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Genetic Testing: Metabolic, Endocrine, and Mitochondrial Disorders

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Defines medical necessity criteria and coding guidance for genetic and molecular testing for hereditary metabolic, endocrine, and mitochondrial disorders for WellCare members.

Policy Summary

PayerWellCare

PolicyGenetic Testing: Metabolic, Endocrine, and Mitochondrial Disorders

Policy CodePolicy N/A

Change TypeCriteria and methodology revisionscoding updates

Effective DateN/A

Next Review DateN/A

Key ActionBegin testing with an affected family member when possible to identify the familial pathogenic variant before testing at-risk relatives.

SourceLink

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ModifiedWellCarePolicy N/A

Genetic Testing: Metabolic, Endocrine, and Mitochondrial Disorders

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Defines medical necessity criteria and coding guidance for genetic and molecular testing for hereditary metabolic, endocrine, and mitochondrial disorders for WellCare members.

Policy Summary

PayerWellCare

PolicyGenetic Testing: Metabolic, Endocrine, and Mitochondrial Disorders

Policy CodePolicy N/A

Change TypeCriteria and methodology revisionscoding updates

Effective DateN/A

Next Review DateN/A

Key ActionBegin testing with an affected family member when possible to identify the familial pathogenic variant before testing at-risk relatives.

SourceLink

POLICY UPDATE CHANGES

Updated monogenic diabetes criteria: changed diagnostic age thresholds (first 6 months -> first 12 months; age cutoff 35 -> 30), reworded autoantibody and C-peptide options, removed specific gene inclusion requirement.

For Mitochondrial Genome Sequencing panel: removed 'and deafness' from I.B.1.i and emphasized tissue testing and NGS methods for mtDNA and nuclear genes.

Semi-annual review updated title to reflect V1.2024, updated overview, coding, reference-table, background and references; replaced 'coverage criteria' with 'criteria' throughout.

Added 'and Molecular' to Other Covered Metabolic, Endocrine, and Mitochondrial Disorders panel and added an autosomal dominant inheritance note.

>1000nuclear genes associated with mitochondrial function mentioned

>=20named disorders covered

81291MTHFR CPT listed

81403+MODY / familial variant CPTs

V1.2024document version

Coverage Criteria

Known Familial Variant Analysis

Covered when ALL of the following are met

Known familial variant analysis — medically necessary: Targeted mutation analysis for a known familial variant (CPT codes: 81403, 81404, 81405, 81406, 81407, 81479) is medically necessary when the member/enrollee has a close relative with a known pathogenic or likely pathogenic variant causing the condition.

Documentation must show the close relative and the known pathogenic or likely pathogenic variant.

MTHFR Variant Analysis

Not covered / investigational

MTHFR variant analysis — investigational: MTHFR targeted variant analysis (examples: 677T, 1298C) (CPT 81291) is considered investigational for all indications, including evaluation for thrombophilia, recurrent pregnancy loss, testing at-risk relatives, and pharmacogenetic uses.

ACMG guidance recommends against ordering MTHFR polymorphism testing for thrombophilia or recurrent pregnancy loss; findings do not change folic acid recommendations.

Monogenic Diabetes (MODY) Panels

Covered when ALL of the following are met

MODY panel — indications: Multigene panel analysis to establish or confirm monogenic diabetes (MODY) (CPT codes: 81403, 81405, 81406, 81407, 81479) is medically necessary when the member has: A) a diagnosis of diabetes within the first 12 months of life; OR B) a diagnosis of diabetes before 30 years of age AND at least one of the following: (a) autoantibody negative, OR (b) retained C-peptide levels; OR C) a diagnosis of diabetes not characteristic of type 1 or type 2 diabetes AND a family history of diabetes consistent with autosomal dominant inheritance.

Consultation with a center specializing in diabetes genetics or a clinical geneticist is recommended for interpretation and counseling. Criteria updated per recent guidelines (age thresholds and biomarker wording).

Mitochondrial Genome Sequencing / Deletion / Nuclear Gene Panels

Covered when ONE of the following is met

Mitochondrial testing — classic phenotype: Mitochondrial genome sequencing (CPT 81460), deletion/duplication analysis (CPT 81465), and/or nuclear gene panel analysis for mitochondrial disorders (CPT 81440) is medically necessary when the member has a classic phenotype of a maternally inherited mitochondrial syndrome (examples: LHON, MELAS, MERRF, MIDD, NARP, Kearns‑Sayre/CPEO) or a recognized nuclear DNA mitochondrial disorder (e.g., MNGIE).

Mitochondrial testing — non-specific phenotype: Mitochondrial genome sequencing, deletion/duplication, and/or nuclear gene analysis is medically necessary when the member has non-specific clinical features suggestive of a primary mitochondrial disorder AND meets ALL: (1) clinical findings of at least two specified features (examples: ptosis, external ophthalmoplegia, proximal myopathy, exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, diabetes mellitus, fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, spasticity, chorea, multiple late term pregnancy loss); AND (2) conventional biochemical laboratory studies (including at least plasma or CSF lactic acid, ketone bodies, plasma acylcarnitines, and urinary organic acids) have been completed and are non-diagnostic; AND (3) additional diagnostic testing indicated by the presentation (e.g., neuroimaging, ECG, EMG, echo, audiology, thyroid testing, EEG, exercise testing) have been completed and are non-diagnostic.

Prefer NGS/ massively parallel sequencing of mtDNA; if blood testing is negative and suspicion remains, test another tissue (muscle or urine) per Mitochondrial Medicine Society recommendations.

Other Covered Metabolic, Endocrine, and Mitochondrial Disorders

Covered when ALL specified criteria are met

Other metabolic/endocrine/mitochondrial disorders — diagnostic testing: Genetic testing to establish or confirm diagnosis of listed rare metabolic, endocrine, and mitochondrial conditions is medically necessary when the member demonstrates clinical features consistent with the disorder (examples include congenital adrenal hyperplasia, congenital disorders of glycosylation, congenital hyperinsulinism, glutaric acidemia type I, homocystinuria (CBS deficiency), methylmalonic acidemia, propionic acidemia, MSUD, biotinidase deficiency, carnitine cycle disorders, Wilson disease, MCAD deficiency, galactosemia, Glut1 DS, alkaptonuria, phenylalanine hydroxylase deficiency, acute intermittent porphyria, McCune‑Albright syndrome, glycogen storage disorders including GSDI and Pompe, hypophosphatasia, Kallmann syndrome, lysosomal storage disorders such as Gaucher and Krabbe, MPS I and II, mucolipidosis IV, urea cycle disorders, malignant hyperthermia, and SHOX deficiency).

List not exhaustive; other disorders evaluated under General Approach to Genetic and Molecular Testing.

Covered indications and testing approach

Covered when criteria per specific panel/guideline are met (see sections for mitochondrial sequencing, known familial variant analysis, MTHFR guidance, and monogenic diabetes/MODY).

Other metabolic/endocrine/mitochondrial disorders: Genetic testing to establish or confirm diagnosis of metabolic, endocrine, and mitochondrial disorders not specifically discussed will be evaluated by the General Approach to Genetic and Molecular Testing policy.

Clinical features and resources may be outlined in GeneReviews, OMIM, Genetics Home Reference, or other scholarly sources.

Known familial variant analysis: If a familial pathogenic variant is known in an affected family member, targeted testing of at‑risk relatives is appropriate to determine carrier or affected status.

When possible, begin testing with an affected family member to identify the familial pathogenic variant prior to testing relatives.

Mitochondrial testing approach: Use massively parallel/NGS sequencing of the mtDNA genome as the preferred methodology; when blood testing is negative and suspicion remains, test another tissue (muscle or urine); consider mtDNA deletion/duplication testing and nuclear gene NGS panels when indicated. Heteroplasmy and tissue specificity should be considered; multigene panels or exome/genome sequencing may be needed if panels are negative.

Targeted mutation analysis for a known familial variant (CPT codes 81403, 81404, 81405, 81406, 81407, 81479) is covered only when the member has a close relative with a known pathogenic or likely pathogenic variant causing the condition. In all other situations, targeted familial variant testing is considered investigational and not covered.

When available, testing should begin with an affected family member to identify the familial pathogenic variant prior to testing at-risk relatives; this approach increases diagnostic yield and ensures that targeted testing is appropriate for the specific variant identified.

The American College of Medical Genetics and Genomics (ACMG) practice guideline advises against ordering MTHFR polymorphism genotyping as part of the clinical evaluation for thrombophilia or recurrent pregnancy loss, and recommends that testing not be ordered for at-risk family members. These guideline conclusions form the basis for the policy's stance on MTHFR testing.

MTHFR targeted variant analysis (examples: 677T, 1298C) reported under CPT 81291 is considered investigational for all indications and therefore not medically necessary.

Ordering MTHFR polymorphism testing for evaluation of thrombophilia, recurrent pregnancy loss, or for asymptomatic at-risk family members is discouraged. The ACMG guideline specifically states that such genotyping should not be part of the clinical evaluation for these indications; if an MTHFR thermolabile variant is identified, ACMG suggests considering a fasting total plasma homocysteine to guide counseling, but MTHFR status does not alter routine folic acid recommendations for women of childbearing age.

Covered Indications

Diagnosis/confirmation of hereditary metabolic, endocrine, or primary mitochondrial disorders

Diagnosis or confirmation is covered when clinical criteria specified in the relevant section are met

Indication — hereditary metabolic, endocrine, or mitochondrial disorders: Genetic testing is medically necessary to establish or confirm hereditary metabolic, non‑cancerous endocrine, or primary mitochondrial disorders when the member meets the clinical criteria specified in the relevant sections for known familial variant testing, monogenic diabetes (MODY), mitochondrial genome and nuclear gene testing, or listed rare disorders.

Coverage is subject to documentation of clinical features, biochemical testing, and family history as required by each section.

Specific named disorders list — metabolic/endocrine/mitochondrial disorders

The following specific metabolic, endocrine, and mitochondrial disorders are examples for which genetic testing may be covered when clinical features are consistent with the condition

Covered named disorders: Examples include: congenital adrenal hyperplasia (21‑hydroxylase deficiency), congenital disorders of glycosylation, congenital hyperinsulinism, glutaric acidemia type I, homocystinuria (CBS deficiency), methylmalonic acidemia, propionic acidemia, Maple Syrup Urine Disease (MSUD), biotinidase deficiency, carnitine palmitoyltransferase II deficiency, primary carnitine deficiency, Wilson disease, medium‑chain acyl‑CoA dehydrogenase (MCAD) deficiency, galactosemia, Glut1 deficiency syndrome (Glut1 DS), alkaptonuria, phenylalanine hydroxylase deficiency, acute intermittent porphyria, McCune‑Albright syndrome, glycogen storage disorders including GSD I and Pompe disease, hypophosphatasia, Kallmann syndrome, lysosomal storage disorders such as Gaucher and Krabbe, mucopolysaccharidosis types I and II (MPS I/II), mucolipidosis IV, urea cycle disorders (e.g., OTC deficiency), malignant hyperthermia susceptibility, and SHOX deficiency.

Coding and Billing

Known familial variant / MODY panel CPT codesCPTCovered

81403	Targeted mutation analysis / Known familial variant (listed among codes 81403–81479)
81404	Targeted mutation analysis (listed)
81405	Targeted mutation analysis / multigene panels (listed)
81406	Targeted mutation analysis (listed)
81407	Targeted mutation analysis (listed)
81479	Unlisted molecular pathology procedure (used in lists)

MTHFR Variant AnalysisCPTNot Covered

81291

MTHFR targeted variant analysis

Mitochondrial sequencing / deletion / nuclear gene panelCPTCovered

81460	Mitochondrial genome sequencing
81465	Mitochondrial deletion/duplication analysis
81440	Nuclear gene panel for mitochondrial disorders

Other covered CPT codesCPTCovered

81400-81408	Other covered molecular pathology CPT range listed for metabolic/endocrine/mitochondrial disorders
81205	CPT code listed among other covered codes
81250	CPT code listed among other covered codes

Age at diabetes diagnosis for MODY consideration — diagnostic age thresholds

Diagnostic age thresholdsDiagnosis of diabetes within the first 12 months of life OR diagnosis before 30 years of age

Additional biomarker/phenotype requirement (if diagnosed <30)Autoantibody negative OR retained C‑peptide levels (one required)

Alternative indication (atypical diabetes)Diagnosis not characteristic of type 1 or type 2 diabetes AND family history consistent with autosomal dominant inheritance

Provider Actions and Requirements

Billing Rule

Confirm coding via Concert Genetics

Coding referenced in this policy is for informational purposes only. Providers must confirm current billing codes and test registrations via the Concert Genetics platform prior to claim submission.

Common CPT codes referenced in policy include targeted/known familial variant codes (e.g., 81403, 81404, 81405, 81406, 81407, 81479) and panels (81403, 81405, 81406, 81407, 81479); MTHFR variant analysis CPT 81291 is listed as investigational for all indications.

Note

Policy update — V1.2024

Policy updated to V1.2024. Coding, criteria, and reference tables were reviewed and revised; see revision history for details. Providers should note that terminology was standardized ("coverage criteria" replaced with "criteria") and several section-specific edits were made to MTHFR and mitochondrial criteria.

Revision Date: 10/23 (V1.2024) — overview, coding, background, references updated; see policy timeline for full change log.

Eligibility Requirements

For targeted familial variant testing to be covered, documentation must demonstrate that the member has a close relative with a known pathogenic or likely pathogenic variant. "Close relatives" are defined to include first-, second-, and third-degree blood relatives (for example: parents, siblings, children; grandparents, aunts/uncles, nieces/nephews; great grandparents and first cousins).

Coverage for known familial variant (targeted) analysis is limited to situations where a familial pathogenic or likely pathogenic variant has already been identified in a close relative. If no affected family member with the known variant is documented, targeted familial testing is investigational and not covered; when possible, testing should start with an affected relative to identify the specific variant to be used for targeted testing.

Eligibility for covered genetic testing generally requires clinical documentation that supports the indication for testing. For familial targeted testing, this includes documentation of the affected relative and the identified pathogenic or likely pathogenic variant. For panel-based or broad testing, supporting clinical findings, biochemical results, and prior nondiagnostic testing (as applicable) should be provided to demonstrate medical necessity.

When requesting testing, include clear clinical indication, relevant family history, and prior test results. For mitochondrial testing consider providing results of conventional biochemical studies and any prior tissue testing; for monogenic diabetes provide age at diagnosis and autoimmune or C-peptide data as applicable.

Documentation supporting genetic test requests should be specific and concise: list the clinical features prompting testing, cite the affected family member and variant when seeking targeted testing, and attach prior laboratory or imaging results that are relevant to the diagnostic evaluation.

Not Covered / Investigational

Targeted analysis for the MTHFR polymorphisms reported with CPT 81291 is considered investigational for all indications and is therefore not covered for any clinical purpose.

Tests described as investigational when used outside the explicit clinical criteria include: targeted familial variant testing when no close relative has a documented pathogenic or likely pathogenic variant; monogenic diabetes (MODY) panels performed outside the defined age/biomarker/family-history criteria; and mitochondrial genome sequencing, deletion/duplication, or nuclear gene analysis when the clinical phenotype and required prior diagnostic workup are not met.

MTHFR polymorphism testing is not supported for evaluation of thrombophilia, for investigation of recurrent pregnancy loss, or for testing asymptomatic at-risk family members per ACMG guidance. Because these uses lack clinical utility, such testing is considered not medically necessary.

Background and Definitions

Hereditary metabolic, non-cancerous endocrine, and mitochondrial disorders are genetic conditions that can present at any age and often have multisystem manifestations. Mitochondrial disorders may arise from variants in either the mitochondrial genome or nuclear genes that support mitochondrial function, and clinical presentations are frequently nonspecific and overlapping.

Because clinical features can be heterogeneous, the policy emphasizes a structured diagnostic approach: when the phenotype is suggestive, begin with appropriate biochemical and diagnostic testing; if testing is nondiagnostic and suspicion persists, proceed to molecular testing using recommended methodologies (for mtDNA prefer NGS and consider tissue testing when blood is negative).

Definition — Primary mitochondrial disorder (mtDNA / nuclear gene causes)

DefinitionPrimary mitochondrial disorder: disorders caused by dysfunction of the mitochondrial respiratory chain due to mutations in mitochondrial DNA (mtDNA) or nuclear genes supporting mitochondrial function.

Genetic causesMay be caused by mtDNA variants (maternal inheritance) or nuclear DNA variants (autosomal recessive or autosomal dominant inheritance).

Gene countOver 1,000 nuclear genes code for proteins that support mitochondrial function.

Policy Summary

PayerWellCare

PolicyGenetic Testing: Metabolic, Endocrine, and Mitochondrial Disorders

Policy CodePolicy N/A

Change TypeCriteria and methodology revisionscoding updates

Effective DateN/A

Next Review DateN/A

Key ActionBegin testing with an affected family member when possible to identify the familial pathogenic variant before testing at-risk relatives.

SourceLink

On This Page

Follow Mitochondrial Medicine Society recommendations for methodology and tissue selection.

MTHFR variant analysis guidance: ACMG recommends against MTHFR polymorphism testing for thrombophilia or recurrent pregnancy loss and for testing at‑risk family members; MTHFR genotype does not change standard folic acid recommendations for women of childbearing age.

MTHFR targeted variant analysis (CPT 81291) is investigational for all indications.

Monogenic diabetes (MODY) testing approach: Infants with diabetes diagnosed in the first 12 months should have immediate molecular testing; consider testing select patients diagnosed before age 30 without typical T1D/T2D features. Consultation with diabetes genetics centers or clinical geneticists is recommended for interpretation and management.

Updated criteria removed requirement for specific genes in panels and revised age/biomarker thresholds per recent guideline updates.

This list is not comprehensive; other disorders may be evaluated under the General Approach policy.

Suspected mitochondrial disease criteria

Suspected mitochondrial disease is covered when supporting clinical features and prior diagnostic testing requirements are met

Suspected mitochondrial disease — clinical and lab support: Coverage is appropriate when the member has either a classic maternally inherited phenotype OR non‑specific features suggestive of mitochondrial disease plus: (1) at least two specified clinical features from the policy's list (e.g., ptosis, external ophthalmoplegia, proximal myopathy, exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, diabetes mellitus, fluctuating encephalopathy, seizures, dementia, migraine, stroke‑like episodes, ataxia, spasticity, chorea, multiple late term pregnancy loss); AND (2) conventional biochemical laboratory studies (including at least plasma or CSF lactic acid, ketone bodies, plasma acylcarnitines, and urinary organic acids) that are non‑diagnostic; AND (3) additional indicated diagnostic testing per presentation completed and non‑diagnostic.

Prefer mtDNA NGS; when blood is negative and suspicion persists, test another tissue (muscle or urine). Follow Mitochondrial Medicine Society recommendations for methodology and tissue selection.

Monogenic diabetes/MODY testing

Covered when ALL of the following are met for monogenic diabetes (MODY) testing in selected patients

MODY testing — neonatal diabetes: All infants diagnosed with diabetes within the first 12 months of life should have molecular genetic testing for neonatal/monogenic diabetes (immediate testing).

ISPAD and ADA guidance recommend immediate testing for infants diagnosed in early life; systematic review supports large‑gene panels for neonatal diabetes.

MODY testing — young adults and select patients: For patients diagnosed before 30 years of age, testing for monogenic diabetes is medically necessary when the patient is autoantibody negative and/or has retained C‑peptide levels, or when the diabetes is not characteristic of type 1 or type 2 diabetes and there is a family history consistent with autosomal dominant inheritance.

Consult diabetes genetics specialty centers or clinical geneticists for interpretation and counseling.

Denial Risk

MODY panels — investigational outside criteria

Multigene MODY panels are covered only when the specific clinical criteria in the policy are met. Use outside those listed indications is investigational and subject to denial.

Covered indications include: diagnosis of diabetes within first 12 months of life; diagnosis before age 30 with either autoantibody negative or retained C‑peptide, or diabetes not characteristic of type 1/2 with autosomal dominant family history.
Investigational when used for other indications (denial risk).

Note

Coverage subject to plan terms

Coverage decisions are subject to each member's plan benefits and medical policy; state Medicaid provisions and Medicare NCDs/LCDs may take precedence where applicable. Verify member eligibility and plan-specific benefits before ordering tests.

Coverage is subject to member contract and plan terms.
For Medicaid members, state Medicaid provisions take precedence over this clinical policy.
For Medicare members, applicable NCDs and LCDs must be reviewed.

Documentation Required

Mitochondrial testing — required documentation and tissue considerations

When ordering mitochondrial testing, include documentation of the clinical findings and prior diagnostic workup. Testing on an inappropriate specimen or without required biochemical testing may result in denial.

Required documentation: detailed clinical phenotype (e.g., ptosis, external ophthalmoplegia, exercise intolerance, seizures, stroke-like episodes, ataxia, spasticity, chorea, recurrent late pregnancy loss, cardiomyopathy, sensorineural deafness, diabetes), results of conventional biochemical studies (plasma or CSF lactic acid, ketone bodies, plasma acylcarnitines, urinary organic acids), and results of additional indicated diagnostic testing (e.g., neuroimaging, ECG, EMG, echocardiography, audiology, thyroid testing, EEG).
Tissue selection considerations: if blood testing is negative but suspicion remains high, document rationale and testing of alternate tissue (e.g., skeletal muscle, urine/buccal epithelium, skin fibroblasts) due to heteroplasmy and tissue-specific variant detection.

Prior Authorization

Preferred testing sequence — start with affected family member

When a familial pathogenic variant is suspected, begin testing with an affected family member when possible to identify the specific familial pathogenic variant before offering targeted testing to at-risk relatives.

Preferred sequence: test an affected family member first; if a pathogenic/likely pathogenic variant is identified, offer targeted known-familial-variant analysis to relatives.
Targeted familial variant testing (e.g., 81403–81479) is medically necessary only when a close relative has a known pathogenic or likely pathogenic variant.

Documentation Required

Documentation required for familial variant and MODY testing

For targeted known familial variant testing and for MODY panel coverage, include clear documentation of the known familial variant or the clinical criteria that justify panel testing. Absence of required documentation may lead to a determination of investigational/not covered.

For Known Familial Variant testing: documentation must show a close relative with a confirmed pathogenic or likely pathogenic variant and details of that variant.
For MODY panels: documentation must include age at diagnosis, autoantibody status and/or C‑peptide results, family history consistent with autosomal dominant inheritance, or other policy-specified criteria.

Documentation Required

Recommended pre-test biochemical evaluation

When mitochondrial disorder is suspected, initial biochemical evaluation should include plasma or CSF lactic acid concentration, ketone bodies, plasma acylcarnitines, and urinary organic acids before genomic testing unless clinical urgency warrants otherwise.

Recommended pre-test biochemical tests: plasma or CSF lactic acid, ketone bodies, plasma acylcarnitines, urinary organic acids.
Document results of these studies as nondiagnostic prior to authorization for mitochondrial genomic testing per policy criteria.

Definition — Known familial variant analysis / targeted mutation analysis definition

DefinitionKnown familial variant analysis (targeted mutation analysis): testing for a specific pathogenic or likely pathogenic variant previously identified in a relative.

When coveredMedically necessary when the member has a close relative with a known pathogenic or likely pathogenic variant causing the condition (targeted CPT codes listed in policy).

Recommended approachWhen possible, begin testing with an affected family member to identify the familial pathogenic variant prior to testing at‑risk relatives.

Definition — Close relatives examples (first-, second-, third-degree) and relation list

First‑degree examplesParents, siblings, and children

Second‑degree examplesGrandparents, aunts, uncles, nieces, nephews, grandchildren, and half‑siblings

Third‑degree examplesGreat‑grandparents, great aunts, great uncles, great grandchildren, and first cousins

Definition — Autosomal dominant inheritance definition

DefinitionAutosomal dominant inheritance: a transmission type in which only one mutated copy of a gene is sufficient for an individual to manifest the disease.

Inheritance pattern notesThe mutation can be inherited from either parent and the disorder is typically seen in successive generations; affected members may vary in severity.

Pedigree clueAn affected family history with members in each generation suggests autosomal dominant inheritance.

Definition — Mitochondrial disease overview

OverviewMitochondrial disease: a heterogeneous group of disorders caused by dysfunctional mitochondria affecting oxidative phosphorylation.

Clinical presentationOften multisystem with neurologic and myopathic features; symptoms are frequently nonspecific and can present at any age.

Inheritance patternsCan result from mtDNA variants (maternal transmission) or nuclear gene variants (autosomal recessive or autosomal dominant transmission).