Highmark Commercial Medical Policy - Pennsylvania
Medical Policy: L-152-006
Topic: Prader-Willi Syndrome Testing
Section: Laboratory
Effective Date: July 1, 2018
Issue Date: July 2, 2018
Last Reviewed: March 2018

SNRPN Methylation Analysis: This test is typically the first test in the evaluation of both Angelman syndrome and Prader-Willi syndrome. It will detect about 80% of patients with Angelman syndrome and greater than 99% of patients with Prader-Willi syndrome. However, DNA methylation analysis does not identify the underlying cause, which is important for determining the risk to future siblings. This risk ranges from less than 1% to up to 50%, depending on the genetic mechanism. Follow-up testing for these causes may be appropriate.
 
FISH Analysis for 15q11-q13 Deletion: If DNA methylation analysis for Angelman (AS) or Prader-Willi syndrome (PWS) is abnormal, deletion analysis is typically the next step. Approximately 70% of cases of both AS and PWS have a deletion in one copy of chromosome 15 involving the 15q11.2-q13 region. When looking specifically for this deletion, FISH (fluorescence in situ hybridization) analysis is most commonly performed. However, chromosome microarray can also detect such deletions (see that policy for guidance).If chromosomal microarray (CMA, array CGH) has already been done, FISH is not likely to be necessary.

Chromosome 15 Uniparental Disomy (UPD): If DNA methylation analysis is abnormal but deletion analysis is normal, UPD analysis next may be appropriate for evaluation of both Angelman (AS) and Prader-Willi syndrome (PWS). About 28% of PWS cases are due maternal UPD (both chromosome 15s are inherited from the mother). Both parents must be tested to diagnose UPD.

Imprinting Center Defect Analysis: This test may be considered in the evaluation of Angelman syndrome (AS) and Prader-Willi syndrome (PWS) when methylation is abnormal, but FISH (or array CGH) and UPD studies are normal. Individuals with such results are presumed to have an imprinting defect. An abnormality in the imprinting process has been described in a minority of cases. However, imprinting center deletions may be familial, and if familial, the recurrence risk can be up to 50%.

Imprinting Center Known Familial Mutation Analysis: If a mutation in the imprinting center has been identified in an affected family member, testing for just the known familial mutation in the imprinting center can be performed for at-risk relatives, including at-risk pregnancies.

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.

SNRPN Methylation Analysis may be considered medically necessary for the following indications:

FISH Analysis for 15q11-q13 Deletion may be considered medically necessary  for the following indications:

Chromosome 15 Uniparental Disomy may be considered medically necessary for the following indications:

Imprinting Center Defect Analysis may be considered medically necessary for the following indications:

Imprinting Center Known Familial Mutation Analysis may be considered medically necessary for the following indications

Services that do not meet the above criteria will be considered not medically necessary.

Procedure Codes
81331, 81402, 81403, 81479, 88271

Professional Statements and Societal Positions

The American College of Medical Genetics and American Society of Human Genetics (2006) recommends two equally-accepted tiered approaches to testing for individuals exhibiting symptoms of Prader-Willi syndrome.

  • Approach one:
    • Methylation analysis will detect greater than 99% of individuals with PWS including those with deletion, uniparental disomy, or imprinting defect. 
      • If methylation testing is abnormal, it confirms the clinical diagnosis. However, to help determine whether there are risks of PWS in other family members it may be necessary to perform FISH, UPD and/or Imprinting Center testing to determine the exact cause of the abnormal methylation.
    • FISH 15q11-q13 (deletion analysis)
      • If FISH testing is abnormal (70% of individuals with PWS will have a deletion) chromosome analysis may be considered to rule out a familial chromosome rearrangement (rare).
      • If FISH testing is normal, it is appropriate to consider UPD analysis.
    • Uniparental Disomy (UPD) analysis of chromosome 15 determines if the patient inherited both copies of chromosome 15 from the mother.
    • If methylation analysis is abnormal, but FISH and UPD analysis are normal, it is usually assumed there is an imprinting center mutation (which carries a higher recurrence risk than other causes). There is limited clinical testing available.
  •  Approach two:
    • FISH 15q11-q13 (deletion analysis)
      • If abnormal, a diagnosis of PWS is confirmed. Chromosome analysis may be considered to rule out a familial chromosome rearrangement (rare).
      • If normal then proceed to methylation analysis.
    • Methylation analysis
      • If methylation analysis is abnormal, PWS diagnosis is confirmed, but UPD testing can occur to better understand recurrence risk.
    • Uniparental Disomy (UPD) analysis of chromosome 15 
      • If methylation analysis is abnormal, but FISH and UPD analysis are normal, it is usually assumed there is an imprinting center mutation (which carries a higher recurrence risk than other causes). There is limited clinical testing available.

Some of the same authors of the ACMG guidelines separately suggested the following:

  • “Clinical findings that should prompt diagnostic testing have been proposed based on analysis of diagnostic criteria met in individuals in whom the diagnosis of PWS has been molecularly confirmed. These differ by age group. The presence of all of the following findings at the age indicated is sufficient to justify DNA methylation analysis for PWS.”
  • "A DNA methylation analysis consistent with PWS is sufficient for clinical diagnosis but not for genetic counseling, which requires identification of the underlying genetic mechanism."

"Prader-Willi syndrome (PWS) is a complex disorder whose diagnosis may be difficult to establish on clinical grounds and whose genetic basis is heterogeneous."


Place of Service: Outpatient

Prader-Willi 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.

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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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