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Concert Genetic Testing: Metabolic, Endocrine, and Mitochondrial
Disorders
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Coding Implications

# CONCERT GENETIC TESTING: METABOLIC, ENDOCRINE, AND MITOCHONDRIAL DISORDERS

See [Important Reminder](#) at the end of this policy for important regulatory and legal
information.

## OVERVIEW

Hereditary metabolic disorders, also known as inborn errors of metabolism, are genetic disorders
that interfere with the body’s metabolism. There are hundreds of inherited metabolic disorders, and
many are screened for at birth through newborn screening programs, while others are identified
after a child or adult shows symptoms of the disorder. Genetic testing for metabolic disorders aids
in quickly identifying the specific disorder so that proper treatment can be initiated and at-risk
family members can be identified.

Hereditary endocrine disorders are a group of conditions involving the endocrine system, a network
of glands that produce and release hormones in order to regulate body functions. This document
aims to address hereditary endocrine disorders that are non-cancerous in nature.

MTHFR variants can affect metabolism of homocysteine; however, the treatment for elevated
homocysteine levels is the same regardless of MTHFR status. The test is generally recognized as
having little clinical utility and therefore is not generally recommended.

Mitochondrial disorders are a clinically heterogeneous group of disorders caused by dysfunction of
the mitochondrial respiratory chain. The diagnosis of a primary mitochondrial disease can be
difficult, as the individual symptoms are nonspecific and symptom patterns often overlap
significantly. Mitochondrial disorders can be caused by mutations in the genes encoded by the
mitochondrial DNA (mtDNA), which are transmitted by maternal inheritance, or by genes encoded
by the nuclear DNA, which are transmitted in an autosomal recessive or autosomal dominant
manner. There are over 1000 nuclear genes coding for proteins that support mitochondrial function.
These disorders can present at any age and many involve multiple organ systems, often with

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neurologic and myopathic features. Of note, a family history in which affected women transmit the
disease to male and female children and affected men do not transmit the disease to their children
suggests the familial variant(s) is in the mtDNA, rather than in a nuclear gene.

Genetic testing for metabolic, endocrine, and mitochondrial disorders aids in identifying the
specific disorder that is present, so that proper treatment (if any) can be initiated, and at-risk
family members can be identified.

# POLICY REFERENCE TABLE

## Coding Implications

This clinical policy references Current Procedural Terminology (CPT®. CPT is a registered
trademark of the American Medical Association. All CPT codes and descriptions are copyrighted
2023, American Medical Association. All rights reserved. CPT codes and CPT descriptions are
from the current manuals and those included herein are not intended to be all-inclusive and are
included for informational purposes only. Codes referenced in this clinical policy are for
informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage.
Providers should reference the most up-to-date sources of professional coding guidance prior to the
submission of claims for reimbursement of covered services.

The tests, associated laboratories, CPT codes, and ICD codes contained within this document
serve only as examples to help users navigate claims and corresponding criteria; as such, they are
not comprehensive and are not a guarantee of coverage or non-coverage. Please see the [Concert
Platform](#) for a comprehensive list of registered tests.

| Criteria Sections | Example Tests (Labs) | Common CPT Codes | Common ICD Codes | Ref |
|-------------------|---------------------|-----------------|-----------------|-----|
| MTHFR Variant Analysis | Methylene tetrahydrofolate Reductase (MTHFR) Thermolabile Variant, DNA Analysis (LabCorp) <br> Methylene tetrahydrofolate Reductase (MTHFR), DNA Mutation Analysis (Quest Diagnostics) | 81291 | E03.9, E55.9, E72.12, E78.2, E78.5, E88.9, O03, N96, R53.83, Z00.00 | 1, 2 |

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| Monogenic Diabetes (Including Maturity Onset Diabetes of the Young (MODY)) | Maturity Onset Diabetes of the Young (MODY) Panel (PreventionGenetics, part of Exact Sciences) <br> Maturity-onset diabetes of the young (MODY) (Ambry Genetics) <br> Monogenic Diabetes (MODY) Five Gene Evaluation (GCK,HNF1A,HNF1B,HNF4A,IPF1) (Athena Diagnostics Inc) | 81403, 81405, 81406, 81407, 81479 | E10, E11, E16.15, 11, E16.2 | 12 |
| Mitochondrial Genome Sequencing, Deletion/Duplication, and/or Nuclear Genes | Mito Genome Sequencing & Deletion Testing (GeneDx) <br> Mitochondrial Full Genome Analysis, Next-Generation Sequencing (NGS), Varies (Mayo Clinic Laboratories) <br> Nuclear Mitochondrial Gene Panel, Next-Generation Sequencing, Varies (Mayo Clinic Laboratories) <br> MitoXpanded Panel (GeneDx) <br> Genomic Unity Comprehensive Mitochondrial Disorders Analysis (Variantyx) | 81460, 81465 <br> 81440 <br> 0417U | E88.40, E88.41, E88.42, E88.49, G31.82, H49.811- H49.819 | 3, 4 |
| Other Covered Metabolic, Endocrine, and Mitochondrial Disorders | See list below | 81400-81408, 81205, 81250 | 6, 7, 8, 9, 10 |  |

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# OTHER RELATED POLICIES

This policy document provides criteria for metabolic, endocrine, and mitochondrial disorders.
Please refer to:
* Genetic Testing: Prenatal and Preconception Carrier Screening for criteria related to
  prenatal or preconception carrier screening.
* Genetic Testing: Prenatal Diagnosis (via amniocentesis, CVS, or PUBS) and Pregnancy
  Loss for criteria related to prenatal and pregnancy loss diagnostic genetic testing.
* Genetic Testing: Preimplantation Genetic Testing for criteria related to genetic testing of
  embryos prior to in vitro fertilization.
* Genetic Testing: Multisystem Inherited Disorders, Intellectual Disability, and
  Developmental Delay for criteria related to genetic disorders that affect multiple organ
  systems.
* Genetic Testing: Hereditary Cancer Susceptibility Syndromes for criteria related to
  genetic testing for hereditary endocrine cancer predisposition syndromes.
* Genetic Testing: General Approach to Genetic and Molecular Testing for criteria related
  to metabolic, endocrine, and mitochondrial disorders not specifically discussed in this or
  another non-general policy, including known familial variant testing.

[back to top](#)

# CRITERIA

It is the policy of health plans affiliated with Centene Corporation® that the specific genetic testing
noted below is medically necessary when meeting the related criteria:



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[back to top](#)

# MONOGENIC DIABETES (INCLUDING MATURITY-ONSET DIABETES OF THE YOUNG (MODY))


   C. The member/enrollee has a diagnosis of diabetes not characteristic of type 1 or type
      2 diabetes, AND
      1. The member/enrollee has a family history of diabetes consistent with an
         autosomal dominant pattern of inheritance.

II. Multigene panel analysis to establish or confirm a diagnosis of monogenic diabetes
    (maturity-onset diabetes of the young (MODY)) (81403, 81404, 81405, 81406, 81407,
    81479) is considered investigational for all other indications.

[back to top](#)

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# MITOCHONDRIAL GENOME SEQUENCING, DELETION/DUPLICATION, AND/OR NUCLEAR GENES


   B. The member/enrollee has non-specific clinical features suggestive of a primary
      mitochondrial disorder and meets ALL of the following:
      1. Clinical findings of at least two of the following:
         a) Ptosis, OR
         b) External ophthalmoplegia, OR
         c) Proximal myopathy, OR
         d) Exercise intolerance, OR
         e) Cardiomyopathy, OR
         f) Sensorineural deafness, OR
         g) Optic atrophy, OR
         h) Pigmentary retinopathy, OR
         i) Diabetes mellitus, OR
         j) Fluctuating encephalopathy, OR
         k) Seizures, OR
         l) Dementia, OR
         m) Migraine, OR
         n) Stroke-like episodes, OR
         o) Ataxia, OR
         p) Spasticity, OR
         q) Chorea, OR
         r) Multiple late term pregnancy loss, AND
      2. Conventional biochemical laboratory studies have been completed and are
         non-diagnostic, including at least: plasma or CSF lactic acid concentration,
         ketone bodies, plasma acylcarnitines, and urinary organic acids, AND
      3. Additional diagnostic testing indicated by the member/enrollee’s clinical
         presentation (e.g., fasting blood glucose, electrocardiography, neuroimaging,
         electromyography, echocardiography, audiology, thyroid testing,
         electroencephalography, exercise testing) have been completed and are non-
         diagnostic.

II. Mitochondrial genome sequencing (81460), deletion/duplication (81465), and/or nuclear
    genes analysis (81440) to establish or confirm a diagnosis of a primary mitochondrial
    disorder is considered investigational for all other indications.

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[back to top](#)

# OTHER COVERED METABOLIC, ENDOCRINE, AND MITOCHONDRIAL DISORDERS

The following is a list of conditions that have a known genetic association. Due to their relative
rareness, it may be appropriate to cover these genetic tests to establish or confirm a diagnosis.

I. Genetic testing to establish or confirm one of the following metabolic, endocrine, and
   mitochondrial conditions to guide management is considered medically necessary when
   the member/enrollee demonstrates clinical features* consistent with the disorder (the list
   is not meant to be comprehensive, see II below):
   A. Congenital adrenal hyperplasia, including:
      1. 21-Hydroxylase deficiency
   B. Congenital disorders of glycosylation
   C. Congenital hyperinsulinism
   D. Disorders of amino acid and peptide metabolism, including:
      1. Glutaric acidemia type I (GA-1)
      2. Homocystinuria caused by cystathionine beta-synthase (CBS) deficiency
      3. Methylmalonic acidemia
      4. Propionic acidemia
      5. Maple Syrup Urine Disease (MSUD)
   E. Disorders of biotin metabolism, including:
      1. Biotinidase deficiency
   F. Disorders of carnitine transport and the carnitine cycle, including:
      1. Carnitine palmitoyltransferase II deficiency
      2. Primary carnitine deficiency
   G. Disorders of copper metabolism, including:
      1. ATP7A-Related copper transport disorders (e.g., Menkes disease, occipital
         horn syndrome (OHS), ATP7A-related distal motor neuropathies)
      2. Wilson disease
   H. Disorders of fatty acid oxidation, including:
      1. Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCAD
         deficiency)
   I. Disorders of galactose metabolism, including:
      1. Galactosemia
   J. Disorders of glucose transport, including:
      1. Glucose transporter type 1 deficiency syndrome (Glut1 DS)
   K. Disorders of phenylalanine or tyrosine metabolism, including:
      1. Alkaptonuria
      2. Phenylalanine hydroxylase deficiency
   L. Disorders of porphyrin and heme metabolism, including:
      1. Acute intermittent porphyria
   M. Fibrous Dysplasia/McCune-Albright Syndrome
   N. Glycogen storage disorders, including:
      1. Glycogen Storage Disease Type I (GSDI)
      2. Pompe disease (GSDII)
   O. Hypophosphatasia
   P. Kallmann syndrome (GnRH deficiency)
   Q. Lysosomal storage disorders, including:
      1. Gaucher disease
      2. Krabbe disease
      3. MPS-Type I (Hurler syndrome)
      4. MPS-Type II (Hunter syndrome)
      5. Mucolipidosis IV
   R. Urea cycle disorders, including:
      1. Ornithine Transcarbamylase (OTC) deficiency
   S. Malignant hyperthermia
   T. SHOX deficiency disorders.

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II. Genetic testing to establish or confirm the diagnosis of all other metabolic, endocrine, and
   mitochondrial disorders not specifically discussed within this or another medical policy will
   be evaluated by the criteria outlined in General Approach to Genetic and Molecular Testing
   (see policy for criteria).

*Clinical features for a specific disorder may be outlined in resources such as GeneReviews, OMIM, National Library
of Medicine, Genetics Home Reference, or other scholarly sources.

[back to top](#)

# DEFINITIONS

1. Mitochondrial disease refers to a heterogenous group of disorders caused by
   dysfunctional mitochondria, the organelles responsible for oxidative phosphorylation
   within the cell.
2. Autosomal dominant inheritance refers to a type of transmission of a genetic condition
   in which only one mutated copy of a gene (rather than two) is necessary for an individual
   to manifest the disease. The mutation can be inherited from either parent, and the disease
   can typically be seen in any sex. A pedigree (family history) that has an autosomal
   dominant disorder will typically have affected family members in each generation,
   though some family members may be more severely affected than others.

[back to top](#)

# BACKGROUND AND RATIONALE

## METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR)

### MTHFR Variant Analysis

American College of Medical Genetics and Genomics (ACMG)

ACMG published a practice guideline for MTHFR polymorphism testing (2013, confirmed 2020)
with the following recommendations:
* MTHFR polymorphism genotyping should not be ordered as part of the clinical evaluation
  for thrombophilia or recurrent pregnancy loss
* MTHFR polymorphism genotyping should not be ordered for at-risk family members (p.
  154)

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# MONOGENIC DIABETES (INCLUDING MATURITY-ONSET DIABETES OF THE YOUNG (MODY))

## Monogenic Diabetes (Including Maturity-Onset Diabetes of the Young (MODY)) Panels

American Diabetes Association

In 2021, the American Diabetes Association made the following recommendations:
* All children diagnosed with diabetes in the first 6 months of life should have immediate
  genetic testing for neonatal diabetes. (Category A)
* Children and those diagnosed in early adulthood who have diabetes not characteristic of
  type 1 or type 2 diabetes that occurs in successive generations (suggestive of an autosomal
  dominant pattern of inheritance) should have genetic testing for maturity-onset diabetes of
  the young. (Category A)
* In both instances, consultation with a center specializing in diabetes genetics is
  recommended to understand the significance of these mutations and how best to approach
  further evaluation, treatment, and genetic counseling. (Category E) (p. 525)

Murphy, et al.

Murphy, et al (2023) performed a systematic review and issued an expert opinion on how to use
precision diagnostics to identify individuals with monogenic diabetes. The article states that the
following individuals should be offered testing for monogenic diabetes:
1. All patients diagnosed with diabetes before the age of 6 months should be tested for
   monogenic forms of neonatal diabetes using the large-gene panel.
2. All patients diagnosed between 6 and 12 months should be tested for monogenic forms of
   neonatal diabetes using the large-gene panel. No demonstrable yield of monogenic etiology
   to support reflexive genetic testing patients diagnosed with diabetes between 12-24 months.
3. Women with gestational diabetes and fasting glucose above 5.5 mmol/L without obesity*
   should be tested for GCK etiology.
4. Those with persisting, mild hyperglycemia (HbA1c 38–62 mmol/mol, or fasting glucose
   5.5–7.8 mmol/L) at any age, in the absence of obesity* should be tested for GCK etiology.

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5. People without obesity under the age of 30 years who are either autoantibody negative  
   and/or have retained C-peptide levels should be tested for monogenic diabetes using a  
   large-gene panel. (p.10)  

International Society for Pediatric and Adolescent Diabetes (ISPAD)  

In 2022, the International Society for Pediatric and Adolescent Diabetes (ISPAD) released a  
clinical practice consensus guideline for the diagnosis and management of monogenic diabetes in  
children and adolescents. The statement includes the following recommendations for genetic  
testing in the setting of neonatal diabetes and maturity onset diabetes of the young:  

“All infants diagnosed with diabetes in the first 6 months of life are recommended to have  
immediate molecular genetic testing. Genetic testing may be considered in infants diagnosed  
between 6 and 12 months, especially in those without islet autoantibodies or who have other  
features suggestive of a monogenic cause.” (p. 1190)  

“The diagnosis of maturity onset diabetes of the young (MODY) is recommended in the following  
scenarios: family history of diabetes in a parent and first-degree relatives of that affected parent in  
persons with diabetes who lack the characteristics of T1D and T2D.” (p. 1191)  

Mitochondrial Genome Sequencing, Deletion/Duplication, and/or Nuclear Genes  

Mitochondrial Medicine Society  

The Mitochondrial Medicine Society (2015) published the following consensus recommendations  
for DNA testing for mitochondrial disorders:  

1. Massively parallel sequencing/NGS of the mtDNA genome is the preferred methodology  
   when testing mtDNA and should be performed in cases of suspected mitochondrial disease  
   instead of testing for a limited number of pathogenic point mutations.  

2. Patients with a strong likelihood of mitochondrial disease because of a mtDNA mutation  
   and negative testing in blood, should have mtDNA assessed in another tissue to avoid the  
   possibility of missing tissue-specific mutations or low levels of heteroplasmy in blood;  
   tissue-based testing also helps assess the risk of other organ involvement and heterogeneity  
   in family members and to guide genetic counseling.  

3. Heteroplasmy analysis in urine can selectively be more informative and accurate than  
   testing in blood alone, especially in cases of MELAS due to the common m. 3243A>G  
   mutation.  

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4. mtDNA deletion and duplication testing should be performed in cases of suspected  
   mitochondrial disease via NGS of the mtDNA genome, especially in all patients undergoing  
   a diagnostic tissue biopsy.  

   a. If a single small deletion is identified using polymerase chain reaction–based  
      analysis, then one should be cautious in associating these findings with a primary  
      mitochondrial disorder.  

   b. When multiple mtDNA deletions are noted, sequencing of nuclear genes involved in  
      mtDNA biosynthesis is recommended.  

5. When a tissue specimen is obtained for mitochondrial studies, mtDNA content (copy  
   number) testing via real-time quantitative polymerase chain reaction should strongly be  
   considered for mtDNA depletion analysis because mtDNA depletion may not be detected in  
   blood.  

   a. mtDNA proliferation is a nonspecific compensatory finding that can be seen in  
      primary mitochondrial disease, secondary mitochondrial dysfunction, myopathy,  
      hypotonia, and as a by-product of regular, intense exercise.  

6. When considering nuclear gene testing in patients with likely primary mitochondrial  
   disease, NGS methodologies providing complete coverage of known mitochondrial disease  
   genes is preferred. Single-gene testing should usually be avoided because mutations in  
   different genes can produce the same phenotype. If no known mutation is identified via  
   known NGS gene panels, then whole exome sequencing should be considered. (p. 692-693)  

GeneReviews: Primary Mitochondrial Disorders Overview  

GeneReviews is an expert-authored review of current literature on a genetic disease, and goes  
through a rigorous editing and peer review process before being published online. Their  
recommendations are as follows:  

Common clinical features of mitochondrial disorders include:  

- ptosis  
- external ophthalmoplegia  
- proximal myopathy  
- exercise intolerance  
- cardiomyopathy  
- sensorineural deafness  
- optic atrophy  
- pigmentary retinopathy  

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- diabetes mellitus  
- fluctuating encephalopathy  
- seizures  
- dementia  
- migraine  
- stroke-like episodes  
- ataxia  
- spasticity  
- chorea  
- high incidence of mid- and late-pregnancy loss  

When a patient’s clinical picture is nonspecific but highly suggestive of a mitochondrial disorder,  
the clinician should start with measurement of plasma or CSF lactic acid concentration, ketone  
bodies, plasma acylcarnitines, and urinary organic acids.  

Traditionally, the diagnosis of mitochondrial disorders has been based on demonstrating  
mitochondrial dysfunction in a relevant tissue biopsy (e.g., a skeletal muscle or liver biopsy, or skin  
fibroblasts), with the particular pattern of biochemical abnormality being used to direct targeted  
molecular genetic testing of mtDNA, specific nuclear genes, or both.  

However, the more widespread availability of molecular diagnostic techniques and the advent of  
exome and genome sequencing has changed the diagnostic approach.  

One important caveat arises from the fact that many mtDNA pathogenic variants are heteroplasmic,  
and the proportion of mutated mtDNA in blood may be undetectable. This can be circumvented by  
analyzing mtDNA from another tissue – typically skeletal muscle or urinary epithelium – in which  
the level of heteroplasmy tends to be higher. Some common mtDNA pathogenic variants (e.g.,  
large-scale deletions causing CPEO) may only be detected in skeletal muscle.  

In individuals with a specific clinical phenotype (e.g., MELAS, LHON, POLG-related disorders) it  
may be possible to reach a diagnosis with targeted analysis of specific mtDNA pathogenic variants  
or single-gene testing of a nuclear gene.  

A mitochondrial disorders multigene panel is most likely to identify the genetic cause of the  
condition while limiting identification of variants of uncertain significance and pathogenic variants  
in genes that do not explain the underlying phenotype.  

Comprehensive genomic testing does not require the clinician to determine which gene is likely  
involved. Such testing includes exome sequencing, genome sequencing, and mitochondrial  
sequencing which can simultaneously analyze nuclear DNA and mtDNA.  

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| Reviews, Revisions, and Approvals | Revision Date | Approval Date |  
|----------------------------------|--------------|--------------|  
| Policy developed.                | 03/23        | 03/23        |  
| Semi-annual review. Updated title to reflect V1.2024 version. Overview, coding, reference-table, background and references updated. Throughout policy: replaced “coverage criteria” with “criteria”. For MTHFR Variant Analysis: under 1. added “but not limited to:”. For Mitochondrial Genome Sequencing, Deletion/Duplication, and/or Nuclear Genes Panel: under I.B.1.1. removed “and deafness”. For Other Covered Metabolic, Endocrine, and Mitochondrial Disorders Panel: under II. Added “and Molecular”; added II.3. “Autosomal dominant inheritance...”. For Background and Rationale: Known Familial Variant Analysis for Metabolic, Endocrine, and Mitochondrial Disorders panel: replaced “inheritance patterns” with “genetic testing”; under MTHFR Variant Analysis: added “. Confirmed 2020”. | 10/23        | 10/23        |  
| Updated table, criteria section labels, and background for maturity-onset diabetes of the young to state “Monogenic diabetes of the young (including maturity-onset diabetes of the young (MODY)”. Updated monogenic diabetes of the young criteria: In I.A., changed from requiring the diabetes diagnosis within the first six months of life to the first 12 months of life. In I.B., changed requirement for the month to have the diagnosis before age 35 years to age 30 years; reworded option for autoantibodies; reworded C-peptide criteria to remove specific values and the requirement for hypoglycemia; replaced criteria for specific features of atypical type 2 diabetes with “diagnosis of diabetes not characteristic of type 1 or type 2 diabetes”; removed requirement for inclusion of specific genes in the panel. Background for monogenic diabetes updated. | 01/24        | 01/24        |  
| Semi-annual review. Updated title to reflect V2.2024 version. In Known Familial Variant Analysis for Metabolic, Endocrine, and Mitochondrial Disorders, moved criteria to policy “Genetic Testing: General Approach to Genetic and Molecular Testing” to consolidate criteria for known familial variant tests. In Monogenic Diabetes (Including Maturity-Onset Diabetes of the Young (MODY)) Panels, criteria set name changed (formerly “Maturity-Onset Diabetes of the Young (MODY)”). Minor rewording for clarity throughout. Coding, reference-table, background and references updated. | 04/24        | 04/24        |  
| Semi-annual review. Updated title to reflect V1.2025. MTHFR Variant Analysis: Streamlined portions of Background and Rationale section for brevity. | 11/24        | 11/24        |  

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