Concert Genetics Genetic Testing: Metabolic, Endocrine, and Mitochondrial Disorders Form

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Concert Genetics Genetic Testing: Metabolic, Endocrine, and Mitochondrial Disorders  
V2.2024  
Date of Last Revision: 04/24  

Revision log  
Coding Implications  

# CONCERT GENETICS 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.  

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 can be transmitted in an autosomal recessive or autosomal dominant manner. There are over 1000 nuclear genes coding for proteins that support mitochondrial function.  

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Concert Genetics Genetic Testing: Metabolic, Endocrine, and Mitochondrial Disorders  
V2.2024  
Date of Last Revision: 04/24  

These disorders can present at any age and many involve multiple organ systems, often with neurologic and myopathic features.  

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.  

Of note, a family history in which affected parents with female reproductive systems transmit the disease to children with male or female reproductive systems and affected parents with male reproductive systems do not transmit the disease to their children suggests the familial variant(s) is in the mtDNA, rather than in a nuclear gene.  

## 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 and associated laboratories and CPT 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 Genetics Platform for a comprehensive list of registered tests.  

| Criteria Sections | Example Tests (Labs) | Common CPT Codes | Common ICD Codes | Ref |
|-------------------|---------------------|-----------------|-----------------|-----|
| MTHFR Variant Analysis | Methylenetetrahydrofolate Reductase (MTHFR) Thermolabile Variant, DNA Analysis (Labcorp) | 81291 | E03.9, E55.9, E72.12, E78.2, E78.5, E88.9, O03, N96, R53.83, Z00.00 | 1, 2 |
|                   | Methylenetetrahydrofolate Reductase (MTHFR), DNA Mutation Analysis (Quest Diagnostics) |     |                 |     |
| Monogenic Diabetes (Including Maturity Onset Diabetes of the Young (MODY)) | Maturity Onset Diabetes of the Young (MODY) Panel (PreventionGenetics, part of Exact Sciences) | 81403, 81405, 81406, 81407, 81479 | E10, E11, E16.15, 11, E16.2 | 12 |
|                   | Maturity-onset diabetes of the young (MODY) (Ambry Genetics) |     |                 |     |
|                   | Monogenic Diabetes (MODY) Five Gene Evaluation (GCK,HNF1A,HNF1B,HNF4A,IPF1) (Athena Diagnostics Inc) |     |                 |     |
| Mitochondrial Genome Sequencing, Deletion/Duplication, and/or Nuclear Genes | Mito Genome Sequencing & Deletion Testing (GeneDx) | 81460, 81465 | E88.40, E88.41, E88.42, E88.49, G31.82, H49.811-H49.819 | 3, 4 |
|                   | Mitochondrial Full Genome Analysis, Next-Generation Sequencing (NGS), Varies (Mayo Clinic Laboratories) |     |                 |     |
|                   | Nuclear Mitochondrial Gene Panel, Next-Generation Sequencing, Varies (Mayo Clinic Laboratories) | 81440 |                 |     |
|                   | MitoXpanded Panel (GeneDx) |     |                 |     |

CENTENE Corporation  

Concert Genetics Genetic Testing: Metabolic, Endocrine, and Mitochondrial Disorders  
V2.2024  
Date of Last Revision: 04/24  

|                   | Genomic Unity Comprehensive Mitochondrial Disorders Analysis (Variantyx) | 0417U |     |     |
|-------------------|---------------------------------------------------------------------|-------|-----|-----|
| Other Covered Metabolic, Endocrine, and Mitochondrial Disorders | See list below | 81400-81408, 81205, 81250 |     | 6, 7, 8, 9, 10 |

## 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 coverage 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.  

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CENTENE Corporation  

Concert Genetics Genetic Testing: Metabolic, Endocrine, and Mitochondrial Disorders  
V2.2024  
Date of Last Revision: 04/24  

# 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:  

  

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.  

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Concert Genetics Genetic Testing: Metabolic, Endocrine, and Mitochondrial Disorders  
V2.2024  
Date of Last Revision: 04/24  

  

*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 source.  

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Concert Genetics Genetic Testing: Metabolic, Endocrine, and Mitochondrial Disorders  
V2.2024  
Date of Last Revision: 04/24  

# DEFINITIONS  

1. Close relatives include first, second, and third degree blood relatives on the same side of the family:  
   a. First-degree relatives are parents, siblings, and children  
   b. Second-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half siblings  
   c. Third-degree relatives are great grandparents, great aunts, great uncles, great grandchildren, and first cousins  
2. Mitochondrial disease refers to a heterogenous group of disorders caused by dysfunctional mitochondria, the organelles responsible for oxidative phosphorylation within the cell.  
3. 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.  

## BACKGROUND AND RATIONALE  

### 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:  

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Concert Genetics Genetic Testing: Metabolic, Endocrine, and Mitochondrial
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• 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
• A clinical geneticist who serves as a consultant for a patient in whom an MTHFR
  polymorphism(s) is found should ensure that the patient has received a thorough and
  appropriate evaluation for his or her symptoms
• If the patient is homozygous for the “thermolabile” variant c.665C to T, the geneticist may
  order a fasting total plasma homocysteine, if not previously ordered, to provide more
  accurate counseling
• MTHFR status does not change the recommendation that women of childbearing age should
  take the standard dose of folic acid supplementation to reduce the risk of neural tube defects
  as per the general population guidelines (p. 154)

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.
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.
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
• 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.

Important Reminder

This clinical policy has been developed by appropriately experienced and licensed health care
professionals based on a review and consideration of currently available generally accepted
standards of medical practice; peer-reviewed medical literature; government agency/program
approval status; evidence-based guidelines and positions of leading national health professional
organizations; views of physicians practicing in relevant clinical areas affected by this clinical
policy; and other available clinical information. The Health Plan makes no representations and
accepts no liability with respect to the content of any external information used or relied upon in
developing this clinical policy. This clinical policy is consistent with standards of medical practice
current at the time that this clinical policy was approved. “Health Plan” means a health plan that
has adopted this clinical policy and that is operated or administered, in whole or in part, by Centene
Management Company, LLC, or any of such health plan’s affiliates, as applicable.

The purpose of this clinical policy is to provide a guide to medical necessity, which is a component
of the guidelines used to assist in making coverage decisions and administering benefits. It does not
constitute a contract or guarantee regarding payment or results. Coverage decisions and the
administration of benefits are subject to all terms, conditions, exclusions, and limitations of the
coverage documents (e.g., evidence of coverage, certificate of coverage, policy, contract of
insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level
administrative policies and procedures.

This clinical policy is effective as of the date determined by the Health Plan. The date of posting
may not be the effective date of this clinical policy. This clinical policy may be subject to
applicable legal and regulatory requirements relating to provider notification. If there is a
discrepancy between the effective date of this clinical policy and any applicable legal or regulatory
requirement, the requirements of law and regulation shall govern. The Health Plan retains the right
to change, amend or withdraw this clinical policy, and additional clinical policies may be
developed and adopted as needed, at any time.

This clinical policy does not constitute medical advice, medical treatment, or medical care. It is not
intended to dictate to providers how to practice medicine. Providers are expected to exercise

professional medical judgment in providing the most appropriate care and are solely responsible for
the medical advice and treatment of member/enrollees. This clinical policy is not intended to
recommend treatment for member/enrollees. Member/enrollees should consult with their treating
physician in connection with diagnosis and treatment decisions.

Providers referred to in this clinical policy are independent contractors who exercise independent
judgment and over whom the Health Plan has no control or right of control. Providers are not
agents or employees of the Health Plan.

This clinical policy is the property of the Health Plan. Unauthorized copying, use, and distribution
of this clinical policy or any information contained herein are strictly prohibited. Providers,
member/enrollees, and their representatives are bound to the terms and conditions expressed herein
through the terms of their contracts. Where no such contract exists, providers, member/enrollees
and their representatives agree to be bound by such terms and conditions by providing services to
member/enrollees and/or submitting claims for payment for such services.

Note: For Medicaid member/enrollees, when state Medicaid coverage provisions conflict with
the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence.
Please refer to the state Medicaid manual for any coverage provisions pertaining to this clinical
policy.

Note: For Medicare member/enrollees, to ensure consistency with the Medicare National
Coverage Determinations (NCD) and Local Coverage Determinations (LCD), all applicable NCDs
and LCDs and Medicare Coverage Articles should be reviewed prior to applying the criteria set
forth in this clinical policy. Refer to the CMS website at http://www.cms.gov for additional
information.