Medical_Policy_Bulletin

Highmark Commercial Medical Policy - Pennsylvania

Medical Policy:	L-161-004
Topic:	Angelman Syndrome Testing
Section:	Laboratory
Effective Date:	November 13, 2017
Issue Date:	November 13, 2017
Last Reviewed:	June 2017

Angelman syndrome (AS) is characterized by developmental delay with intellectual disability, severe speech impairment — usually with minimal or no word use, gait ataxia and limb tremors, seizures and microcephaly, happy demeanor with hand flapping and a decreased need for sleep. Features of AS are caused by a missing or defective UBE3A gene inherited from the patient’s mother.

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.

AS testing may be considered medically necessary when the following criteria are met:

SNRPN/UBE3A Methylation Analysis

Genetic Counseling;
- Pre and post-test genetic counseling by an appropriate provider; and
Previous Testing:
- No previous SNRPN/UBE3A methylation analysis; and
Diagnostic Testing for Symptomatic Individuals:
- Developmental delay, typically severe to profound, without loss of milestones; and
- Some combination of the following:
  - Movement or balance disorder, typically with ataxia; or
  - Frequent laughter/smiling, apparent happy demeanor; easily excitable personality (often with uplifted hand-flapping; or waving movements), or hypermotoric behavior; or
  - Speech impairment with no or minimal number of words.

Procedure Codes

81331

AS testing may be considered medically necessary when the following criteria are met:

FISH Analysis for 15q11-q13 Deletion

Genetic Counseling;
- Pre and post-test genetic counseling by an appropriate provider; and
Previous Testing:
- No previous chromosomal microarray
- No previous 15q11-q13 deletion analysis; and
Diagnostic Testing for Symptomatic Individuals:
- Developmental delay, typically severe to profound, without loss of milestones; and
- Some combination of the following:
  - Movement or balance disorder, typically with ataxia; or
  - Frequent laughter/smiling, apparent happy demeanor; easily excitable personality (often with uplifted hand-flapping; or waving movements), or hypermotoric behavior; or
  - Speech impairment with no or minimal number of words.

Procedure Codes

88271

AS testing may be considered medically necessary when the following criteria are met:

Chromosome 15 Uniparental Disomy

Genetic Counseling;
- Pre and post-test genetic counseling by and appropriate provider ; and
Previous Testing:
- SNRPN/UBE3A methylation analysis results are abnormal; and
- 15q11-q13 deletion analysis is negative; and
- No previous chromosome 15 UPD studies; and
Diagnostic Testing for Symptomatic Individuals:
- Developmental delay, typically severe to profound, without loss of milestones; and
- Some combination of the following:
  - Movement or balance disorder, typically with ataxia; or
  - Frequent laughter/smiling, apparent happy demeanor; easily excitable personality (often with uplifted hand-flapping; or waving movements), or hypermotoric behavior; or
  - Speech impairment with no or minimal number of words.

Procedure Codes

81402

AS testing may be considered medically necessary when the following criteria are met:

Imprinting Center Defect Analysis

Genetic Counseling;
- Pre and post-test genetic counseling by and appropriate provider; and
Previous Testing:
- SNRPN/UBE3A methylation analysis results are abnormal; and
- 15q11-q13 deletion analysis is negative; and
- Previous chromosome 15 UPD testing is negative; and
- No previous imprinting center (IC) analysis; and
Diagnostic Testing for Symptomatic Individuals:
- Developmental delay, typically severe to profound, without loss of milestones; and
- Some combination of the following:
  - Movement or balance disorder, typically with ataxia; or
  - Frequent laughter/smiling, apparent happy demeanor; easily excitable personality (often with uplifted hand-flapping; or waving movements), or hypermotoric behavior; or
  - Speech impairment with no or minimal number of words.

Procedure Codes

81479

AS testing may be considered medically necessary when the following criteria are met:

UBE3A Sequencing

Genetic Counseling;
- Pre and post-test genetic counseling by an appropriate provider and
Previous Testing:
- SNRPN/UBE3A methylation analysis results are normal; and
- No previous sequencing of UBE3A; and
Personal History:
- Developmental delay, typically severe to profound, without loss of milestones; and
- Movement or balance disorder, typically with ataxia; and
- Frequent laughter/smiling, apparent happy demeanor; easily excitable personality (often with uplifted hand-flapping, or waving movements), or hypermotoric behavior; and
- Speech impairment with no or minimal number of words.

Procedure Codes

81406

AS testing may be considered medically necessary when the following criteria are met:

UBE3A Deletion/Duplication Analysis

Genetic Counseling:
- Pre and post-test genetic counseling by an appropriate provider; an
Previous Testing
- SNRPN/UBE3A methylation analysis results are normal; and
- Normal UBE3A sequencing; and
Personal History:
- Developmental delay, typically severe to profound, without loss of milestones; and
- Movement or balance disorder, typically with ataxia; and
- Frequent laughter/smiling, apparent happy demeanor; easily excitable personality (often with uplifted hand-flapping, or waving movements),or hypermotoric behavior; and
- Speech impairment with no or minimal number of words.

Procedure Codes

81479

AS testing may be considered medically necessary when the following criteria are met:

UBE3A Known Familial Mutation Analysis or Imprinting Center Known Familial Mutation Analysis

Genetic Counseling;
- Pre and post-test genetic counseling by an appropriate provider; and
Previous Testing:
- No previous UBE3A sequencing or imprinting center defect analysis testing; and
Family History:
- Familial UBE3A or imprinting center defect mutation known in blood relative.

Procedure Codes

81403, 81479

Professional Statements and Societal Positions

Consensus guidelines from the American College of Medical Genetics and American Society of Human Genetics (2006) recommend two equally-accepted tiered approaches to testing.

Approach one :
- Start with UBE3A methylation analysis:
  - If abnormal, a diagnosis is confirmed.
  - Consider the following to identify the underlying cause for recurrence risk counseling.
- FISH 15q11-q13 (deletion analysis)
  - If FISH testing is abnormal, FISH testing on the mother should be done to rule-out an inherited chromosome abnormality(rare).
  - If FISH testing is normal, consider UPD analysis.
- Uniparental Disomy (UPD) analysis of chromosome 15 to determine whether the patient inherited both copies of chromosome 15 from the father.
- If FISH and UPD analysis are normal, an imprinting center mutation is a likely cause and should be evaluated (which may carry a higher recurrence risk than other causes).
Approach two:
- Start with FISH 15q11-q13 (deletion analysis):
  - If abnormal, a diagnosis is confirmed.
  - If normal then proceed to methylation analysis.
- UBE3A Methylation analysis
  - If methylation analysis is abnormal, the diagnosis is confirmed, but UPD testing may be done to better estimate recurrence risk.
- Uniparental Disomy (UPD) analysis of chromosome 15.
- If methylation analysis is abnormal, but FISH and UPD analysis are normal, an imprinting center mutation is a likely cause and should be evaluated (which may carry a higher recurrence risk than other causes).

An expert-authored review (2011) comments on the utility of familial mutation analysis:

"Individuals with an imprinting center (IC) deletion can have a phenotypically normal mother who also has an IC deletion. If a proband's mother has a known IC deletion, the risk to the sibs is 50%."
"UBE3A mutations can be inherited or de novo. In addition, several cases of mosaicism for a UBE3A mutation have been noted. If a proband's mother has a UBE3A mutation, the risk to the sibs is 50%."
"If a proband's mother carries a known IC deletion or UBE3A mutation, the mother's sisters are also at risk of carrying the IC deletion or the mutation. Each child of the unaffected sisters who are carriers is at a 50% risk of having AS. Unaffected maternal uncles of the proband who are carriers are not at risk of having affected children, but are at risk of having affected grandchildren through their unaffected daughters who have inherited the IC deletion or UBE3A mutation from them."

Place of Service: Outpatient

AS 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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Link to References

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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