Highmark Commercial Medical Policy - Pennsylvania

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Medical Policy: L-165-004
Topic: Rett Syndrome Testing
Section: Laboratory
Effective Date: November 13, 2017
Issue Date: November 13, 2017
Last Reviewed: June 2017

Rett syndrome is an X-linked disorder of brain development that affects about 1 in 10,000 females. Males are rarely affected. Girls with Rett syndrome appear normal when they are born and as infants but by 6 to 18 months begin to lose motor and language skills, which eventually stabilizes. Classic Rett syndrome is generally diagnosed by established clinical diagnostic criteria. Diagnostic criteria have also been suggested for variant Rett syndrome, but diagnostic criteria are imperfect for reliably diagnosing Rett syndrome. Genetic testing may be useful to confirm a diagnosis (particularly when unclear based on clinical criteria) and to identify the mutation for genetic counseling purposes. Rett syndrome is caused by genetic changes (mutations) in the MECP2 gene, located on the X chromosome. Females have two X chromosomes and males have one X chromosome and one Y chromosome.

This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.

Policy Position Coverage is subject to the specific terms of the member’s benefit plan.

MECP2 known familial mutation analysis may be considered medically necessary when the following criteria are met:

  • Genetic Counseling:
    • Pre and post-test genetic counseling by an appropriate provider; and
  • Previous Testing:
    • No previous genetic testing of MECP2; and 
    • MECP2 mutation identified in 1st degree biologic relative; or
  • Prenatal Testing for At-Risk Pregnancies:
    • MECP2 mutation identified in a previous child of either parent.
Procedure Codes

MECP2 sequencing may be considered medically necessary when the following criteria are met:

  • Genetic Counseling:
    • Pre and post-test genetic counseling by an appropriate provider; and
  • Previous Testing:
    • No previous MECP2 sequencing/scanning; and
    • No known MECP2 mutation in family; and 
  • Diagnostic Testing for Symptomatic Individuals:
    • Meets clinical diagnostic criteria for classic Rett syndrome, atypical Rett syndrome or probable or possible Rett syndrome; and
    • Genetic testing is necessary because there is uncertainty in clinical diagnosis.
Procedure Codes

MECP2 deletion/duplication analysis may be considered medically necessary when the following criteria are met:

  • Previous testing:
    • No previous deletion/duplication analysis of MECP2; and
    • No mutations detected in full sequencing/scanning of MECP2.
Procedure Codes

Professional Statements and Societal Positions

The National Institute for Health and Clinical Excellence (NICE) released evidence-based guidelines titled “Autism: Recognition, referral and diagnosis of children and young people on the autism spectrum,” in 2011. The guidelines state that Rett syndrome should be considered in the case of developmental regression and that genetic testing for such conditions should be considered on an individual basis.

The consensus guideline from the American Academy of Pediatrics (2006) on the clinical genetic evaluation of a child with mental retardation (MR) or developmental delays (DD) states that:

  • "Molecular genetic diagnostic testing is used to establish the genetic etiology for DD/MR when the diagnosis is considered established clinically (e.g. a girl who fulfills established clinical diagnostic criteria for typical Rett syndrome) or suspected clinically."
  • "The clinical geneticist may suggest testing for MECP2 mutation when the patient does not fulfill the clinical diagnostic criteria for the syndrome in question but when deemed appropriate to address the question of an 'atypical presentation' of the known clinical syndrome."

No evidence-based U.S. testing guidelines for carrier testing are identified.

Approximately 99% of cases of Rett syndrome are the result of a new genetic change (de novo mutation) in the affected person and are not inherited from a carrier parent. Cases of minimally affected or unaffected female carriers of MECP2 mutations have been reported.

Cases of MECP2 mutations in only the germline (egg or sperm) of parents of affected people have been reported. In one study, prenatal diagnosis was offered to nine couples who had a previous child with Rett syndrome due to a known de novo MECP2 mutation. One of the nine pregnancies was found to have the same MECP2 mutation as in the affected sibling. Another similar study of three families did not find the known de novo familial MECP2 mutation during prenatal diagnosis. However, these authors suggest that since germline mosaicsm cannot be predicted or ruled out in families who have a child with Rett syndrome, prenatal diagnosis should be offered. If a mutation of unclear significance is found in an affected person, testing both the mother and the father may be appropriate to help to determine if the mutation is actually causing the disease.

Place of Service: Outpatient

Rett Syndrome Testing is typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.

The policy position applies to all commercial lines of business

Denial Statements

Services that do not meet the criteria of this policy will not be considered medically necessary. A network provider cannot bill the member for the denied service unless: (a) the provider has given advance written notice, informing the member that the service may be deemed not medically necessary; (b) the member is provided with an estimate of the cost; and (c) the member agrees in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.


Medical policies do not constitute medical advice, nor are they intended to govern the practice of medicine. They are intended to reflect Highmark's reimbursement and coverage guidelines. Coverage for services may vary for individual members, based on the terms of the benefit contract.

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The Claims Administrator/Insurer complies with applicable Federal civil rights laws and does not discriminate on the basis of race, color, national origin, age, disability, or sex. The Claims Administrator/Insurer does not exclude people or treat them differently because of race, color, national origin, age, disability, or sex. The Claims Administrator/ Insurer:
  • Provides free aids and services to people with disabilities to communicate effectively with us, such as:
    • Qualified sign language interpreters
    • Written information in other formats (large print, audio, accessible electronic formats, other formats)
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    • Qualified interpreters
    • Information written in other languages
If you need these services, contact the Civil Rights Coordinator.

If you believe that the Claims Administrator/Insurer has failed to provide these services or discriminated in another way on the basis of race, color, national origin, age, disability, or sex, you can file a grievance with: Civil Rights Coordinator, P.O. Box 22492, Pittsburgh, PA 15222, Phone: 1-866-286-8295, TTY: 711, Fax: 412-544-2475, email: CivilRightsCoordinator@highmarkhealth.org. You can file a grievance in person or by mail, fax, or email. If you need help filing a grievance, the Civil Rights Coordinator is available to help you.

You can also file a civil rights complaint with the U.S. Department of Health and Human Services, Office for Civil Rights electronically through the Office for Civil Rights Complaint Portal, available at https://ocrportal.hhs.gov/ocr/portal/lobby.jsf, or by mail or phone at:

U.S. Department of Health and Human Services
200 Independence Avenue, SW
Room 509F, HHH Building
Washington, D.C. 20201
1-800-368-1019, 800-537-7697 (TDD)

Complaint forms are available at http://www.hhs.gov/ocr/office/file/index.html.

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Highmark retains the right to review and update its medical policy guidelines at its sole discretion. These guidelines are the proprietary information of Highmark. Any sale, copying or dissemination of the medical policies is prohibited; however, limited copying of medical policies is permitted for individual use.

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