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CurrentBlue Cross Blue Shield - NebraskaPolicy M.78

MA Specialty Testing: Multisystem Genetic Conditions

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Policy governing coverage criteria for broad and targeted genomic tests used to diagnose suspected multisystem genetic disorders for Blue Cross Blue Shield - Nebraska members.

Policy Summary

PayerBlue Cross Blue Shield - Nebraska

PolicyMA Specialty Testing: Multisystem Genetic Conditions

Policy CodePolicy M.78

Change TypeAnnual review — no material changes

Effective DateMay 1, 2026

Next Review DateJan 1, 2027

Key ActionObtain prior authorization and document genetics evaluation and required clinical criteria when requesting coverage for exome/genome or targeted genomic tests.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

Standard EScoverage of standard exome sequencing with trio preference

≥1 yearreanalysis timing requirement for exome/genome data

CMA recommendedCMA first‑tier for DD/ID/ASD

Not coveredASD/ID multigene panels

24%rapid sequencing diagnostic yield (NSIGHT2)

Coverage Criteria — Genomic and Related Testing

Standard Exome Sequencing

Covered when ALL of the following are met:

Standard Exome Coverage Criteria: A. The member has not previously had genome sequencing; B. Alternate etiologies have been considered and ruled out when possible (e.g., environmental exposure, injury, infection, isolated prematurity); C. Clinical presentation does not fit a well-described syndrome for which single-gene or targeted multigene panel testing is available; D. The member’s personal and family histories have been evaluated by a Medical Geneticist, Genetic Counselor or an Advanced Practice Nurse in Genetics (APGN); E. The member meets at least one of the following clinical findings: (1) unexplained epilepsy at any age OR (2) global developmental delay or intellectual disability with onset prior to age 18 years OR (3) at least one congenital anomaly (functional and/or structural) OR (4) at least TWO of: (a) bilateral sensorineural hearing loss of unknown etiology, (b) symptoms of a complex neurological disorder (e.g., dystonia, hemiplegia, spasticity, epilepsy, myopathy, muscular dystrophy), (c) family history suggestive of a genetic etiology including consanguinity, (d) clinical or laboratory findings suggestive of an inborn error of metabolism, (e) autism, (f) severe neuropsychiatric condition (e.g., schizophrenia, bipolar disorder, Tourette syndrome, self-injurious behavior, reverse sleep-wake cycles), (g) period of unexplained developmental regression unrelated to epilepsy or autism.

Trio testing preferred when possible.

Standard Exome Sequencing (duplicate)

Covered when ALL of the following are met (duplicate entry — same criteria as Standard Exome Sequencing):

Policy Summary

PayerBlue Cross Blue Shield - Nebraska

PolicyMA Specialty Testing: Multisystem Genetic Conditions

Policy CodePolicy M.78

Change TypeAnnual review — no material changes

Effective DateMay 1, 2026

Next Review DateJan 1, 2027

Key ActionObtain prior authorization and document genetics evaluation and required clinical criteria when requesting coverage for exome/genome or targeted genomic tests.

SourceLink

On This Page

Standard Exome Coverage Criteria (duplicate): A. The member has not previously had genome sequencing; B. Alternate etiologies have been considered and ruled out when possible (e.g., environmental exposure, injury, infection, isolated prematurity); C. Clinical presentation does not fit a well-described syndrome for which single-gene or targeted multigene panel testing is available; D. The member’s personal and family histories have been evaluated by a Medical Geneticist, Genetic Counselor or an Advanced Practice Nurse in Genetics (APGN); E. The member meets at least one of the following clinical findings: (1) unexplained epilepsy at any age OR (2) global developmental delay or intellectual disability with onset prior to age 18 years OR (3) at least one congenital anomaly (functional and/or structural) OR (4) at least TWO of: (a) bilateral sensorineural hearing loss of unknown etiology, (b) symptoms of a complex neurological disorder (e.g., dystonia, hemiplegia, spasticity, epilepsy, myopathy, muscular dystrophy), (c) family history suggestive of a genetic etiology including consanguinity, (d) clinical or laboratory findings suggestive of an inborn error of metabolism, (e) autism, (f) severe neuropsychiatric condition (e.g., schizophrenia, bipolar disorder, Tourette syndrome, self-injurious behavior, reverse sleep-wake cycles), (g) period of unexplained developmental regression unrelated to epilepsy or autism.

Trio testing preferred when possible.

Standard ES/GS coverage rationale

Guideline- and evidence-based rationale for ES/GS coverage and examples of appropriate presentations:

Guideline-based indications: ES or GS is recommended as a first- or second-tier test for pediatric patients with one or more congenital anomalies prior to one year of age, or for patients with intellectual disability/developmental delay with onset prior to 18 years (ACMG).

ACMG 2021 guideline statements support ES/GS as first- or second-tier.

PLUGS-supported presentations: Coverage is supported when clinical presentation does not fit a well-described syndrome after evaluation and specific features are present such as epilepsy, bilateral sensorineural hearing loss, moderate to severe intellectual disability, global developmental delay, or multiple congenital anomalies; or when combinations of personal and family history features (neuropsychiatric, metabolic, single-organ abnormalities) are present (PLUGS 2023).

Rule out alternate etiologies prior to testing when possible.

PLUGS/Panel criteria for ES/GS

Coverage for ES/GS when presentation does not fit a well-described syndrome and other conditions are met:

PLUGS/Panel criteria for ES/GS: Clinical presentation does not fit a well-described syndrome for which targeted testing is available; etiology remains unknown after clinical and radiologic evaluation; AND the patient has either specific features (e.g., epilepsy, bilateral sensorineural hearing loss, moderate to severe ID, global developmental delay, multiple congenital anomalies) OR a combination of personal/family history features (neuropsychiatric, metabolic, single organ abnormalities).

PLUGS genomic sequencing guidance (2023).

Reanalysis of Exome or Genome Sequencing Data

Reanalysis may be considered reasonable and necessary when ANY of the following are met:

Reanalysis Indications: A. Prior exome or genome sequencing was performed at least 1 year ago; OR B. The member’s phenotype has expanded to include clinical findings not present at the time of the initial analysis AND results of prior exome or genome sequencing do not explain the new findings.>= 1 year for prior testing

If reanalysis of exome data is not possible, genome sequencing criteria may be used.

Reanalysis of Exome/Genome Sequencing (alternate)

Alternate/complimentary reanalysis criteria phrased as ANY-of:

Reanalysis (alternate phrasing): Prior exome or genome sequencing performed at least 1 year ago; OR member’s phenotype has expanded since initial testing and prior results do not explain new findings; reanalysis appropriate when pipelines/knowledge have advanced to potentially yield new diagnoses.>= 1 year since prior sequencing

Median new diagnosis rate from reanalysis ~15%; consider logistical limits if reanalysis of original data is not possible.

Rapid Exome Sequencing

Rapid exome sequencing (rES) coverage when ALL of the following are met (trio preferred):

Rapid Exome (rES) Criteria: A. The member is an acutely-ill infant (12 months of age or younger); B. The member has not previously had genome sequencing; C. Alternate etiologies have been considered and ruled out when possible; D. Clinical presentation does not fit a well-described syndrome for which rapid single-gene or targeted multigene panel testing is available; E. The member’s personal and family histories have been evaluated by a Medical Geneticist, Genetic Counselor or APGN; AND F. The member meets at least one of: unexplained epilepsy; global developmental delay; at least one congenital anomaly; OR at least TWO of: bilateral sensorineural hearing loss, complex neurological disorder features, suggestive family history including consanguinity, clinical/laboratory findings of inborn error of metabolism, severe neuropsychiatric condition, or unexplained developmental regression.age <= 12 months

Trio testing preferred when possible; rES not reasonable for other indications.

Standard Genome Sequencing

Standard genome sequencing coverage when ALL of the following are met (trio preferred):

Standard Genome Sequencing Criteria: A. Alternate etiologies have been considered and ruled out when possible; B. Clinical presentation does not fit a well-described syndrome for which single-gene or targeted multigene panel testing is available; C. The member’s personal and family histories have been evaluated by a Medical Geneticist, Genetic Counselor or APGN; AND D. The member meets at least one of: previously uninformative exome sequencing with exome reanalysis not possible; unexplained epilepsy at any age; global developmental delay/intellectual disability with onset prior to 18 years; at least one congenital anomaly; OR at least TWO of the listed supportive features (hearing loss, complex neurologic symptoms, suggestive family history, metabolic findings, autism, severe neuropsychiatric condition, unexplained developmental regression).

When genome sequencing is performed, the mitochondrial genome is assumed included.

Rapid Genome Sequencing

Rapid genome sequencing (rGS) coverage when ALL of the following are met (trio preferred):

Rapid Genome Sequencing (rGS) Criteria: A. The member is an acutely-ill infant (12 months of age or younger); B. Alternate etiologies have been considered and ruled out when possible; C. Clinical presentation does not fit a well-described syndrome for which rapid single-gene or targeted panel testing is available; D. The member’s personal and family histories have been evaluated by a Medical Geneticist, Genetic Counselor or APGN; AND E. The member meets at least one of: unexplained epilepsy; multiple congenital anomalies affecting unrelated organ systems; epileptic encephalopathy; OR at least TWO of: organ system abnormality, complex neurological features, suggestive family history including consanguinity, laboratory findings of inborn error of metabolism, or abnormal response to standard therapy.age <= 12 months

Mitochondrial genome is assumed included when genome sequencing is performed; trio testing preferred.

Rapid exome/genome sequencing — critically ill infants

Criteria for rapid sequencing use in critically ill infants in intensive care settings:

Critically ill infants (NICU/PICU/CVICU): Patient is an infant with disease of unknown etiology admitted to an ICU setting (NSIGHT2 trial criteria, age ≤4 months at admission supported for first-tier rapid testing); rapid sequencing is likely to impact immediate management and is more efficient/economical than separate testing approaches.age <= 4 months (NSIGHT2 RCT support)

NSIGHT2 demonstrated ~24% diagnostic yield for rapid exome sequencing in this population.

Rapid sequencing coverage rationale

Context and examples where rapid ES/GS is appropriate:

Rapid sequencing coverage rationale: Rapid ES/GS is covered when the patient is acutely ill with an unknown likely genetic etiology AND rapid sequencing is more efficient and economical than separate single-gene tests or panels (for example, multiple multisystem congenital anomalies, epileptic encephalopathy, or ill infants where diagnosis may impact immediate management).

PLUGS and NSIGHT2 provide rationale and evidence for these indications.

Mitochondrial Genome Sequencing / Nuclear Gene Panel

Mitochondrial testing — ONE of the following qualifies:

Mitochondrial Testing - classic phenotype: Member has a classic maternally inherited mitochondrial syndrome phenotype (examples include LHON, MELAS, MERRF, MIDD, NARP, Kearns-Sayre/CPEO) OR a nuclear DNA mitochondrial disorder phenotype (e.g., MNGIE).

Massively parallel sequencing/NGS of the mtDNA genome preferred; consider tissue other than blood when heteroplasmy suspected.

Mitochondrial Testing - non-specific features: Member has non-specific clinical features suggestive of a primary mitochondrial disorder AND meets ALL additional requirements: (1) clinical findings of at least two listed features (ptosis, ophthalmoplegia, proximal myopathy, exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, diabetes, fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, spasticity, chorea, multiple late pregnancy loss); AND (2) conventional biochemical laboratory studies (plasma or CSF lactic acid, ketone bodies, plasma acylcarnitines, urinary organic acids) and additional indicated diagnostic testing have been completed and are non-diagnostic.

Prefer NGS nuclear gene panels with complete coverage; if panels non-diagnostic consider ES.

Combined Mitochondrial DNA and Exome Sequencing

Combined mtDNA and exome sequencing coverage — BOTH criteria must be met:

Combined mtDNA + Exome: A. The member meets clinical criteria for mitochondrial genome sequencing/deletion/duplication and/or nuclear gene panel testing; AND B. The member meets clinical criteria for Standard Exome Sequencing.

Use when tests cannot be performed or billed separately (e.g., proprietary codes 0214U/0215U).

Comprehensive Connective Tissue Disorders Panel & Related Tests

Connective tissue disorder panels and single-gene testing — condition-specific ALL/ANY/N-of logic:

Comprehensive connective tissue panel: Member meets criteria for at least one of: Marfan syndrome, Loeys-Dietz syndrome, classical Ehlers-Danlos syndrome (cEDS), or vascular Ehlers-Danlos syndrome (vEDS).

Panels not reasonable for isolated hypermobility or hEDS.

FBN1 (Marfan) - ANY of: Aortic root enlargement (Z-score ≥2) or dissection; OR ectopia lentis; OR systemic score ≥7 using listed features.systemic score >= 7; aortic Z-score >=2

Sequence and deletion/duplication analysis of FBN1 appropriate to confirm Marfan syndrome.

Loeys-Dietz - >=2 features: Member meets at least two of: characteristic facial features, bifid uvula/cleft palate, tortuosity of aorta/branches, aortic dilatation/dissection, joint hypermobility, or a first-degree relative with clinical LDS.>=2 features

If both aortic root enlargement and ectopia lentis are present, include or prior test FBN1.

Classic Ehlers-Danlos (cEDS) - ALL: Member has skin hyperextensibility and atrophic scarring; AND meets generalized joint hypermobility OR at least three minor criteria; AND the panel includes at minimum COL5A1 and COL5A2.panel must include COL5A1 and COL5A2

Testing for hEDS is investigational.

COL3A1 (vEDS) - ANY of: Arterial rupture/dissection <40 years; OR spontaneous sigmoid colon perforation without diverticular disease; OR uterine rupture in third trimester without prior C-section; OR carotid‑cavernous fistula without trauma; OR close relative with clinical vEDS; OR at least two minor criteria.>=2 minor criteria or any major

Sequence and deletion/duplication analysis of COL3A1 appropriate.

Chromosomal Microarray Analysis (CMA)

Chromosomal microarray (CMA) coverage — ANY of the following qualifies:

CMA Coverage: Developmental delay and/or intellectual disability (excluding isolated speech/language delay) OR autism spectrum disorder OR multiple congenital anomalies not specific to a well-delineated genetic syndrome OR short stature.

CMA is recommended as a first-tier diagnostic test per AAP and ACMG.

Chromosomal microarray analysis (CMA) / ASD Panel Exclusion

ASD/ID panel exclusion and summary:

ASD/ID Panel Exclusion: Autism spectrum disorder / intellectual disability multigene panel analysis is considered not reasonable and necessary for all indications.

No exceptions stated in this section.

Disorder-specific testing examples and logic

Disorder-specific single-gene or panel testing statements (examples and logic):

SNRPN/UBE3A (Angelman/Prader-Willi): Angelman: member meets both functionally severe developmental delay by 6–12 months AND at least one of severe speech impairment, movement/balance disorder, or characteristic behavior. Prader-Willi: age-specific features described (neonatal hypotonia with poor suck; infant/toddler hypotonia with poor appetite and developmental delay; older child/adolescent hypotonia history plus hyperphagia/obesity and other features). Recommended testing sequence: methylation → deletion analysis → UPD analysis → imprinting defect analysis.

Methylation analysis is primary diagnostic test; additional techniques (FISH/array) to define mechanism.

Beckwith‑Wiedemann / Russell-Silver (NH-CSS): BWS: testing indicated for Tier 1 features (e.g., macroglossia, omphalocele, embryonal tumor, hemihyperplasia, macrosomia >90th/97th centile, hyperinsulinemic hypoglycemia) or Tier 2 features; Russell‑Silver: molecular testing recommended when ≥3 NH‑CSS features (policy notes diagnosis established with ≥4 when molecular confirmation present).BWS: tiered features; SRS: >=3 NH-CSS (molecular confirmation often with >=4)

Molecular assays include methylation and CNV testing at 11p15.5 and CDKN1C sequencing as appropriate.

CHD7 / CHARGE: CHD7 sequencing/deletion-duplication analysis when member has at least two CHARGE clinical features (coloboma, choanal atresia/stenosis, cleft palate, cranial nerve dysfunction, ear malformations, cardiovascular malformations, hypogonadotropic hypogonadism, developmental delay, short stature, characteristic facial/neck/hand features, brain MRI clivus/cerebellar vermis hypoplasia).>=2 features

Perform testing to establish/confirm CHARGE when criteria met.

Noonan / RASopathy panel: Perform multigene panel when member has at least one characteristic feature (characteristic facies, short stature, congenital heart defect, developmental delay, broad/webbed neck, unusual chest shape, widely spaced nipples, cryptorchidism, lentigines, café-au-lait macules). Consider single-gene PTPN11 testing first given ~50% detection before broader panel when appropriate.

Use phenotype-driven testing; panels not covered for unrelated indications.

FMR1 (Fragile X): FMR1 repeat and methylation analysis when: unexplained intellectual disability/developmental delay; male with unexplained ASD; female with ASD plus compatible features or family history; primary ovarian insufficiency; or age ≥50 with progressive intention tremor and cerebellar ataxia of unknown origin.

Repeat and methylation analysis is diagnostic assay.

PIK3CA and TSC testing

PIK3CA and TSC testing indications and tissue considerations:

PIK3CA testing indications: PIK3CA sequencing for individuals with focal/segmental overgrowth or specified brain imaging findings (hemimegalencephaly, focal cortical dysplasia, dysplastic megalencephaly) OR early-childhood onset overgrowth/vascular/lymphatic/cutaneous/digital/kidney/benign tumor features; mosaicism may require testing of multiple tissue types and negative blood does not exclude diagnosis.

Consider multiple tissue sources for mosaic disorders.

TSC1/TSC2 testing indications: TSC1/TSC2 sequencing and/or deletion/duplication when member has at least one major feature or ≥2 minor features of TSC as listed (e.g., angiofibromas, cardiac rhabdomyoma, cortical tubers, hypomelanotic macules, renal angiomyolipomas).

Identification of pathogenic variant sufficient for diagnosis and informs surveillance.

NF1 / NF2 testing

Neurofibromatosis (NF1/NF2) testing criteria:

NF1 testing: NF1 sequencing and/or deletion/duplication may be considered when member has ≥1 diagnostic feature (six or more café-au-lait macules with size criteria; two or more neurofibromas or one plexiform neurofibroma; axillary/inguinal freckling; optic glioma; two or more Lisch nodules; distinctive osseous lesion) OR a biological parent meeting diagnostic criteria.

Genetic testing can confirm diagnosis prior to full clinical criteria in some children; negative test sensitivity ~95%.

NF2 testing: NF2 sequencing and/or deletion/duplication may be considered when member has NF2 pathogenic variant identified in tumor tissue; OR adult with bilateral vestibular schwannomas; OR unilateral vestibular schwannoma plus ≥2 additional features; OR multiple meningiomas with additional criteria; OR child with ≥2 pediatric features listed.

Refer to updated consensus diagnostic criteria for NF2-related schwannomatosis.

Monogenic diabetes panels

Monogenic diabetes (MODY) multigene panel coverage ANY-of:

Monogenic diabetes panel: Multigene panel may be considered when: diabetes diagnosed within first 12 months of life; OR diabetes before age 30 AND at least one of: autoantibody negative OR retained C-peptide; OR diabetes not characteristic of type 1/2 AND family history consistent with autosomal dominant inheritance.

Use panels (codes 81403, 81405, 81406, 81407, 81479) as appropriate.

Other covered multisystem inherited disorders and Covered Procedures

Other covered multisystem inherited disorders and covered procedures list:

Other covered multisystem disorders: Genetic testing may be reasonable and necessary to establish or confirm diagnosis for listed rare multisystem inherited disorders (examples: Alagille, Alport, Branchio-oto-renal, Coffin-Siris, Cornelia de Lange, FGFR2 craniosynostosis syndromes, Holoprosencephaly, Holt-Oram, Incontinentia pigmenti, Joubert, Kabuki, MYH9-related disorders, Proteus, Pseudoxanthoma elasticum, Rubinstein-Taybi, Schwannomatosis, Waardenburg) when clinical features are consistent.

Coverage tied to clinical criteria and policy guidance; specific procedure codes listed in policy code tables.

Reanalysis coverage rationale

Reanalysis coverage rationale and suggested intervals:

Reanalysis rationale: Reanalysis is supported when phenotype changes or new clinical/family history suggests previously unrecognized variants, or when sufficient time has passed (>18 months suggested) to allow new variant data/pipeline improvements that may increase diagnostic yield (median new diagnosis rate ~15%).>18 months suggested interval

If original raw data cannot be reanalyzed due to platform/pipeline changes, genome sequencing criteria may apply.

Mitochondrial genome and nuclear gene testing — strategy

Mitochondrial testing strategy and rationale:

mtDNA testing modalities: Use massively parallel sequencing/NGS of the mitochondrial genome as preferred method and include deletion/duplication and heteroplasmy analysis; consider testing alternative tissues (urine, muscle, fibroblasts) when blood testing is negative and clinical suspicion remains due to heteroplasmy.

Simultaneous mtDNA and nuclear DNA testing appropriate for urgent or phenotypically complex referrals.

Nuclear gene testing approach: When nuclear gene testing is considered for likely primary mitochondrial disease, prefer NGS multigene panels providing complete coverage of known mitochondrial disease genes; if panels are non-diagnostic, consider whole exome sequencing.

Recommendations from Mitochondrial Medicine Society and Mavraki et al.

Connective tissue disorders — testing rationale & thresholds

Connective tissue disorder testing rationale and measurement thresholds:

Marfan syndrome testing rationale: Order FBN1 sequencing and deletion/duplication analysis when proband has aortic root enlargement (Z-score >2.0) or ectopia lentis, or when systemic score ≥7 per listed features; molecular confirmation establishes diagnosis in proband with an FBN1 pathogenic variant plus aortic root enlargement or ectopia lentis.aortic root Z-score >2.0; systemic score >=7

GeneReviews guidance referenced.

cEDS testing rationale: Sequence COL5A1 and COL5A2 first when clinical criteria for classic Ehlers-Danlos syndrome are met (skin hyperextensibility and atrophic scarring plus generalized joint hypermobility or ≥3 minor criteria); >90% of cEDS patients have COL5A1/COL5A2 variants.panel must include COL5A1 and COL5A2

International EDS Consortium/GeneReviews recommendations.

CMA indications and ASD/ID panel exclusion rationale

CMA and ASD/ID panel evidence stance:

CMA first-tier rationale: Chromosomal microarray is recommended as a first-tier diagnostic test in children with global developmental delay/intellectual disability, autism spectrum disorder, or multiple congenital anomalies when causal diagnosis unknown (AAP/ACMG).

CMA not reasonable for isolated speech/language delay.

ASD/ID panels not covered: Autism spectrum disorder / intellectual disability multigene panel analysis is considered not reasonable and necessary for all indications due to insufficient evidence of improved health outcomes.

Concert Evidence Review and policy statement.

Imprinting and overgrowth syndromes — testing strategy

Imprinting and overgrowth syndromes testing logic (Angelman, Prader-Willi, Beckwith-Wiedemann, Russell-Silver):

Angelman/Prader-Willi testing: Perform DNA methylation analysis of 15q11.2-q13 as primary diagnostic test for suspected Angelman or Prader-Willi when age-specific clinical criteria are met; if methylation is abnormal or normal then proceed along recommended sequential testing (deletion analysis, UPD, imprinting center defect) to determine mechanism.

GeneReviews recommended testing sequence: methylation → deletion → UPD → imprinting defect analysis.

Beckwith-Wiedemann / Russell-Silver: For Beckwith-Wiedemann, perform H19/KCNQ1OT1 methylation analysis, 11p15 CNV testing, and CDKN1C sequencing when Tier 1 or Tier 2 clinical findings present. For Russell‑Silver, perform molecular testing when NH‑CSS criteria met (≥3–4 features as specified).BWS: Tier 1/2 features; SRS: >=3 NH-CSS (molecular confirmation often with >=4)

Testing guided by tiered clinical features and GeneReviews guidance.

Disorder‑specific testing criteria (group)

Disorder-specific criteria group (aggregate examples and operational notes):

Disorder-specific testing criteria (aggregate): Perform disorder-targeted sequencing/deletion-duplication or multigene panels when clinical diagnostic criteria or guideline-recommended features are met (examples include BWS tiered features, NH-CSS for SRS, CHD7/CHARGE features, Noonan/RASopathy phenotype with option to test PTPN11 first, FMR1 indications, PROS/PIK3CA features, TSC major/minor features, NF1/NF2 diagnostic features).varies by disorder

Reference GeneReviews, ACMG, and specialty consensus guidance for feature lists and testing pathways.

Covered procedures/panels (codes)

Covered procedures and code-based coverage linkage:

Covered procedures/panels: Coverage applies to listed CPT/HCPCS molecular pathology and genomic sequencing codes (examples include exome/genome sequencing codes, rapid/proprietary CPT-PLA codes, mtDNA and nuclear mitochondrial panels, chromosomal microarray, FMR1 testing, methylation assays, and molecular pathology levels) when provided for members who meet the corresponding clinical criteria in this policy.

Use listed procedure codes for authorization and claims; prior authorization may be required per payer process.

Suspected multisystem genetic disorder — umbrella criteria

Umbrella criteria for suspected multisystem genetic disorder when ES/reanalysis criteria are met:

Suspected multisystem genetic disorder: When the member meets the Standard Exome Sequencing criteria or reanalysis criteria (prior testing ≥1 year or phenotype expansion with prior results non-explanatory), genetic testing for suspected multisystem inherited disorders is supported under this policy (includes epilepsy, GDD/ID, congenital anomalies, complex neurological syndromes, mitochondrial disorders, and other rare constitutional conditions).

Evaluation by genetics professional and documentation required; repeat standard exome/genome sequencing is not reasonable except as specified.

Pediatric population indications

Age- and acuity-specific indications (pediatric emphasis and guideline support):

Pediatric indications: Pediatric patients with congenital anomalies, intellectual disability/developmental delay with onset prior to 18 years, or other multisystem features are supported for ES/GS as first- or second-tier testing (ACMG 2021).onset <18 years for ID/DD; congenital anomalies prior to 1 year supported for ES/GS

PLUGS and AAP/ACMG guidance cited.

Presentation not fitting a well-described syndrome — PLUGS guidance

Guidance when presentation does not fit a well-described syndrome (PLUGS):

Presentation not fitting a well-described syndrome: When clinical evaluation fails to identify a well-described syndrome and etiology remains unknown after appropriate evaluation, ES/GS is supported if the member has specified features (e.g., epilepsy, bilateral sensorineural hearing loss, moderate to severe ID, GDD, multiple congenital anomalies) or combinations of personal/family history features (neuropsychiatric, metabolic, single-organ abnormalities).

PLUGS 2023 guidance supports genomic sequencing in these contexts.

Acutely ill infants in ICU — rapid sequencing context

Acutely ill infants in ICU — rapid testing context and evidence:

Acutely ill infants in ICU: Rapid exome or genome sequencing is appropriate when infants are acutely ill (ICU setting) and a genetic diagnosis could impact immediate management, and when rapid sequencing is more efficient/economical than serial testing; NSIGHT2 RCT supports use in infants ≤4 months with ~24% diagnostic yield.

Reserve rapid sequencing for situations where it changes immediate clinical management and is cost/efficiency justified.

Suspected mitochondrial disease — testing approach

Suspected mitochondrial disease — testing recommendations and tissue considerations:

Suspected mitochondrial disease criteria: For suspected primary mitochondrial disease with multisystem clinical features or suggestive biochemistry, mtDNA sequencing (including heteroplasmy and deletion analysis) and nuclear gene NGS panels providing complete coverage are preferred; document completed conventional biochemical studies and other diagnostic testing that are non-diagnostic before molecular testing and consider alternative tissues when blood testing is negative due to heteroplasmy.

Mitochondrial Medicine Society and Mavraki et al. guidance referenced.

Repeat standard exome sequencing is explicitly identified as not reasonable and necessary except where the policy criteria permit (e.g., when reanalysis or other specific criteria apply). The policy requires that standard exome sequencing be reserved for members who meet the listed clinical criteria (including no prior genome sequencing, evaluation by genetics professionals, and specific clinical findings) and states that routine repeat testing outside those indications may be denied.

The policy identifies multiple tests and circumstances that are not reasonable and necessary when performed outside the specified clinical indications. Examples include routine repeat exome/genome sequencing, rapid sequencing for non‑acute indications, screening of asymptomatic/healthy individuals, use of comprehensive connective tissue panels for isolated hypermobility or hEDS, and autism spectrum disorder/intellectual disability multigene panels, which are considered not covered for any indication.

Coding — CPT, HCPCS, and Molecular Procedure Codes

Proprietary/CPT-PLA and temporary CPT codesCPT-PLACovered

0094U	GENOME RAPID SEQUENCE ANALYSIS
0156U	COPY NUMBER SEQUENCE ANALYSIS
0212U	RARE DS WHL GEN&MITOCHDRL DNA SEQ ALYS PROBAND
0213U	RARE DS WHL GEN&MITOCHDRL DNA SEQ ALYS EA CMPRTR
0214U	RARE DS WHL XOM
0215U	RARE DS WHL XOM
0265U	RARE DO WHL GENOME&MITOCHDRL DNA SEQ ALYS
0417U	RARE DS WHL MITOCHDRL GEN SEQ ALYS 335 NUC GENES
0425U	GENOME RAPID SEQ ANALYSIS EACH COMPARATOR GENOME
0426U	GENOME ULTRA-RAPID SEQUENCE ANALYSIS

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Covered CPT/CPT4 and molecular pathology codesCPTCovered

81185	CACNA1A GENE ANALYSIS FULL GENE SEQUENCE
81228	CYTOGENOM CONST MICROARRAY COPY NUMBER VARIANTS
81229	CYTOGENOM CONST MICROARRAY COPY NUMBER&SNP VAR
81243	FMR1 ANALYSIS EVAL TO DETECT ABNORMAL ALLELES
81244	FMR1 GENE ANALYSIS CHARACTERIZATION OF ALLELES
81302	MECP2 GENE ANALYSIS FULL SEQUENCE
81321	PTEN GENE ANALYSIS FULL SEQUENCE ANALYSIS
81331	SNRPN/UBE3A METHYLATION ANALYSIS
81354	CYTOG ALYS CHRML ABNOR INTEROG CPY NMBR VRNT OGM
81400	MOLECULAR PATHOLOGY PROCEDURE LEVEL 1

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Genomic Sequencing / Panel CodesCPT

81410	AORTIC DYSFUNCTION/DILATION GENOMIC SEQ ANALYSIS
81411	AORTIC DYSFUNCTION/DILATION DUP/DEL ANALYSIS
81415	EXOME SEQUENCE ANALYSIS
81416	EXOME SEQUENCE ANALYSIS EACH COMPARATOR EXOME
81417	EXOME RE-EVAL OF PREVIOUSLY OBTAINED EXOME SEQ
81425	GENOME SEQUENCE ANALYSIS
81426	GENOME SEQUENCE ANALYSIS EACH COMPARATOR GENOME
81427	GENOME RE-EVALUATION OF PREC OBTAINED GENOME SEQ
81440	NUCLEAR MITOCHONDRIAL 100 GENE GENOMIC SEQ
81442	NOONAN SPECTRUM DISORDERS GEN SEQ ANALYS 12 GEN

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Referenced genomic and related CPT/HCPCS codesmixed

81415	Exome sequencing (proband)
81416	Exome sequencing (proband + parent(s))
81417	Reanalysis of exome data
81425	Genome sequencing (proband)
81426	Genome sequencing (proband + parent(s))
81427	Reanalysis of genome data
0212U	Genomic Unity Whole Genome Analysis - Proband (Variantyx, Inc.)
0213U	Genomic Unity Whole Genome Analysis - Comparator
0214U	Genomic Unity Exome PLUS Analysis - Proband
0215U	Genomic Unity Exome PLUS Analysis - Comparator

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Covered — Rapid and comprehensive genomic sequencingmixedCovered

rWES / rWGS	Rapid exome sequencing or rapid genome sequencing (singleton or trio) used in acutely ill infants
Exome/Genome sequencing	Comprehensive genomic testing including exome and genome sequencing

Covered — Mitochondrial testingmixedCovered

mtDNA sequencing / deletion/duplication	Massively parallel sequencing/NGS of the mitochondrial genome and mtDNA deletion/duplication testing
Nuclear gene NGS panels	NGS multigene panels for mitochondrial nuclear genes

Covered — Connective tissue gene testingmixedCovered

FBN1 sequencing / deletion-duplication	Sequencing and deletion/duplication analysis for FBN1 (Marfan)
COL5A1/COL5A2 sequencing	Sequence analysis for classical Ehlers-Danlos syndrome (cEDS)
COL3A1 sequencing / deletion-duplication	Testing for vascular Ehlers-Danlos syndrome (vEDS)

Covered — Imprinting and methylation testingmixedCovered

Methylation analysis (15q11-q13, H19/KCNQ1OT1)	Methylation testing for Angelman, Prader-Willi, Beckwith-Wiedemann syndromes
UPD analysis / FISH / deletion/duplication	Uniparental disomy testing, FISH, and CNV analysis for imprinting disorders

Covered — Chromosomal Microarray (CMA)mixedCovered

CMA (array-based testing)

Chromosomal microarray analysis recommended as first-tier for GDD/ID, ASD, multiple congenital anomalies

Combined test HCPCS / Proprietary CodesHCPCS

0214U	Combined exome and mitochondrial testing (example code referenced in NOTE)
0215U	Combined exome and mitochondrial testing (example code referenced in NOTE)

Monogenic diabetes panel codesCPT

81403	Exome (gene panel) / listed in monogenic diabetes section
81405	Multigene panel (listed in monogenic diabetes section)
81406	Multigene panel (listed in monogenic diabetes section)
81407	Multigene panel (listed in monogenic diabetes section)
81479	Unlisted molecular pathology procedure (used for some gene panels as listed)

Molecular Pathology Level CodesCPT

81406

MOLECULAR PATHOLOGY PROCEDURE LEVEL 7

Molecular Pathology Level CodesCPT

81407

MOLECULAR PATHOLOGY PROCEDURE LEVEL 8

Molecular Pathology Level CodesCPT

81408

MOLECULAR PATHOLOGY PROCEDURE LEVEL 9

Reanalysis interval — recommended interval for reanalysis

Recommended minimum interval for reanalysisReanalysis of prior exome or genome sequencing is considered when the member had prior sequencing at least 1 year ago (>= 1 year)

Alternative indication for reanalysisReanalysis may also be considered when the member’s phenotype has expanded to include clinical findings not present at the time of the initial analysis and prior results do not explain new findings

Applicable procedure codesReanalysis references CPT codes 81417 (exome reanalysis) and 81427 (genome reanalysis)

Panel gene count requirements — minimum gene counts for named panels

Aortic dysfunction/dilation panel minimum genesAortic dysfunction/dilation genomic sequencing panel must include sequencing of at least 9 genes (including FBN1, TGFBR1, TGFBR2, COL3A1, MYH11, ACTA2, SLC2A10, SMAD3, MYLK)

Noonan spectrum panel minimum genesNoonan spectrum / RASopathy genomic sequencing panel must include at least 12 genes (examples listed in policy)

X‑linked intellectual disability (XLID) panel minimum genesXLID panels are specified to include at least 60 genes (policy examples include ARX, ATRX, CDKL5, FMR1, HUWE1, KDM5C, L1CAM, MECP2, MED12, MID1, OCRL, RPS6KA3, SLC16A2)

Connective tissue duplication/deletion panel requirementAortic duplication/deletion analysis panel must include analyses for TGFBR1, TGFBR2, MYH11, and COL3A1

HCPCSHCPCS

S3870

Cgh test developmental delay

Quick Code Search / procedure codes placeholdermixed

No codes listed

Provider Actions — Authorization, Documentation, and Ordering Guidance

Prior Authorization

Obtain prior authorization for listed specialty genomic test codes

Prior authorization is required per payer processes for the listed specialty genomic CPT/HCPCS codes when seeking coverage for these tests.

Examples of affected proprietary and CPT-PLA codes include 0094U, 0212U–0215U, 0425U, 0426U, 0532U (see policy code table).
When seeking authorization, reference the specific procedure code from the policy's code list.

Prior Authorization

Prior authorization required for panels per condition‑specific criteria

Obtain prior authorization for multigene panels or other targeted panels to establish medical necessity using the policy’s condition‑specific criteria before testing.

Submit documentation that the member meets the policy’s condition‑specific clinical criteria for the requested panel.
Some panel CPT codes listed in the policy require prior authorization or coverage determination.

Prior Authorization

Prior authorization for rapid sequencing only in appropriate scenarios

Reserve rapid exome/genome sequencing for acutely ill infants or situations where rapid sequencing is more efficient and economical than separate recommended tests; obtain prior authorization consistent with these conditions.

Rapid sequencing covered when patient is an acutely‑ill infant (≤12 months) and rapid testing is more efficient/economical than sequential testing.
Policy notes rapid sequencing should be used only when it is more efficient/economical than separate single‑gene tests or panels.

Prior Authorization

Follow CMA first‑tier guidance and obtain authorization as required

When ordering chromosomal microarray (CMA) for developmental delay/intellectual disability, ASD, or multiple congenital anomalies, follow first‑tier CMA guidance and obtain prior authorization per payer policies when required.

CMA is recommended as a first‑tier diagnostic test for GDD/ID, ASD, or multiple congenital anomalies.
Ensure documentation supports the indication (CMA is not reasonable for isolated speech/language delay).

Prior Authorization

Check approval/denial/hold status via Quick Code Search

Use the Quick Code Search tool to determine whether a procedure + diagnosis code pair will be approved, denied, or held for review before submitting requests.

Enter the procedure code, then the diagnosis code, and click 'Add Code Pair' to check approval status.
Quick Code Search results identify pairs listed in the policy and indicate if they will be approved, denied, or held for review.

Prior Authorization

Submit procedure‑diagnosis code pairs for listed procedures

Submit certain listed procedure codes as a procedure‑diagnosis pair via the Quick Code Search when required by the policy to determine authorization status.

Some policy-listed codes (including proprietary/CPT‑PLA and temporary CPT codes shown in the code table) must be added as a code pair in Quick Code Search.
Adding the required code pair is necessary to receive the policy-based approval/denial/hold determination.

Billing Rule

Use policy‑listed CPT/HCPCS codes for authorization and claims

When requesting authorization or filing claims, use the specific CPT/HCPCS codes listed in the policy to identify the test being requested or billed.

Reference the policy’s listed procedure codes (examples include 81415–81417, 81425–81427, 81440, 81460, S3870) when seeking prior authorization or claims adjudication.
Using the policy‑listed codes ensures the request maps to the clinical criteria in the policy.

Step Therapy

Order combined mtDNA + exome only when both criteria are met

Order combined mtDNA + exome sequencing only when the member meets both mitochondrial testing criteria and standard exome sequencing criteria, and use combined test codes when exome and mtDNA cannot be billed separately.

Combined testing is appropriate only when both clinical criteria sets are met.
The policy references specific combined codes (e.g., 0214U, 0215U) for tests that cannot be performed or billed separately.

Step Therapy

Follow stepwise testing for 15q11‑q13 (methylation → deletion → UPD → imprinting defect)

Follow the recommended sequential testing algorithm for 15q11‑q13: begin with UBE3A/SNRPN methylation analysis, then proceed to deletion analysis, UPD analysis, and imprinting defect analysis as indicated.

Start with methylation analysis; if normal, proceed to deletion analysis of 15q11‑q13.
If deletion analysis is normal, consider UPD analysis; if UPD is normal, proceed to imprinting defect analysis.

Step Therapy

Follow a tiered diagnostic approach; ES/GS as first‑line for GDD/ID

Apply a tiered diagnostic approach for GDD/ID: consider ES/GS as first‑line (Tier 1) and reserve tests such as Fragile X and metabolic testing for later tiers per guideline recommendations.

Tier 1: exome or genome sequencing for appropriate patients.
Tier 2: Fragile X testing and metabolic testing; Tier 3: additional specialized tests or reanalysis as indicated.

Step Therapy

Use comprehensive NGS panels for mitochondrial testing and document tissue rationale

When considering nuclear gene testing for suspected primary mitochondrial disease, use NGS multigene panels that provide complete coverage of known mitochondrial disease genes; document tissue rationale when heteroplasmy is a concern.

Prefer NGS panels with complete coverage; avoid single‑gene testing unless specifically indicated.
If blood testing is negative but suspicion remains, consider alternative tissues (e.g., muscle or urine) due to heteroplasmy.

Step Therapy

Consider PTPN11 single‑gene testing first in Noonan phenotype

For suspected Noonan syndrome, consider targeted PTPN11 single‑gene testing first because PTPN11 accounts for approximately half of molecular diagnoses, then proceed to broader multigene panels if appropriate.

PTPN11 single‑gene testing is often the highest‑yield initial test (~50% detection).
If PTPN11 testing is negative and phenotype warrants, proceed to a Noonan/RASopathy multigene panel.

Documentation Required

Document evaluation of alternate etiologies, genetics evaluation, and prior testing dates

Provide documentation that alternate etiologies were considered and ruled out, that the member’s personal and family histories were evaluated by a genetics professional, and include prior exome/genome test dates when applicable.

Document consideration and exclusion of alternate etiologies (environmental, infectious, prematurity, etc.).
For reanalysis requests, include the date of prior exome/genome testing (reanalysis eligible ≥1 year after prior test).

Documentation Required

Document genetics specialist evaluation (Medical Geneticist/Genetic Counselor/APGN)

Ensure documentation shows the member’s personal and family histories were evaluated by a Medical Geneticist, Genetic Counselor, or Advanced Practice Nurse in Genetics (APGN) as required for exome/genome and mitochondrial testing criteria.

Include notes from the evaluating genetics professional describing the clinical assessment and rationale for testing.
Genetics evaluation is a required element of the coverage criteria for sequencing modalities.

Documentation Required

Provide prerequisite biochemical testing documentation for mitochondrial testing

For mitochondrial testing, include documentation that conventional biochemical laboratory studies (plasma or CSF lactic acid, ketone bodies, plasma acylcarnitines, urinary organic acids) and other indicated diagnostic testing were completed and non‑diagnostic.

List results of required biochemical studies and any additional diagnostic tests that were non‑diagnostic prior to ordering molecular testing.
This documentation is required to satisfy the mitochondrial testing coverage criteria.

Documentation Required

Document how member meets clinical diagnostic criteria for targeted condition

Document how the member meets the specific diagnostic clinical criteria for the targeted condition (e.g., developmental delay/ID definitions, aortic root Z‑score for Marfan, disorder‑specific major/minor features).

Include standardized measurements (e.g., aortic root Z‑score) and explicit symptom counts that map to policy criteria.
For disorder‑specific tests, document the clinical features used to justify the selected test or panel.

Documentation Required

Provide and document pre‑test genetic counseling and secondary findings discussion

Advise and document pre‑test genetic counseling that addresses the possibility of secondary/incidental findings, documents patient preferences (including opt‑out decisions), and outlines plans for result return.

Document that counseling occurred and the patient’s choices about receiving secondary findings.
Record the plan for returning results and post‑test counseling arrangements.

Documentation Required

Document tissue source and rationale for mitochondrial testing when heteroplasmy suspected

When heteroplasmy is suspected, document the tissue source selected for mitochondrial testing and the rationale for testing that tissue (e.g., urine or muscle instead of blood).

State why an alternate tissue was chosen (e.g., higher expected heteroplasmy level) and include prior test results that informed tissue selection.
Documentation supports the policy expectation that tissue selection may be necessary for accurate mtDNA detection.

Documentation Required

Document measurements and clinical features for connective tissue disorder testing

For connective tissue disorder testing, document relevant clinical findings and standardized measurements (e.g., aortic root Z‑score, systemic score for EDS) to justify targeted gene testing or panels.

Include measured aortic root Z‑score and systemic/major‑minor criteria counts when applicable.
Reference GeneReviews or relevant society guidance in the clinical rationale documentation.

Documentation Required

Obtain and document three‑generation family history for suspected TSC

Obtain and document a three‑generation family history when tuberous sclerosis complex (TSC) is suspected to determine additional family members at risk and support testing.

Record affected relatives across three generations and relevant clinical features for each relative.
Family history supports the diagnostic and surveillance rationale for TSC testing.

Billing Rule

Use Quick Code Search to verify procedure+diagnosis code pair support

Use the Quick Code Search feature to enter the procedure code and a diagnosis code (at least the first 3 characters) to determine if a code pair will be approved, denied, or held for review before submitting authorization/claims.

Enter the procedure code, then the diagnosis code, then click 'Add Code Pair' to check policy support.
Both a procedure and a diagnosis are required for code‑pair submission.

Documentation Required

Obtain plan authorizations—policy does not guarantee benefit coverage

Recognize that medical policies do not guarantee authorization; providers remain responsible for obtaining required authorizations per the member’s benefit contract and plan terms.

Medical Policies inform plan administration but authorization depends on the member’s specific benefit contract.
Policies may change; verify authorization requirements at time of request.

Denial Risk

Denial risk: repeat or non‑qualifying exome/genome analyses

Be aware that repeat standard exome/genome sequencing and reanalysis outside the policy’s specified criteria are considered not reasonable and necessary and may be denied.

Repeat standard exome sequencing is explicitly considered not reasonable and necessary.
Reanalysis (81417, 81427) is allowed only per the policy criteria (e.g., ≥1 year since prior testing or phenotype expansion).

Denial Risk

Repeat standard exome sequencing will be denied

Standard exome sequencing performed previously should not be repeated; repeat standard exome sequencing is considered not reasonable and necessary and will be denied.

Policy statement: 'Repeat standard exome sequencing is considered not reasonable and necessary.'

Denial Risk

Repeat standard genome sequencing will be denied

Repeat standard genome sequencing is considered not reasonable and necessary and may be denied when requested outside policy criteria.

Policy indicates repeat standard genome sequencing is not reasonable and necessary.

Denial Risk

Denial risk: out‑of‑criteria rapid sequencing requests

Rapid exome/genome sequencing requested for indications outside the policy’s acute infant/ICU criteria or other specified scenarios is considered not reasonable and necessary and may be denied.

Rapid sequencing is covered for acutely‑ill infants (≤12 months) meeting policy criteria; use outside these indications risks noncoverage.
Policy notes rapid sequencing is not reasonable and necessary for all other indications.

Denial Risk

ASD/ID multigene panels are denied for any indication

Autism spectrum disorder / intellectual disability multigene panel analysis is considered not reasonable and necessary for all indications and will be denied.

Policy statement: 'The use of an autism spectrum disorder / intellectual disability panel is considered not reasonable and necessary for all indications.'
Concert Evidence Review (06/01/2025) found insufficient evidence to support coverage.

Denial Risk

Do not order ASD/ID multigene panels—requests will be denied

Ordering an autism/ID multigene panel will be denied; do not submit authorization requests for these panels as they are not supported for coverage.

Policy explicitly excludes ASD/ID panels from reasonable and necessary services.
Evidence review concluded insufficient evidence to demonstrate improved health outcomes from ASD/ID panels.

Denial Risk

Appropriateness requirement for rapid sequencing—coverage risk if not justified

Reserve rapid exome/genome sequencing for situations where it is more efficient/economical than separate single‑gene or panel testing; inappropriate use may not be covered.

PLUGS guidance: rapid sequencing should be used only when it is more efficient and economical than the separate tests that would otherwise be recommended.
Document rationale comparing alternatives when requesting rapid sequencing.

Denial Risk

Coverage risk: ASD/ID multigene panels lack evidence

ASD/ID multigene panels lack sufficient evidence and are not supported for health plan coverage; ordering or billing such panels carries a high risk of denial.

Concert Evidence Review found no qualifying evidence in the review period to support coverage.
Policy states ASD/ID panels are not supported for health plan coverage.

Denial Risk

Quick Code Search: unsupported code pairs may be denied or held

Unsupported procedure/diagnosis code pairs identified by Quick Code Search may be denied or held for review; verify code‑pair support before submission to avoid denials or delays.

Quick Code Search will indicate if a procedure/diagnosis pair will be approved, denied, or held for review.
Use the tool to avoid submitting unsupported pairs that may trigger denials or administrative holds.

Billing Rule

Procedure + diagnosis required for code‑pair submission

Both a procedure code and a diagnosis code are required when submitting code pairs via Quick Code Search; omission of either may result in a hold or denial.

Enter at least the first three characters of the diagnosis code along with the procedure code when adding a code pair.
The policy requires both elements; missing information can prevent determination and delay processing.

Denial Risk

Plan benefit determination governs final authorization

Authorization decisions are governed by the member’s benefit contract; the Medical Policy itself does not constitute authorization or a guarantee of coverage.

Providers must verify plan benefits and obtain any required authorizations per the applicable benefit contract.
Medical Policies guide coverage determinations but do not replace plan‑specific benefit rules.

Definitions and Key Terms

Trio Testing definition

DefinitionTesting of the child and both biological/genetic parents to increase diagnostic yield and reduce false-positive findings

PurposeImproves interpretation of de novo vs inherited variants and reduces variants of uncertain significance

Typical usePreferred when performing ES or GS for suspected constitutional/heritable disorders

Exome Sequencing (ES) definition

DefinitionExome Sequencing (ES) sequences all protein-coding regions of genes (the exome)

ScopeDetects single nucleotide variants and small indels within coding regions; may be paired with deletion/duplication analysis separately

Typical indicationUsed for evaluation of unexplained multisystem genetic conditions when phenotype does not fit a well‑described syndrome

Genome Sequencing (GS) definition

DefinitionGenome Sequencing (GS) sequences the complete DNA sequence including coding and non-coding elements

Mitochondrial genome noteWhen genome sequencing is performed, the mitochondrial genome is assumed to be included as part of the analysis

ScopeDetects single nucleotide variants, small indels, and non-coding variants not captured by ES

Reanalysis of ES/GS

DefinitionBioinformatic re-review of reported and unreported variants from the original ES/GS assay

Typical triggersPerformed when phenotype has changed/expanded or prior test was non-diagnostic and advances in classification/pipelines could yield a diagnosis

Timing considerationReanalysis considered reasonable when prior sequencing was >= 1 year ago or phenotype expanded

Mitochondrial genome inclusion

Policy noteWhen genome sequencing is performed, the mitochondrial genome is assumed to be included in the analysis

ImplicationSeparate mtDNA sequencing may not be required if GS with mtDNA analysis is performed

Reference contextApplies to standard and rapid genome sequencing modalities

Combined test

DefinitionA combined test refers to mitochondrial DNA sequence and deletion/duplication analysis performed together with exome sequencing when both clinical criteria are met

When usedAppropriate when the member meets criteria for both mitochondrial testing and standard exome sequencing

Billing noteUsed when exome and mitochondrial sequencing cannot be performed or billed separately (examples: 0214U, 0215U)

Autism spectrum disorder definition (DSM-V-based)

DefinitionAutism spectrum disorder defined per DSM‑V as persistent deficits in social communication and interaction across multiple contexts

Examples of deficitsIncludes impairments in social‑emotional reciprocity, nonverbal communicative behaviors, and difficulty developing/maintaining relationships

Clinical contextRelevant for determining eligibility for genetic testing in ASD with accompanying features (not isolated ASD)

Developmental delay / Intellectual disability definitions

Developmental delay (DD)Slow-to-meet or not reaching milestones in one or more developmental domains for a child

Intellectual disability (ID)Per DSM‑V: age ≥5 with IQ ≤70 or clinical diagnosis with deficits in intellectual and adaptive functioning with onset during development

Clinical implicationDD/ID are qualifying features for genomic testing per policy criteria when onset is prior to 18 years (DD/GDD typically in younger children)

Heteroplasmy definition

DefinitionHeteroplasmy is presence of a mixture of more than one type of mitochondrial DNA within a cell or individual

Tissue variabilityHeteroplasmy levels can vary by tissue; pathogenic mtDNA variants may be undetectable in blood but detectable in muscle or urine

Testing considerationWhen heteroplasmy suspected, consider testing tissues other than blood (e.g., muscle, urine, fibroblasts) to increase detection

Aortic root Z-score

DefinitionAortic root Z‑score is a standard measurement of aortic root size adjusted for age and body size

Threshold relevanceA Z‑score >2.0 is suggestive of aortic root enlargement and is used as a criterion for Marfan/FBN1 testing

Interpretation noteZ‑score >2.0 corresponds approximately to ≥95th percentile; Z‑score >3.0 corresponds to ≥99th percentile

BWS molecular findings

Molecular mechanismsBWS diagnosis can be supported by abnormal methylation at 11p15.5, copy number variants at 11p15.5, or heterozygous pathogenic variants in CDKN1C

Clinical tiersPolicy describes Tier 1 (highly suggestive) and Tier 2 (less specific) clinical features guiding testing

Growth thresholdsMacrosomia often defined using cutoffs of >90th or >97th centile depending on study

NH-CSS (Netchine-Harbison)

DefinitionNH‑CSS (Netchine‑Harbison Clinical Scoring System) is the clinical diagnostic scoring system for Silver‑Russell Syndrome (SRS)

Testing thresholdMolecular testing recommended when ≥4 of 6 NH‑CSS criteria are met (some individuals with 3/6 may have molecular confirmation)

Use caseNH‑CSS guides decision to pursue molecular confirmation for SRS

Genome/Exome sequencing (proband/comparator) definition

DefinitionGenome/Exome sequencing of a proband with optional comparator genomes (parents/siblings) including mitochondrial DNA and other variant types

Comparator useComparator (parent/sibling) sequencing aids interpretation and is represented by separate comparator codes (e.g., 81416, 81426) in billing guidance

Additional contentIncludes detection of small sequence changes, deletions/duplications, STR expansions, and variants in non-uniquely mappable regions when supported by test

Molecular pathology procedure levels (81400-81406)

DefinitionMolecular pathology procedure levels (81400–81406) categorize tests by breadth/complexity from single‑variant assays to multi‑exon/full gene sequencing

Level examplesLevels 1–7 described for increasing complexity; higher Level descriptors (Level 7–9) denote analysis of many exons or large single‑gene sequencing

Coding implicationProcedure level informs billing and may correspond to analytic complexity required for certain diagnostic tests

Molecular pathology procedure levels (Level 7-9)

Level 7–9 descriptorsLevel 7–9 CPT descriptors correspond to increasing analytic complexity (e.g., Level 7: analysis of 11–25 exons; Level 9: analysis of >50 exons or full gene sequencing)

ExamplesLevel 9 examples include full gene sequence testing for many disease genes (ABCA4, ATM, CEP290, COL1A1, DMD, FBN1, etc.)

Use in policyThese levels are listed among covered molecular pathology codes and guide test categorization and billing

Panel requirements — minimum gene counts

Aortic panel requirementAortic dysfunction/dilation genomic sequencing panel must include at least 9 genes (FBN1, TGFBR1, TGFBR2, COL3A1, MYH11, ACTA2, SLC2A10, SMAD3, MYLK)

Noonan spectrum panel requirementNoonan spectrum (RASopathy) genomic sequencing panel must include at least 12 genes (policy lists core RASopathy genes)

XLID panel requirementX‑linked intellectual disability panels must include at least 60 genes (examples provided in policy)

Not Covered / Exclusions

Services that are not covered include screening of asymptomatic or healthy individuals for genetic disorders and routine repeat standard exome sequencing. Reanalysis of prior exome/genome data is allowed only under the policy’s specified criteria (for example, prior sequencing ≥1 year ago or expanded phenotype); otherwise reanalysis and repeat sequencing are considered not reasonable and necessary.

Use of an Autism Spectrum Disorder/Intellectual Disability multigene panel is expressly considered not reasonable and necessary for all indications under this policy.

The ACMG guidance cited in the policy indicates that isolated autism without intellectual disability or congenital malformation was outside the scope of recommendations supporting ES/GS and therefore may not be an appropriate indication for exome or genome sequencing in the absence of additional features.

A recent Concert evidence review and the policy conclude there is insufficient evidence to support health plan coverage of ASD/ID multigene panels; accordingly, these panels are not supported for coverage by this policy.

Genetic testing performed solely to predict future complications is not supported by the policy, and a negative genetic test does not always exclude a diagnosis (for example, NF1 testing has an estimated sensitivity of approximately 95%); therefore testing intended only to forecast complications or to definitively rule out disease when clinical criteria remain strongly suggestive is not covered.

Within the excerpted document content there are no additional explicit not‑covered tests or exclusions listed beyond those already described in the policy text.

Eligibility Requirements and Preconditions for Coverage

Family history suggestive of a genetic etiology, including consanguinity, may satisfy part of the clinical criteria for exome coverage and can count toward qualifying findings when assessing eligibility for sequencing.

For requests for reanalysis, documentation must include dates of prior exome or genome testing; reanalysis eligibility is limited to cases where prior sequencing was performed at least 1 year earlier or where the member’s phenotype has expanded and prior results do not explain new findings.

Top-level eligibility requirements include demonstration that alternate etiologies were considered, evaluation by an appropriate genetics professional, and that the clinical presentation meets the condition‑specific criteria outlined for standard exome, genome, or panel testing.

Additional eligibility nodes referenced in the policy inventory (reserved entries) reflect condition‑specific qualifiers such as age at onset, number and type of clinical features, and prior testing requirements; these items should be documented to establish coverage eligibility.

Reserved eligibility entries indicate that some criteria may be condition‑specific (for example, tiered features for Beckwith‑Wiedemann or required gene content for named panels) and should be reviewed against the full policy when preparing authorization requests.

Background and Evidence Summary

This policy addresses coverage for broad and targeted genomic tests—exome and genome sequencing (standard and rapid), multigene panels, chromosomal microarray, and mitochondrial genome/nuclear gene testing—for suspected multisystem genetic disorders. It emphasizes evaluation by genetics professionals, consideration of alternate etiologies, and condition‑specific clinical criteria to establish medical necessity.

24%Diagnostic yield — rapid exome/genome in acutely ill infants (NSIGHT2)

15%Median new diagnosis rate from ES/GS reanalysis (PLUGS summary)

22.5%VUS rate — exome/genome (Rehm et al. 2023)

32.6%VUS rate — multigene panels (Rehm et al. 2023)

Reanalysis is supported when prior sequencing was performed and either ≥1 year has passed or the phenotype has expanded; the cited PLUGS review notes a median new diagnosis rate via reanalysis of about 15% and suggests an optimal reanalysis interval of greater than 18 months, supporting periodic reanalysis under the policy conditions.

For suspected mitochondrial disease the policy recommends NGS‑based mtDNA sequencing and comprehensive nuclear gene panels with consideration of testing tissues beyond blood (e.g., urine or muscle) because heteroplasmy can cause variants to be undetectable in blood; biochemical testing should be completed and non‑diagnostic before proceeding to molecular testing when indicated.

Coding and Billing Notes (Provider-Facing)

Billing Rule

Billing/order sequencing: ES/GS as first‑line for GDD/ID per tiered guidance

If exome/genome is ordered as first‑line for GDD/ID, coordinate ordering and billing consistent with ES/GS being first‑line and reserve other tests (e.g., Fragile X, metabolic testing) for later tiers per the policy’s tiering guidance.

Document why ES/GS is appropriate as Tier 1 for the patient’s presentation before ordering.
Ordering/billing workflow should reflect ES/GS as first‑line when criteria are met to avoid unnecessary downstream testing.

Billing Rule

Avoid billing ASD/ID multigene panels—high denial risk

Do not bill for autism/ID multigene panels; these tests are not supported for coverage and carry a high risk of claim denial.

The policy designates ASD/ID panels as not reasonable and necessary for all indications.
Concert Evidence Review concluded insufficient evidence for coverage; avoid billing these panels.

Billing Rule

Operational billing step: verify code/diagnosis pair via Quick Code Search

Operationally, verify procedure+diagnosis pairs using Quick Code Search before billing to determine whether the combination is supported by policy and to reduce claim denials or holds.

Add the procedure code and diagnosis code into Quick Code Search to confirm approval status prior to claim submission.
Use Quick Code Search dropdowns when the policy lists the codes to assist with correct pairing.

Billing Rule

Billing rule: use policy‑listed CPT/HCPCS codes for authorization and claims

When seeking authorization or submitting claims, use the specific CPT/HCPCS codes listed in the policy to ensure the request aligns with the covered procedures and the policy’s clinical criteria.

Reference the policy’s enumerated codes (e.g., 81415–81417, 81425–81427, 81440, 81460, S3870) when requesting prior authorization or submitting claims.
Using listed codes facilitates mapping the request to the policy’s coverage logic and reduces administrative issues.

Policy Revision History

2026-05-01policy_effectiveLatest

Policy M.78 (Multisystem Genetic Conditions) became effective.

2027-01-01next_review_scheduled

Next scheduled policy review date set for continued evaluation and updates.