diagnosis of Genetic Disorders

Defines medical necessity criteria, investigational and not-medically-necessary positions for standard, rapid, and reanalysis exome and genome sequencing (including trio and comparator testing) for diagnosing suspected genetic disorders; includes coding implications and clinical considerations. This part is the first of two and includes criteria, notes/definitions, clinical guidance, and references.

Policy Summary

PayerCentene

PolicyV1.2024 Concert Genetics Genetic Testing Exome and Genome Sequencing for the Diagnosis of Genetic Disorders

Policy CodePolicy N/A

Change TypeWording, structural edits; CPT additions/replacements

Effective Date

Next Review Date

Key ActionDocument that pre- and post-test counseling and evaluation by a Medical Geneticist, Genetic Counselor, or APGN occurred and that non-genetic etiologies were considered and ruled out to support medical necessity.

SourceLink

POLICY UPDATE CHANGES

Date of Last Revision recorded as 11/2023 in the header/footer of this part.

Replaced 'coverage criteria' with 'criteria' and updated Overview, coding, reference tables, background and references across the policy.

Added CPT codes 0425U and 0426U to the policy reference table and criteria for Rapid Genome Sequencing.

Removed CPT code 0209U and added 0212U to Standard Genome Sequencing reference table.

Added 'Reanalysis of Whole Exome Sequencing Data' and expanded background and rationale with several literature references (including Rehm et al 2023).

MultipleCovered Indications

Coverage Summary

This policy covers both Exome Sequencing (ES/WES) and Genome Sequencing (GS/WGS). ES targets the protein-coding regions (~1% of the genome) while GS sequences the complete genome including noncoding regions; GS can better detect some large deletions/duplications and may have a higher diagnostic yield when used first-line. Rapid/ultrarapid options accelerate turnaround: rapid ES/GS returns preliminary results in days and is addressed for acutely ill infants, while ultrarapid GS (typically <72 hours) is explicitly noted as investigational. The policy recognizes that ES reanalysis is commonly performed and that an optimal interval for reanalysis is approximately 18 months to 2 years. Overall stance: standard and rapid ES/GS are covered when criteria are met; ultrarapid GS is considered investigational and reanalysis is recommended prior to moving to GS when possible.

Key thresholds and quick facts

Age for acutely-ill infant<= 12 months

WES reanalysis interval>= 18 months (typical; optimal ~18 months–2 years)

Screening asymptomatic individualsInvestigational (not medically necessary)

Medical Necessity Criteria (Standard, Rapid, and Reanalysis)

Standard Genome Sequencing (81425, 81426, 0212U, 0213U, 0265U, 0267U)

Standard genome sequencing is medically necessary when ALL of the following are met:

ALL of the following

A.: Member previously had uninformative whole exome sequencing (WES) OR WES reanalysis is not possible
B. Member meets at least one of
- Unexplained epilepsy diagnosed at any age
- Developmental delay or intellectual disability with onset prior to age 18 years
- Diagnosed with one or more congenital anomalies before the age of 1 year

Not Medically Necessary / Investigational Indications

Examples of scenarios that may result in denial include testing for population screening or asymptomatic/healthy individuals, repeat standard exome sequencing when repeat testing is listed as not medically necessary, and claims for investigational indications. The policy also requires documentation that alternate (non-genetic) etiologies were considered and that single-gene or targeted panel testing is not appropriate; failure to meet these requirements may lead to denial. Note that ultrarapid GS is currently considered investigational.

Coding (CPT / Proprietary Codes)

Standard Exome Sequencing CPTCPTCovered

81415	Exome sequencing, proband or single
81416	Exome sequencing, with parental samples (duo/trio) - typically comparator codes
0214U	Proprietary/annotated exome (example vendor code listed in policy)
0215U	Comparator exome (duo/trio) - example vendor code

Reanalysis of Exome Data CPTCPTCovered

81417

Reanalysis of whole exome sequencing data

Standard Genome Sequencing CPTCPTCovered

81425	Whole genome sequencing, proband or singleton
81426	Whole genome sequencing, with parental samples (duo/trio) / additional analysis
0212U	Proprietary whole genome analysis - example vendor code
0213U	Comparator whole genome analysis - example vendor code
0265U	Proprietary whole genome + optical mapping (example vendor code)
0267U	Proprietary combined whole genome analysis (example vendor code)

Rapid Genome Sequencing CPT/ProprietaryCPTCovered

0094U	Rapid whole genome sequencing (vendor example)
0425U	Rapid comparator genome sequencing (vendor example)
0426U	Ultra-rapid whole genome sequencing (vendor example)

Rapid Exome Sequencing CPTCPTCovered

81415	Used for rapid exome sequencing when criteria met
81416	Used for trio rapid exome sequencing when criteria met

Examples of Other Proprietary/Test Codes referencedmixed

0212U	Standard genome proprietary code (appears in policy examples)
0213U	Standard genome comparator code (appears in policy examples)
0265U	Praxis Combined Whole Genome & Optical Genome Mapping example
0267U	Praxis combined code example

Added/Updated CPT codes for Rapid Genome SequencingCPT

0425U	CPT code added to policy reference table for Rapid Genome Sequencing (no further description provided in document part)
0426U	CPT code added to policy reference table for Rapid Genome Sequencing (no further description provided in document part)

Standard Genome Sequencing CPT code updateCPT

0209U	Removed from policy reference table
0212U	Added to policy reference table for Standard Genome Sequencing

The revision history documents coding updates: removal of 0209U and addition of 0212U to the Standard Genome Sequencing reference table, and addition of 0425U and 0426U to the Rapid Genome Sequencing references. The policy instructs use of the updated codes where applicable.

Provider Actions — Prior Authorization, Documentation & Billing

Prior Authorization

Pre- and post-test counseling and evaluation required

Pre- and post-test counseling and evaluation are required for medical necessity. Counseling and evaluation must be performed by an appropriate provider such as a Medical Geneticist, Genetic Counselor, or an Advanced Practice Nurse in Genetics (APGN).

Documentation Required

Documentation of ruled-out alternate etiologies

Providers must document that alternate (non-genetic) etiologies have been considered and ruled out when possible.

Environmental exposure
Injury
Infection
Isolated prematurity

Background and Clinical Evidence

Exome Sequencing sequences protein-coding regions and captures most heritable disease-causing variants; Genome Sequencing sequences coding and noncoding regions and can detect additional structural variants and some findings not seen on ES. Studies and guidance cited indicate GS may have a modestly higher diagnostic yield than ES in some settings and that ES reanalysis often identifies diagnoses comparable to performing GS after an uninformative ES. Reanalysis practices include periodic case- or variant-level re-evaluation, with an optimal reanalysis interval around 18 months to 2 years. Trio testing is preferred when possible to increase diagnostic yield and reduce false positives. Finally, ultrarapid GS is specifically called out in the background as investigational.

Reference	Summary
ACMG 2021 guideline	Recommends ES/GS as first- or second-tier for congenital anomalies before age 1 and for ID/DD before age 18; supports clinical utility and notes changes in management in >50% of patients (systematic review)
NSGC 2022 (epilepsy)	Recommends offering genetic testing to individuals with unexplained epilepsy at any age and recommends multi-gene/comprehensive testing (ES/GS or panels) as first-tier
Published reanalysis studies	Reanalysis of ES data after >18 months can identify additional diagnoses; WGS yields modest additional diagnoses beyond reanalysis (Tan et al. 2020; Alfares et al. 2018)
VUS rate comparison (Rehm et al 2023)	Analysis across labs showed lower VUS rate for exome/genome sequencing (22.5%) versus multigene panels (32.6%)
Systematic review (Malinowski et al 2020)	Systematic evidence review summarized outcomes from ES/GS in pediatric patients with congenital anomalies or intellectual disability and reported clinical utility, including frequent changes in clinical management

Definitions/glossary:

• Exome Sequencing (ES): Sequencing of all protein-coding regions (exons) of the genome.

• Genome Sequencing (GS): Sequencing of the complete DNA sequence including coding and non-coding regions.

• Trio Testing: Testing of the child and both biological/genetic parents to increase diagnostic yield and reduce false positives.

• Comparator Exome Sequencing: Exome sequencing of a comparator (typically one or both biological parents) used to inform pathogenicity of variants.

• Congenital anomalies: Structural or functional abnormalities usually evident at birth or shortly thereafter, not specific to a well-delineated genetic syndrome.

• Developmental delay: Delay in expected milestones in one or more areas of development for a child's age.

Revision History & Policy Changes

11/2023non-materialLatest

Date of Last Revision recorded as 11/2023 in header/footer of the document (non-material note).

10/2023 - 11/2023material

Replaced phrase 'coverage criteria' with 'criteria' throughout the policy and performed multiple wording and structural edits across Standard Exome, Rapid Exome, Standard Genome, and Rapid Genome sections; clinician qualification wording changed to 'Medical Geneticist (APGN)' and 'Genetic Counselor'.

11/2023material

Policy Revisions and Criteria Changes (detailed list)

Policy Summary

PayerCentene

PolicyV1.2024 Concert Genetics Genetic Testing Exome and Genome Sequencing for the Diagnosis of Genetic Disorders

Policy CodePolicy N/A

Change TypeWording, structural edits; CPT additions/replacements

Effective Date

Next Review Date

SourceLink

On This Page

Etiology most likely genetic based on

Multiple congenital abnormalities affecting unrelated organ systems
OR TWO of the following
- Abnormality of at least one organ system
- Dysmorphic features
- Encephalopathy
- Symptoms of a complex neurodevelopmental disorder (e.g., dystonia, hemiplegia, spasticity/hypertonia, epilepsy, hypotonia)
- Family history strongly suggestive of a genetic etiology, including consanguinity
- Clinical or laboratory findings suggestive of an inborn error of metabolism

Documentation Required

Clinical presentation justification

Providers must document that the clinical presentation does not fit a well-described syndrome for which single-gene or targeted multi-gene panel testing is available and that a diagnosis cannot be made in a timely manner by standard clinical evaluation (excluding invasive procedures such as muscle biopsy).

Documentation Required

Pre- and post-test counseling requirement

The Standard Genome Sequencing criteria explicitly require documentation that pre- and post-test counseling and evaluation were performed by an appropriate provider (Medical Geneticist, Genetic Counselor, or APGN). Providers must document that counseling occurred for WGS requests.

Billing Rule

CPT code usage updates

CPT code usage updates in the policy: CPT codes 0425U and 0426U were added for Rapid Genome Sequencing, and CPT code 0209U was removed and replaced by 0212U in the Standard Genome Sequencing reference table. Use the updated CPTs when filing claims where applicable.

Added: 0425U, 0426U (Rapid Genome Sequencing)
Replaced: 0209U -> 0212U (Standard Genome Sequencing)

Documentation Required

Clinical justification per updated criteria

The revised criteria added and clarified multiple indication elements; providers must document clinical justification per the updated criteria, including that the clinical presentation is unexplained and that results are predicted to impact management.