Genetic Testing for Fragile X-Associated Disorders Product

bmchp.org | 888-566-0008 wellsense.org | 877-957-1300

Medical Policy and InterQual® Criteria

Genetic Testing for Fragile X-Associated Disorders

Policy Number: OCA 3.571 Version Number: 22 Version Effective Date: 03/01/21

Product Applicability All Plan+ Products

Well Sense Health Plan Boston Medical Center HealthNet Plan Well Sense Health Plan MassHealth Qualified Health Plans/ConnectorCare/Employer Choice Direct Senior Care Options ◊

Notes: + Disclaimer and audit information is located at the end of this document. ◊ The guidelines included in this Plan policy are applicable to members enrolled in Senior Care Options only if there are no criteria established for the specified service in a Centers for Medicare & Medicaid Services (CMS) national coverage determination (NCD) or local coverage determination (LCD) on the date of the prior authorization request. Review the member’s product-specific benefit documents at www.SeniorsGetMore.org to determine coverage guidelines for Senior Care Options.

Policy Summary Genetic testing for a fragile X-associated disorder is considered medically necessary for the diagnosis of an adult or pediatric member with unexplained intellectual disability, developmental delay, and/or symptoms or findings consistent with an autism spectrum disorder when InterQual® criteria are met. Prior authorization is required. The Plan’s prior authorization requirements for genetic testing are based on the type of genetic test requested, indication(s) for testing, and if the test is ordered, administered, and processed by participating providers and participating laboratories (or non- participating providers and non-participating laboratories). Review the Plan’s Preimplantation Genetic Testing medical policy, policy number OCA 3.726, rather than InterQual® criteria for medical guidelines

Genetic Testing for Fragile X-Associated Disorders

+ Plan refers to Boston Medical Center Health Plan, Inc. and its affiliates and subsidiaries offering health coverage plans to enrolled members. The Plan operates in Massachusetts under the trade name Boston Medical Center HealthNet Plan and in other states under the trade name Well Sense Health Plan. 1 of 28

for preimplantation genetic testing; preimplantation genetic testing is a covered service for some BMC HealthNet Plan members, as specified in the member’s applicable benefit document available at www.bmchp.org.

For genetic tests ordered, administered, and processed by participating providers and participating laboratories, Plan prior authorization is required for all molecular and chromosomal genetic testing EXCEPT for a limited number of prenatal genetic screening tests for a member when billed with one (1) of the ICD-10 primary pregnancy diagnosis codes and corresponding procedure codes specified in the Applicable Coding section of this policy. The primary pregnancy diagnosis codes waived from the prior authorization requirement are NOT applicable for Senior Care Options members. When genetic tests are order, administered, and processed by non-participating providers and/or non-participating laboratories (NOT contracted with the Plan), prior authorization is require for all genetic testing, including prenatal genetic screening tests; the list of ICD-10 primary pregnancy diagnosis codes waived from the prior authorization process would NOT apply to non-participating providers and non- participating laboratories. Biochemical genetic tests used to study the amount or activity level of proteins to indicate changes to the DNA require prior authorization when specified in the Plan’s Code Look-Up Tools, Prior Authorization Matrix, or a Plan medical policy available at www.bmchp.org for services provided to BMC HealthNet Plan members (including Senior Care Options members) and at www.wellsense.org for testing requested for Well Sense Health Plan members.

The Plan recommends that adequate pre-test genetic counseling and post-test genetic counseling be provided by a health care professional with expertise in genetics for all genetic testing conducted with Plan members. Genetic counseling provided to a Plan member (and/or guardian if the member is under the age of 18) should be documented in the member’s medical record and conducted by an appropriately trained practitioner with expertise and experience in genetics, including a provider acting within the scope of the provider’s license and practice, clinical geneticist, or genetic counselor.

The Plan complies with coverage guidelines for all applicable state-mandated benefits and federally- mandated benefits that are medically necessary for the member’s condition. It will be determined during the prior authorization process if the genetic test is considered medically necessary or experimental and investigational for the requested indication. The Plan’s Medically Necessary medical policy, policy number OCA 3.14, indicates the product-specific definitions of medically necessary treatment, and the Plan’s Experimental and Investigational Treatment medical policy, policy number OCA 3.12, includes the product-specific definitions of experimental or investigational treatment. Plan- adopted InterQual® criteria and the following medical policies include prior authorization guidelines for genetic testing and related services:

1. Chromosomal Microarray Analysis for Unexplained Intellectual Disabilities and/or Multiple Congenital Anomalies medical policy, policy number OCA 3.573, with the medical policy listing the primary pregnancy diagnosis codes and corresponding procedure codes waived for prior authorization; applicable InterQual® criteria are used to determine medical necessity

Genetic Testing for Fragile X-Associated Disorders

2. Drug Screening/Testing for Drugs of Abuse and/or Controlled Substances medical policy, policy number OCA 3.98, includes guidelines related to specimen validity testing using DNA authentication in conjunction with drug testing for BMC HealthNet Plan members

3. Genetic/Genomic Testing and Pharmacogenetics medical policy, policy number OCA 3.727, with either medical policy criteria or Plan-adopted InterQual® criteria used to determined medical necessity based on the type of genetic test requested and the indication(s) for testing; the medical policy lists the primary pregnancy diagnosis codes and corresponding procedure codes waived for prior authorization

4. Genetic Testing for Hereditary Thrombophilia medical policy, policy number OCA 3.728, with medical policy criteria used to determined medical necessity

5. Preimplantation Genetic Testing medical policy, policy number OCA 3.726, with medical policy criteria used to determined medical necessity ONLY when preimplantation genetic testing is a covered service for a Plan member

Description of Item or Service Testing for Fragile X-Associated Disorders: DNA-based molecular analysis test that detects the fragile X mutation which is an expansion (lengthening) of trinucleotide repeats CGG within the FMR1 gene. Based on the test results, the patient is classified as normal, intermediate (or “gray zone”), premutation or full mutation based on the number of CGG repeats. Patients with a full mutation are considered affected with fragile X syndrome; those with a premutation are carriers and may have a FMR1-related disorder such as fragile X-associated primary ovarian insufficiency (FXPOI) or fragile X- associated tremor/ataxia syndrome (FXTAS).

Medical Policy Statement The Plan considers genetic testing for a fragile X-associated disorder to be medically necessary for the diagnosis of an adult or pediatric member with unexplained intellectual disability, developmental delay, and/or symptoms or findings consistent with an autism spectrum disorder when ordered by an appropriately trained and licensed provider and InterQual® criteria are met and documented in the member’s medical record. Plan prior authorization may or may not be required when applicable criteria are met, as specified below in EITHER item A or item B:

A. Prior authorization is REQUIRED for a fragile X-associated disorder when the member is not pregnant and/or when testing is ordered, administered, and/or processed by a non-participating provider and/or non-participating laboratory for a pregnant member. InterQual® criteria must be met.*

Genetic Testing for Fragile X-Associated Disorders

* Note: For sequential or second-line testing, the order of genetic testing is determined by the treating physician or a licensed practitioner (such as an advanced practitioner registered nurse or physician assistant when operating within the scope of the provider’s license) and may include chromosomal microarray analysis (CMA) or genetic testing for fragile X-associated disorders for a member with symptoms or findings consistent with an autism spectrum disorder, developmental delay, or intellectual disability. The Plan will authorize the first genetic test requested by the treating provider when InterQual® criteria are met; the second test (either sequential genetic testing or second-line genetic testing) will be approved if InterQual® criteria are met and the first test is negative. If the provider will be ordering sequential testing (with the same date of service for a collected blood sample), prior authorization must be obtained for BOTH genetic testing for CMA and fragile X-associated disorders BEFORE testing is performed. The member’s medical record must document a negative test result for the first genetic test if sequential testing is performed. InterQual® criteria must be met for each requested genetic test.

B. Prior authorization is NOT required for prenatal genetic testing for a pregnant member/member’s fetus (either a routine pregnancy or high-risk pregnancy) for a fragile X-associated disorder when ALL of the following criteria are met, as specified below in items 1 through 3:

1. The pregnant member’s claim for the genetic screening test is submitted to the Plan with the following codes documented on the claim, as specified in the Applicable Coding section of this policy and included below in BOTH item a and item b:

a. The appropriate procedure code for genetic testing for a fragile X-associated disorder; AND

b. One (1) of the Plan-specific pregnancy diagnosis codes (for either a routine or high-risk pregnancy) specified in the Applicable Coding section of this policy is listed as the primary diagnosis for the member and prior authorization is waived for the applicable genetic testing procedure code(s) for that primary pregnancy diagnosis code;◊ AND

2. The genetic test is ordered, administered, and processed by a participating provider and a participating laboratory; AND

3. There is medical record documentation of medical necessity for the genetic screening test(s) for the pregnant member and InterQual® criteria are met (which the Plan may validate with medical record audit rather than through the prior authorization process).◊

◊ Note: The member’s medical record must document the medical necessity of testing (RATHER than requiring prior authorization), as stated in InterQual® criteria for genetic testing for the requested indication(s). The primary pregnancy diagnosis codes waived from the prior authorization requirement are NOT applicable for Senior Care Options members.

Genetic Testing for Fragile X-Associated Disorders

Limitations The Plan considers genetic testing for a fragile X associated disorder to be medically necessary when InterQual® criteria are met. When InterQual® criteria are NOT met; Plan Medical Director review is required for individual consideration.

Definitions Autism Spectrum Disorder (ASD): A group of biologically based neurodevelopmental disorders characterized by impairments in three major domains: socialization, communication and behavior. It has been estimated that as many as 1 in 100 children are affected by ASD.

Chromosomal Microarray Analysis (CMA): Also known cytogenomic constitutional (genome-wide) microarray analysis or cytogenomic microarray analysis, CMA is a high-resolution, whole-genome screening used as a diagnostic tool to identify genetic abnormalities not detected with conventional cytogenetic analysis (e.g., karoytping and FISH); CMA provides more refined testing by detecting smaller deletions and duplications in genomic material, potentially increasing the diagnostic yield in targeted populations. CMA collectively describes two (2) different laboratory techniques, comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) arrays.

Developmental Delay: Failure to meet expected developmental milestones due to a significant delay in one (1) or more developmental skills, including gross or fine motor, speech/language, cognitive, social/personal, and/or adaptive development (e.g., activities of daily living or self-care). A significant delay in two (2) or more of these developmental categories is considered global development delay and is thought to predict future intellectual disability. The term ‘developmental delay’ is used with children typically younger than five (5) years old.

Developmental Disorder/Developmental Disability: A severe, chronic disability of an individual that is attributable to a mental or physical impairment, or combination of mental and physical impairment, and is manifested before the individual attains the age of 22. The disability is likely to continue indefinitely, results in substantial functional limitations in three (3) or more of the following areas of major life activity: self-care, receptive and expressive language, learning, mobility, self-direction, capacity for independent living, and economic self-sufficiency. The disability reflects the individual's need for a combination and sequence of special, interdisciplinary, or generic services, individualized support or other forms of assistance that are of lifelong or of extended duration and are individually planned and coordinated. (Definition from the Developmental Disabilities Assistance and Bill of Rights Act of 2000, Public Law 106-402.)

First-Degree Relative: A blood relative of an individual who shares approximately 50% of their genes defined as a parent, full sibling, and children.

Genetic Testing for Fragile X-Associated Disorders

Fragile X-Associated Disorder: A genetic disorder caused by changes in the FMR1 gene, including fragile X syndrome, fragile X-associated tremor/ataxia syndrome, and fragile X-associated primary ovarian insufficiency. Genetic testing may be done on an individual’s DNA with a blood sample or from the DNA of a fetus with a chorionic villus sampling (CVS), amniocentesis sample, or percutaneous umbilical cord blood sampling (PUBS).

Fragile X-Associated Primary Ovarian Insufficiency (FXPOI): A genetic condition in which the ovaries are not functioning at full capacity in an FMR1 premutation carrier. Common symptoms of FXPOI include absent or irregular periods, symptoms of menopause such as hot flashes, early menopause, and infertility

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): A genetic neurodegenerative disorder in an FMR1 premutation carrier occurring more commonly in phenotypical males (including individuals typical male karyotype with only one [1] X chromosome) than in phenotypical females (including individuals with typical karyotype with two [2] X chromosomes). Most individuals have no related medical, developmental or neurological problems prior to the appearance of FXTAS symptoms, which usually occur after age 50. FXTAS symptoms include ataxia (balance problems), intention tremors memory loss, mood instability, psychiatric symptoms, and cognitive decline.

Fragile X Syndrome: A genetic condition involving changes in part of the X chromosome. It is the most common form of inherited intellectual disability in males (including individuals with typical male karyotype with only one [1] X chromosome) and a significant cause of intellectual disability in females (including individuals with typical female karyotype with two [2] X chromosomes). Fragile X syndrome is caused by a change in the FMR1 gene. A small section of the gene code (CGG) is repeated on a fragile area of the X chromosome. The fragile X mutation involves an expanded number of the CGG repeats.

Genetic Testing: According to U.S. Library of Medicine, genetic testing is defined as a type of medical test that identifies changes in chromosomes, genes, or proteins. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person’s chance of developing or passing on a genetic disorder. More than 1,000 genetic tests are currently in use, and more are being developed. Several methods can be used for genetic testing:

1. Molecular genetic tests (or gene tests) study single genes or short lengths of DNA to identify variations or mutations that lead to a genetic disorder.

2. Chromosomal genetic tests analyze whole chromosomes to see if there are large genetic changes, such as an extra copy of a chromosome or missing DNA, that cause a genetic condition.

3. Biochemical genetic tests study the amount or activity level of proteins; abnormalities in either can indicate changes to the DNA that result in a genetic disorder.

Genetic Testing for Fragile X-Associated Disorders

Intellectual Disability (ID): As stated by the American Association on Intellectual and Developmental Disabilities (AAIDD), intellectual disability is a disability originating before age 18 which is characterized by significant limitations both in intellectual functioning and in adaptive behavior (including conceptual, social, and practical adaptive skills). The degree of ID varies from one individual to another and may range from mild to profound. An individual's level of ID can be defined by their intelligence quotient (IQ) or by the amount and type of support they need. The term ‘intellectual disability’ generally applies to older children where IQ testing is valid and reliable. According to the American Academy of Pediatrics (AAP), the term ‘intellectual disability’ is suggested as an alternative term for ‘mental retardation.’

Next-Generation Sequencing (NGS or Massively Parallel Sequencing): Genetic testing that involves sequencing of millions of DNA fragments using the following three (3) levels of molecular analysis: (1) Disease-targeted gene panels to sequence genes with an established role in the targeted disease, (2) exome sequencing of coding regions of the genome to include less common variants associated with the disease (i.e., a coding region is the segment of a gene that contains a protein-coding sequence called an exon in all 22,000 genes of the human genome); and (3) genome sequencing of both the coding and non-coding regions of the genome (i.e., the non-coding regions in between exons are called introns). Multiple sequencing platforms and different processes result in variability in test results among laboratories.

Second-Degree Relative: A blood relative of an individual who shares approximately 25% of their genes defined as a grandparent, grandchildren, aunt, uncle, nephew, niece, and half-siblings.

Single Nucleotide Polymorphisms (SNPs): The most common type of genetic variation among individuals. Each SNP represents a difference in a single DNA building block, called a nucleotide. SNPs occur normally throughout a person’s DNA; normally these variations are found in the DNA between genes. If more than one (1) percent of a population does not carry the same nucleotide at a specific position in the DNA sequence, then this variation can be classified as a SNP. Most SNPs have no effect on health or development. When there is sufficient scientific evidence to support the clinical utility of testing, SNPs may help predict an individual’s response to certain drugs, susceptibility to environmental factors, risk of developing particular diseases, and/or susceptibility to genetic diseases within families.

Third-Degree Relative: A blood relative of an individual who shares 12.5% of the individual’s genes as defined as a biological first cousin, great grandmother, or great grandfather.

Genetic Testing for Fragile X-Associated Disorders

X-Linked Disorder: A chromosomal abnormality caused by mutations in genes on the X chromosome, one (1) of the two (2) sex chromosomes in each cell. In phenotypical females/individuals with two (2) X chromosomes, a mutation in one (1) of the two (2) copies of the gene in each cell is sufficient to cause an X-linked dominant disorder, and a mutation would have to occur in both copies of the gene to cause an X-linked recessive disorder. Because it is unlikely that phenotypical females (including individuals with typical female karyotype with two [2] X chromosomes) will have two (2) altered copies of this gene, phenotypical males (including individuals with typical male karyotype with only one [1] X chromosome) are affected by X-linked recessive disorders much more frequently than phenotypical females (including individuals with typical female karyotype with two [2] X chromosomes). The high clinical variability in female patients often makes the determination of an X-linked dominant disorder vs. an X-linked recessive disorder difficult. In phenotypical males (including individuals with typical male karyotype with only one [1] X chromosome), a mutation in the only copy of the gene in each cell causes an X-linked disorder. A characteristic of X-linked inheritance is that biological fathers (including biological parents with only one [1] X chromosome) cannot pass X-linked traits to their biological sons (including biological children with only one [1] X chromosome); this results in no phenotypical male-to- phenotypical male transmission. Examples of X-linked disorders include adrenoleukodystrophy, Alport syndrome, choroideremia, Fabry disease, fragile X syndrome, hemophilia A, hemophilia B, Hunter syndrome, incontinentia pigmenti, Lesch-Nyhan syndrome, muscular dystrophy, and X-linked intellectual disability. (Source: Genetic Home Reference from the U. S. Department of Health & Human Services.)

Applicable Coding The Plan uses and adopts up-to-date Current Procedural Terminology (CPT) codes from the American Medical Association (AMA), International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10) diagnosis codes developed by the World Health Organization and adapted in the United Stated by the National Center for Health Statistics (NCHS) of the Centers for Disease Control under the U.S. Department of Health and Human Services, and the Health Care Common Procedure Coding System (HCPCS) established and maintained by the Centers for Medicare & Medicaid Services (CMS). Since the AMA, NCHS, and CMS may update codes more frequently or at different intervals than InterQual® and Plan policy updates, the list of applicable codes included in InterQual® criteria and this Plan policy is for informational purposes only, may not be all inclusive, and is subject to change without prior notification. Whether a code is listed in the Applicable Coding section of this Plan policy or included in InterQual® criteria does not constitute or imply member coverage or provider reimbursement. Providers are responsible for reporting all services using the most up-to-date industry-standard procedure and diagnosis codes as published by the AMA, NCHS, and CMS at the time of the service.

Providers are responsible for obtaining prior authorization for the services specified in this Plan policy, even if an applicable code appropriately describing the service that is the subject of this Plan policy is not included in the Applicable Coding section of this Plan policy or not specified in InterQual® criteria. Coverage for services is subject to benefit eligibility under the member’s benefit plan. Refer to the member’s benefits document in effect at the time of the service to determine coverage or non- Genetic Testing for Fragile X-Associated Disorders

coverage as it applies to an individual member. Review the Plan’s reimbursement policies for Plan billing guidelines.

Plan prior authorization is required for all molecular and chromosomal genetic testing, except for prenatal genetic screening tests for a member with one of the Plan-specified, routine or high-risk pregnancy diagnosis codes specified in the Applicable Coding section of this policy when InterQual® criteria are met. The medical necessity for genetic screening test(s) for the pregnant member for targeted population-based screening must be documented in the member’s medical record; the Plan may validated with medical record audit the medical necessity of genetic testing when the prior authorization requirement is waived. Prior authorization may or may not be required for medically necessary, non-invasive prenatal genetic screening, as specified below.

Plan-Specified, Description: Prior authorization is NOT required for medically necessary Routine Pregnancy prenatal genetic screening for fragile X testing for a member when billed and High-Risk with one (1) of the following Plan-specified, routine pregnancy or high-risk Pregnancy ICD-10 pregnancy ICD-10 primary diagnosis codes in combination with the CPT Primary Diagnosis codes specified below, InterQual® criteria are met, and the genetic test is Codes ordered, administered, and processed by a participating provider and a participating laboratory.

Plan note: A mother may include a female member, a member born with female reproductive organs, and/or a member with typical female karyotype with two (2) X chromosomes. The pregnancy diagnosis codes waived from the prior authorization requirement are NOT applicable for Senior Care Options members. O09.00 - O09.93 Supervision of high-risk pregnancy O28.3 Abnormal ultrasonic finding on antenatal screening of mother O28.5 Abnormal chromosomal and genetic finding on antenatal screening of mother O35.0xx0 - O35.9xx9 Maternal care for known or suspected fetal abnormality and damage O36.01 - O36.93 Maternal care for other fetal problems Z34.00 - Z34.93 Encounter for supervision of normal pregnancy Z36.0-Z36.9 Encounters for antenatal screenings

Genetic Testing for Fragile X-Associated Disorders

CPT Codes Description: Codes covered when medically necessary.

Prior authorization is required UNLESS the following CPT codes are billed with one (1) of the Plan-specified routine pregnancy or high-risk pregnancy ICD-10 primary diagnosis codes listed above, InterQual® criteria are met, and the genetic test is ordered, administered, and processed by a participating provider and a participating laboratory. 81171 AFF2 (AF4/FMR2 family, member 2 [FMR2]) (e.g., fragile X mental retardation 2 [FRAXE]) gene analysis; evaluation to detect abnormal (e.g., expanded) alleles

Plan note: The Plan complies with industry-wide payment guidelines in effect on the date of service, including CMS National Correct Coding Initiative (NCCI) edits related to unbundling of codes for genetic testing for fragile X- associated disorders in combination with chromosomal/cytogenomic microarray analysis. 81172 AFF2 (AF4/FMR2 family, member 2 [FMR2]) (e.g., fragile X mental retardation 2 [FRAXE]) gene analysis; characterization of alleles (e.g., expanded size and methylation status)

Plan note: The Plan complies with industry-wide payment guidelines in effect on the date of service, including CMS National Correct Coding Initiative (NCCI) edits related to unbundling of codes for genetic testing for fragile X- associated disorders in combination with chromosomal/cytogenomic microarray analysis. 81243 FMR1 (Fragile X mental retardation 1) (e.g., fragile X mental retardation) gene analysis; evaluation to detect abnormal (e.g., expanded) alleles

Plan note: The Plan complies with industry-wide payment guidelines in effect on the date of service, including CMS National Correct Coding Initiative (NCCI) edits related to unbundling of codes for genetic testing for fragile X- associated disorders in combination with chromosomal/cytogenomic microarray analysis. 81244 FMR1 (Fragile X mental retardation 1) (e.g., fragile X mental retardation) gene analysis; characterization of alleles (e.g., expanded size and promoter methylation status)

Genetic Testing for Fragile X-Associated Disorders

81401 Molecular pathology procedure, Level 2 (e.g., 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using non-sequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat)

AFF2 (AF4/FMR2 family, member 2 [FMR2]) (e.g., fragile X mental retardation 2 {FRAXE]), evaluation to detect abnormal (e.g., expanded) alleles

Plan notes: 1. This CPT code includes numerous types of tests. See the CPT® codebook for a detailed description of this code. 2. The Plan complies with industry-wide payment guidelines in effect on the date of service, including CMS National Correct Coding Initiative (NCCI) edits related to unbundling of codes for genetic testing for fragile X- associated disorders in combination with chromosomal/cytogenomic microarray analysis. 81404 Molecular pathology procedure, Level 5 (e.g., analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis)

NLGN4X (neuroligin 4, X-linked) (e.g., autism spectrum disorders), duplication/deletion analysis

Genetic Testing for Fragile X-Associated Disorders

81405 Molecular pathology procedure, Level 6 (e.g., analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11- 25 exons), regionally targeted cytogenomic array analysis

NLGN4X (neuroligin 4, X-linked) (e.g., autism spectrum disorders), full gene sequence

Plan note: 1. This CPT code includes numerous types of tests. See the CPT® codebook for a detailed description of this code. 2. The Plan complies with industry-wide payment guidelines in effect on the date of service, including CMS National Correct Coding Initiative (NCCI) edits related to unbundling of codes for genetic testing for fragile X- associated disorders in combination with chromosomal/cytogenomic microarray analysis. 88248 Chromosome analysis for breakage syndromes; baseline breakage, score 50- 100 cells, count 20 cells, 2 karyotypes (e.g., for ataxia telangiectasia, Fanconi anemia, fragile X)

Clinical Background Information Fragile X syndrome is a genetic condition characterized by moderate intellectual disability in affected males (including individuals born with male reproductive organs and/or with typical male karyotype with only one [1] X chromosome) and a spectrum of cognitive deficiencies in affected females (including individuals born with female reproductive organs and/or with typical female karyotype with two [2] X chromosomes) that include behavioral problems, learning disability mild or moderate intellectual disability. Males (including individuals born with male reproductive organs and/or with typical male karyotype with only one [1] X chromosome) may have a characteristic appearance (i.e., large head, long face, prominent forehead and chin, and protruding ears), connective tissue findings (i.e., joint laxity), and large testes (post-puberty). Behavioral abnormalities, sometimes including autism spectrum disorder, are also common.

According to the American Academy of Pediatrics (AAP) and the American College of Medical Genetics and Genomics (ACMG), cytogenomic microarray analysis and genetic testing for fragile X syndrome are designated as a first-line test for generalized developmental delay and/or intellectual disability of an unknown etiology. Some children will present both with global developmental delay and clinical

Genetic Testing for Fragile X-Associated Disorders

features of autism. The best approach to the diagnostic evaluation of these children is based on the judgment of the clinical geneticist and the treating provider.

Fragile X syndrome and other fragile X-associated disorders are caused by a change in the FMR1 gene. A small section of the gene code (CGG) is repeated on a fragile area of the X chromosome. The fragile X mutation involves an expanded number of the CGG repeats. According to the American College of Medical Genetics and Genomics (ACMG), CGG-repeat-expansion full mutations account for greater than 99% of cases of fragile X syndrome. Therefore, tests that effectively detect and measure the CGG repeat region of the FMR1 gene are greater than 99% sensitive. This test can be used for prenatal diagnosis in cells obtained from amniocentesis and chorionic villus sampling (CVS), with some variation in CVS results as compared with blood and amniocytes.

All genes, including the FMR1 gene are made up of a long series of chemicals called nucleotides, with each gene being unique. In the FMR1 gene in every person, there is a section in a region known as the 5'-untranslated region, in which there are a certain number of repeats of the three nucleotide sequence CGG. In healthy people, there are in between 5 to 44 of these repeats. In patients with Fragile X syndrome, the repeats are generally in between 200 to 2000. Individuals with between 55 to 200 repeats are said to have pre-mutations and are at risk for further expansion of the repeat length. They may also be at risk for conditions like premature ovarian failure or Fragile X associated tremor and ataxia syndrome (FXTAS).

Individuals who may benefit from genetic testing for fragile X syndrome include: children with symptoms of fragile X syndrome including developmental, speech, language, or motor delay; children or adults with a diagnosis of learning disabilities of unknown etiology, autism, autistic spectrum disorder, or pervasive developmental disorder, or intellectual disabilities. Individuals with a family history of fragile X syndrome, or intellectual disability or autism of unknown cause, may consider carrier testing to determine if they are at risk of transmitting the disease to future generations. Known carriers who are pregnant may consider prenatal genetic testing to determine if the fetus carries the sequence variant.

At the time of the Plan’s most recent policy review, the Centers for Medicare & Medicaid Services (CMS) has implemented the following national coverage determinations (NCDs) related to genetic tests: NCD for Colorectal Cancer Screening Tests (210.3) for coverage of immunoassay and guaiac fecal occult blood tests and the Cologuard™ - Multitarget Stool DNA (sDNA) test when CMS applicable criteria are met, NCD for Pharmacogenomic Testing for Warfarin Response (90.1) for medically necessary indications for testing as determined by CMS, and NCD for Cytogenetic Studies (190.3) for coverage based on CMS guidelines. CMS has determined that next generation sequencing (NGS) is reasonable and necessary as a diagnostic laboratory test and is covered nationally when performed in a CLIA-certified laboratory, when ordered by a treating physician, and when applicable CMS requirements are met, as specified in the CMS national coverage analysis (NCA) CAG-00450N. Medicare uses a combination of national and local coverage determinations for making coverage decisions for genetic tests. Medicare administrative contractors (MAC) may implement local coverage

Genetic Testing for Fragile X-Associated Disorders

determinations (LCDs) that apply only within their own jurisdictions. Verify if applicable CMS criteria are in effect (through an NCD, LCD, or other CMS guidelines) for the specified genetic test, product name, site-specific gene analysis, and the indication for testing on the date of the prior authorization request for a Senior Care Options member.

References American Academy of Neurology (AAN) and Child Neurology Society (CNS). AAN and CNS Guideline Summary for Clinicians. Screening and Diagnosis for Autism. Accessed at: http://tools.aan.com/professionals/practice/guidelines/guideline_summaries/Autism_Guideline_for_C linicians.pdf

American Academy of Neurology (AAN) and Child Neurology Society (CNS). Shevell M, Ashwal S, Donley D, Flint J, Gingold M, Hirtz D, Majnemer A, Noetzel M, Sheth RD; Quality Standards Subcommittee of the AAN; Practice Committee of the CNS. Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society. Neurology. 2003 Feb 11; 60(3):367-80.

American Academy of Neurology (AAN). Policy & Guidelines. Accessed at: https://www.aan.com/policy-and-guidelines/guidelines/

American Academy of Pediatrics (AAP). Guideline Summaries. Accessed at: https://www.guidelinecentral.com/summaries/organizations/american-academy-of-pediatrics/

American Academy of Pediatrics (AAP). Hersh JH, Saul RA. Committee on Genetics. Health Supervision for Children with Fragile X Syndrome. Pediatrics. 2011 May; 127(5):994-1006. doi: 10.1542/peds.2010- 3500. Epub 2011 Apr 25. PMID: 21518720.

American Academy of Pediatrics (AAP). Hyman SL, Levy SE, Myers SM, Council on Children with Disabilities, Section on Development and Behavioral Pediatrics. Pediatrics. 2020 Jan;145(1):e20193447. doi: https://doi.org/10.1542/peds.2019-3447.

American Academy of Pediatrics (AAP). Moeschler JB, Shevell M, and Committee on Genetics. Clinical Report: Comprehensive Evaluation of the Child with Intellectual Disability or Global Developmental Delays. Pediatrics. 2014 Sep; 134(3):e903-18. doi: 10.1542/peds.2014-1839. PMID: 25157020.

American College of Medical Genetics and Genomics (ACMG). ACMG Board of Directors. Direct-to- consumer genetic testing: a revised position statement of the ACMGC. Genet Med. 2016 Feb; 18(2):207-8. doi: 10.1038/gim.2015.190. Epub 2015 Dec 17. PMID: 26681314.

Genetic Testing for Fragile X-Associated Disorders

American College of Medical Genetics and Genomics (ACMG). Manning M, Hudgins L; Professional Practice and Guidelines Committee ACMG. Array based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010 Nov; 12(11):742-5. doi: 10.1097/GIM.0b013e3181f8baad. PMID: 20962661.

American College of Medical Genetics and Genomics (ACMG). Monaghan KG, Lyon E, Spector EB; ACMG. ACMG Standards and Guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics. Genet Med. 2013 Jul; 15(7):575-86. doi: 10.1038/gim.2013.61. Epub 2013 Jun 13. PMID: 23765048.

American College of Medical Genetics and Genomics (ACMG). Practice Guidelines. Accessed at: http://www.acmg.net/ACMG/Medical-Genetics-Practice-Resources/Practice-Guidelines.aspx

American College of Medical Genetics and Genomics (ACMG). Schaefer GB, Mendelsohn NJ; Professional Practice and Guidelines Committee. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013 May; 15(5):399-407. doi: 10.1038/gim.2013.32. Epub 2013 Mar 21. Erratum in: Genet Med. 2013. Aug; 15(8):669. PMID: 23519317.

The American College of Obstetricians and Gynecologists (ACOG). ACOG’s Clinical Guidelines. Accessed at: https://www.acog.org/About-ACOG/ACOG-Departments/Deliveries-Before-39-Weeks/ACOG- Clinical-Guidelines?IsMobileSet=false

The American College of Obstetricians and Gynecologists (ACOG). Committee Opinion. Carrier Screening in the Age of Genomic Medicine. Number 690. 2017 Mar. Accessed at: https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on- Genetics/Carrier-Screening-in-the-Age-of-Genomic-Medicine?IsMobileSet=false

The American College of Obstetricians and Gynecologists (ACOG). Committee Opinion. Carrier Screening for Genetic Conditions. Number 691. 2017 Mar. Reaffirmed 2019. Accessed at: https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2017/03/carrier- screening-for-genetic-conditions?utm_source=redirect&utm_medium=web&utm_campaign=otn

The American College of Obstetricians and Gynecologists (ACOG). Committee Opinion. Counseling About Genetic Testing and Communication of Genetic Test Results. Number 693. 2017 April. Accessed at: https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on- Genetics/Counseling-About-Genetic-Testing-and-Communication-of-Genetic-Test-Results

Genetic Testing for Fragile X-Associated Disorders

The American College of Obstetricians and Gynecologists (ACOG). Committee Opinion. Primary Ovarian Insufficiency in Adolescents and Young Women. Number 605. Reaffirmed 2020. Accessed at: https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2014/07/primary-ovarian- insufficiency-in-adolescents-and-young- women?utm_source=redirect&utm_medium=web&utm_campaign=otn

The American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal–Fetal Medicine. ACOG Committee on Genetics and Society for Maternal–Fetal Medicine’s Publication Committee. Microarrays and Next-Generation Sequencing Technology: The Use of Advanced Genetic Diagnostic Tools in Obstetrics and Gynecology. ACOG Committee Opinion. Number 682. 2016 Dec. Accessed at: http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on- Genetics/Microarrays-and-Next-Generation-Sequencing-Technology

Anderson JA, Hayeems RZ, Shuman C, Szego MJ, Monfared N, Bowdin S, Zlotnik Shaul R, Meyn MS. Predictive genetic testing for adult-onset disorders in minors: a critical analysis of the arguments for and against the 2013 ACMG guidelines. Clin Genet. 2015 Apr; 87(4):301-10. doi: 10.1111/cge.12460. Epub 2014 Oct 7. PMID: 25046648.

Basehore MJ, Friez MJ. Molecular analysis of fragile X syndrome. Curr Protoc Hum Genet. 2014 Jan 21;80:Unit 9.5. doi: 10.1002/0471142905.hg0905s63. PMID: 19806593.

Budworth H, McMurray CT. A Brief History of Triplet Repeat Disorders. Methods Mol Biol. 2013:1010:3- 17. doi: 10.1007/978-1-62703-411-1_1. PMID: 23754215.

Centers for Disease Control and Prevention (CDC). Autism Spectrum Disorder (ASD). Accessed at: https://www.cdc.gov/ncbddd/autism/addm-network-funding.html

Centers for Medicare & Medicaid Services (CMS). Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N). 2018 Mar 16. Accessed at: https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=290

Centers for Medicare and Medicaid Services (CMS). Manuals. Publication # 100-02. Medicare Benefit Policy Manual. Accessed at: https://www.cms.gov/Regulations-and- Guidance/Guidance/Manuals/Internet-Only-Manuals-IOMs-Items/CMS012673.html

Centers for Medicare and Medicaid Services (CMS). Manuals. Publication # 100-03. Medicare National Coverage Determinations (NCD) Manual. Accessed at: https://www.cms.gov/Regulations-and- Guidance/Guidance/Manuals/internet-Only-Manuals-IOMs-Items/CMS014961.html

Centers for Medicare & Medicaid Services (CMS). National Coverage Analyses (NCAs) Alphabetical Index. Accessed at: https://www.cms.gov/medicare-coverage-database/indexes/nca-open-and-closed- index.aspx

Genetic Testing for Fragile X-Associated Disorders

Centers for Medicare & Medicaid Services (CMS). National Coverage Determinations (NCDs) Alphabetical Index. Accessed at: https://www.cms.gov/medicare-coverage-database/indexes/ncd- alphabetical-index.aspx

Centers for Medicare & Medicaid Services (CMS). National Coverage Determination (NCD) for Colorectal Cancer Screening Tests (210.3). Effective Date 2014 Oct 9.

Centers for Medicare & Medicaid Services (CMS). National Coverage Determination (NCD) for Cytogenetic Studies (190.3). Effective Date 1998 Jul 16.

Centers for Medicare & Medicaid Services (CMS). National Coverage Determination (NCD) for Pharmacogenomic Testing for Warfarin Response (90.1). Effective Date 2009 Aug 3.

Centers for Medicare & Medicaid Services (CMS). Update on Mapping the Landscape of Genetic Tests for Non-Cancer Diseases/Conditions. Agency for Healthcare Research and Quality (AHRQ) Technology Assessment Program. Final Report. 2012 May 22. Accessed at: https://www.cms.gov/medicare- coverage-database/details/technology-assessments-details.aspx?TAId=87

Centers for Medicare & Medicaid Services (CMS). Welcome to the Medicare Coverage Database. Accessed at: https://www.cms.gov/medicare-coverage-database/

Child Neurology Society (CNS). Practice Parameters. Accessed at: https://www.childneurologysociety.org/resources/practice-parameters

Commonwealth of Massachusetts. Division of Insurance (DOI) Bulletins. Accessed at: https://www.mass.gov/lists/doi-bulletins

Commonwealth of Massachusetts. Mandatory Benefits Guide. Consumer Affairs and Business Regulation. Accessed at: http://www.mass.gov/ocabr/docs/doi/consumer/healthlists/mndatben.pdf

Commonwealth of Massachusetts. MassHealth Provider Bulletins. Accessed at: https://www.mass.gov/masshealth-provider-bulletins

Commonwealth of Massachusetts. MassHealth Provider Manuals. Accessed at: https://www.mass.gov/lists/masshealth-provider-manuals

Commonwealth of Massachusetts. MassHealth Transmittal Letters. Accessed at: https://www.mass.gov/masshealth-transmittal-letters

Genetic Testing for Fragile X-Associated Disorders

European Molecular Genetics Quality Network (EMQN). Biancalana V, Glaeser D, McQuaid S, Steinbach P. EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders. Eur J Hum Genet. 2015 Apr;23(4):417-25. doi: 10.1038/ejhg.2014.185. Epub 2014 Sep 17. PMID: 25227148.

Genetics Home Reference. U.S. National Library of Medicine. Fragile X syndrome. Accessed at: https://ghr.nlm.nih.gov/condition/fragile-x-syndrome

Genetic Home Reference. U.S. National Library of Medicine. What are Single Nucleotide Polymorphisms (SNPs)? Accessed at: https://ghr.nlm.nih.gov/primer/genomicresearch/snp

Genetics Home Reference. U.S. National Library of Medicine. What are the types of genetic tests? 2020 Sep 22. Accessed at: https://ghr.nlm.nih.gov/primer/testing/uses

Genetics Home Reference. U.S. National Library of Medicine. What is genetic testing? Accessed at: https://ghr.nlm.nih.gov/primer/testing/genetictesting

Haga SB, Burke W, Agans R. Primary-care physicians' access to genetic specialists: an impediment to the routine use of genomic medicine? Genet Med. 2013 Jul;15(7):513-4. doi: 10.1038/gim.2012.168. Epub 2013 Jan 10. PMID: 23306802.

Hagerman RJ, Berry-Kravis E, Hazlett HC, Bailey DB Jr, Moine H, Kooy RF, Tassone F, Gantois I, Sonenberg N, Mandel JL, Hagerman PJ. Fragile X Syndrome. Nat Rev Dis Primers. 2017 Sep 29;3:17065. doi: 10.1038/nrdp.2017.65. PMID: 28960184.

Hayes. Clinical Utility Evaluation. Clinical Utility of Genetic Testing to Aid in the Evaluation of Idiopathic Autism Spectrum Disorder. Dallas, TX: Hayes; 2018 Aug 22. Annual Review 2020 Jul 28.

Hayes. Clinical Utility Evaluation. Clinical Utility of Genetic Testing to Aid in the Evaluation of Syndromic or Complex Autism Spectrum Disorder. Dallas, TX: Hayes; 2018 Aug 22. Annual Review 2020 Jul 28.

Hayes. Clinical Utility Evaluation. Clinical Utility of Genetic Testing for Primary Diagnosis of Autism Spectrum Disorder. Dallas, TX: Hayes; 2018 Jun 29. Annual Review 2020 Jul 28.

Hayes. Clinical Utility Evaluation. Clinical Utility of Prenatal Genetic Testing for Autism Spectrum Disorder. Dallas, TX: Hayes; 2018 Sep 28. Annual Review 2020 Jul 30.

Hayes. Clinical Utility Evaluation. Genetic Testing For Fragile X-Associated Primary Ovarian Insufficiency (FXPOI). Dallas, TX: Hayes; 2017 Mar 9. Annual Review 2020 Jan 7.

Genetic Testing for Fragile X-Associated Disorders

Hayes. Clinical Utility Evaluation. Genetic Testing For Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). Dallas, TX: Hayes; 2017 Mar 30. Annual Review 2020 Feb 9.

Hayes. Clinical Utility Evaluation. Genetic Testing For Fragile X Syndrome. Dallas, TX: Hayes; 2017 Feb 16. Annual Review 2020 Jan 26.

Hayes. Laboratory Test Insights. Fragile X. Dallas, TX: Hayes; 2018 Dec 6.

Hayes. Laboratory Test Insights. Fragile X-Associated Tremor/Ataxia Syndrom (FXTAS): CGG Repeat Analysis. Dallas, TX: Hayes; 2018 Dec 6.

Hayes. Laboratory Test Insights. Fragile X: CGG Repeat Analysis. Dallas, TX: Hayes; 2018 Dec 6.

Hayes. Laboratory Test Insights. Fragile X Comprehensive Analysis. Dallas, TX: Hayes; 2018 Dec 6.

Hayes. Laboratory Test Insights. Fragile X DNA Analysis. Dallas, TX: Hayes; 2018 Dec 6.

Hayes. Laboratory Test Insights. Fragile X-Related Disorders. Dallas, TX: Hayes; 2018 Dec 6.

Hayes. Laboratory Test Insights. Fragile X Syndrome. Dallas, TX: Hayes; 2018 Dec 6.

Hayes. Laboratory Test Insights. XSense(R), Fragile X with Reflex. Dallas, TX: Hayes; 2018 Dec 6

Hayes. Laboratory Test Insights. XSense(R), Fragile X with Reflex (NY). Dallas, TX: Hayes; 2018 Dec 6

Hayes. Precision Medicine Insights. Expanded Carrier Screening. Dallas, TX: Hayes; 2020 Aug 17.

Hayes. Precision Medicine Research Brief. Comprehensive Non-Specific Intellectual Disability Panel. Dallas, TX: Hayes; 2015 Dec 23.

Hersh JH, Saul RA; Committee on Genetics. Health supervision for children with fragile X syndrome. Pediatrics. 2011 May; 127(5):994-1006. doi: 10.1542/peds.2010-3500. Epub 2011 Apr 25. PMID: 21518720.

International Society of Psychiatric Genetics (ISPG). Genetic Testing and Psychiatric Disorders. 2019 Mar 11. Accessed at: https://ispg.net/genetic-testing-statement/

Lozao R, Azarang A, Wilaisakditipakorn T, Hagerman R. Fragile X syndrome: A review of clinical management. Intractable Rare Dis Res. 2016 Aug;5(3):145–57. doi: 10.5582/irdr.2016.01048. PMID: 27672537.

Genetic Testing for Fragile X-Associated Disorders

Maortua H, Martínez-Bouzas C, García-Ribes A, Martínez MJ, Guillen E, Domingo MR, Calvo MT, Guitart M, Gabau E, Botella MP, Gener B, Rubio I, López-Aríztegui MA, Tejada MI. MECP2 gene study in a large cohort: testing of 240 female patients and 861 healthy controls (519 females and 342 males). J Mol Diagn. 2013 Sep; 15(5):723-9. doi: 10.1016/j.jmoldx.2013.05.002. Epub 2013 Jun 26. PMID: 23810759.

McGrew SG, Peters BR, Crittendon JA, Veenstra-Vanderweele J. Diagnostic yield of chromosomal microarray analysis in an autism primary care practice: which guidelines to implement? J Autism Dev Disord. 2012 Aug;42(8):1582-91. doi: 10.1007/s10803-011-1398-3. PMID: 22089167.

Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, Faucett A, Feuk L, Friedman JM, Hamosh A, Jackson L, Kaminsky EB, Kok K, Krantz ID,Kuhn RM, Lee C, Ostell JM, Rosenberg C, Scherer SW, Spinner NB, Stavropoulos DJ, Tepperberg JH, Thorland EC, Vermeesch JR, Waggoner DJ, Watson MS, Martin CL, Ledbetter DH. Consensus Statement: Chromosomal Microarray Is a First-Tier Clinical Diagnostic Test for Individuals with Developmental Disabilities or Congenital Anomalies. Am J Hum Genet. 2010 May 14;86(5):749-64. doi: 10.1016/j.ajhg.2010.04.006. PMID: 20466091.

Moeschler JB, Shevell M; Committee on Genetics. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics. 2014 Sep;134(3):e903-18. doi: 10.1542/peds.2014-1839. PMID: 25157020.

National Fragile X Foundation. The Three Fragile X-associated Disorders. Accessed at: https://fragilex.org/fragile-x-associated-disorders/

National Human Genome Research Institute. National Institutes of Health. Genetic Testing FAQ. Accessed at: https://www.genome.gov/FAQ/Genetic-Testing

National Human Genome Research Institute. National Institutes of Health. Genomic Education Websites. Accessed at: https://www.genome.gov/about-genomics/teaching-tools/Genomics- Education-Websites

National Human Genome Research Institute. National Institutes of Health. Health Professional Genetics Resources Online. Accessed at: https://www.genome.gov/11510371/health-professional-genetics- resources-online

National Institute for Health and Care Excellence (NICE). Autism spectrum disorder in under 19s: recognition, referral and diagnosis. CG128. 2011 Sep. Last Updated 2017 Dec 20. Accessed at: https://www.nice.org.uk/guidance/cg128

Genetic Testing for Fragile X-Associated Disorders

National Society of Genetic Counselors (NSGC). Finucane B, Abrams L, Cronister A, Archibald AD, Bennett RL, McConkie-Rosell A. Genetic Counseling and Testing for FMR1 Gene Mutations: Practice Guidelines of the NSGC. J Genet Couns. 2012 Dec;21(6):752-60. doi: 10.1007/s10897-012-9524-8. Epub 2012 Jul 14. PMID: 22797890.

National Society of Genetic Counselors (NSGC). NSGC Practice Guidelines. Accessed at: https://www.nsgc.org/practiceguidelines

New Hampshire Department of Health and Human Services. Billing Manuals. Accessed at: https://nhmmis.nh.gov/portals/wps/portal/BillingManuals

New Hampshire Department of Health and Human Services. Provider Notices. Accessed at: https://www.dhhs.nh.gov/ombp/pharmacy/notices.htm

Saul RA, Tarleton JC. FMR1-Related Disorders. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews®[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 1998 Jun 16 [updated 2012 Apr 26]. PMID: 20301558.

Shen Y, Dies KA, Holm IA, Bridgemohan C, Sobeih MM, Caronna EB, Miller KJ, Frazier JA, Silverstein I, Picker J, Weissman L, Raffalli P, Jeste S, Demmer LA, Peters HK, Brewster SJ, Kowalczyk SJ, Rosen- Sheidley B, McGowan C, Duda AW 3rd, Lincoln SA, Lowe KR, Schonwald A, Robbins M, Hisama F, Wolff R, Becker R, Nasir R, Urion DK, Milunsky JM, Rappaport L, Gusella JF, Walsh CA, Wu BL, Miller DT; Autism Consortium Clinical Genetics/DNA Diagnostics Collaboration. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics. 2010 Apr;125(4):e727-35. doi: 10.1542/peds.2009-1684. Epub 2010 Mar 15. PMID: 20231187.

Society of Obstetricians and Gynecologists of Canada (SOGC) and Canadian College of Medical Geneticists (CCMG). Wilson RD, De Bie I, Armour CM, Brown RN, Campagnolo C, Carroll JC, Okun N, Nelson T, Zwingerman R, Audibert F, Brock JA, Brown RN, Campagnolo C, Carroll JC, De Bie I, Johnson JA, Okun N, Pastruck M, Vallée-Pouliot K, Wilson RD, Zwingerman R, Armour C, Chitayat D, De Bie I, Fernandez S, Kim R, Lavoie J, Leonard N, Nelson T, Taylor S, Van Allen M, Van Karnebeek C. Joint SOGC- CCMG Opinion for Reproductive Genetic Carrier Screening: An Update for All Canadian Providers of Maternity and Reproductive Healthcare in the Era of Direct-to-Consumer Testing. J Obstet Gynaecol Can. 2016 Aug;38(8):742-762.e3. doi: 10.1016/j.jogc.2016.06.008. PMID: 27638987.

Genetic Testing for Fragile X-Associated Disorders

Tarpey PS, Smith R, Pleasance E, Whibley A, Edkins S, Hardy C, O'Meara S, Latimer C, Dicks E, Menzies A, Stephens P, Blow M, Greenman C, Xue Y, Tyler-Smith C, Thompson D, Gray K, Andrews J, Barthorpe S, Buck G, Cole J, Dunmore R, Jones D, Maddison M, Mironenko T, Turner R, Turrell K, Varian J, West S, Widaa S, Wray P, Teague J, Butler A, Jenkinson A, Jia M, Richardson D, Shepherd R, Wooster R, Tejada MI, Martinez F, Carvill G, Goliath R, de Brouwer AP, van Bokhoven H, Van Esch H, Chelly J, Raynaud M, Ropers HH, Abidi FE, Srivastava AK, Cox J, Luo Y, Mallya U, Moon J, Parnau J, Mohammed S, Tolmie JL, Shoubridge C, Corbett M, Gardner A, Haan E, Rujirabanjerd S, Shaw M, Vandeleur L, Fullston T, Easton DF, Boyle J, Partington M, Hackett A, Field M, Skinner C, Stevenson RE, Bobrow M, Turner G, Schwartz CE, Gecz J, Raymond FL, Futreal PA, Stratton MR. A systematic, large-scale resequencing screen of X- chromosome coding exons in mental retardation. Nat Genet. 2009 May; 41(5):535-43. doi: 10.1038/ng.367. Epub 2009 Apr 19. PMID: 19377476.

Tassone F. Newborn screening for fragile X syndrome. JAMA Neurol. 2014 Mar;71(3):355-9. doi: 10.1001/jamaneurol.2013.4808. PMID: 24395328.

Tsafrir A, Altarescu G, Margalioth E, Brooks B, Renbaum P, Levy-Lahad E, Rabinowitz R, Varshaver I, Eldar-Geva T. PGD for fragile X syndrome: ovarian function is the main determinant of success. Hum Reprod. 2010 Oct;25(10):2629-36. doi: 10.1093/humrep/deq203. Epub 2010 Aug 16. PMID: 20713414.

Policy History Original Effective Original Policy Original Approval Date Date* and Version Policy Owner Approved by Number Regulatory Approval: N/A 09/01/11 Medical Policy MPCTAC and QIC Version 1 Manager as Chair of Internal Approval: MPCTAC 05/18/11: Medical Policy, Criteria, and Technology Assessment Committee (MPCTAC) 06/30/11: Quality Improvement Committee (QIC) *Effective Date for the BMC HealthNet Plan Commercial Product(s): 01/01/12 *Effective Date for the Well Sense Heath Plan New Hampshire Medicaid Product(s): 01/01/13 *Effective Date for the Senior Care Options Product(s): 01/01/16

Policy Revisions History Revision Review Effective Date Summary of Revisions Approved by Date and Version Number 12/01/11 Added new 2012 codes Version 2 12/01/11: MPCTAC 12/01/11: QIC Genetic Testing for Fragile X-Associated Disorders

Policy Revisions History 05/01/12 References updated, applicable CPT codes Version 3 05/16/12: MPCTAC added, and clinical guidelines revised to 06/27/12: QIC clarify that a first degree relative is a biological parent, biological child, or biological sibling (rather than parent, child, or sibling). 07/30/12 Off cycle review for Well Sense Health Plan. Version 4 08/03/12: MPCTAC Revised Summary, Medical Policy Statement, 09/05/12: QIC and Definitions sections. 09/01/12 References updated and referenced Version 5 09/19/12: MPCTAC Experimental and Investigational Treatment 10/24/12: QIC and the Preimplantation Genetic Testing policies. 08/14/13 and Off cycle review for Well Sense Health Plan Version 6 08/14/13: MPCTAC 08/15/13 and merged policy format. Incorporate policy (electronic vote) revisions dated 09/01/12 (as specified above) 08/15/13: QIC for the Well Sense Health Plan product; these policy revisions were approved by MPCTAC on 09/19/12 and QIC on 10/24/12 for applicable Plan products. 10/01/13 Review for effective date 03/01/14. Updated 03/01/14 10/16/13: MPCTAC and 11/01/13 Summary, Description of Item or Service, Version 7 11/20/13: MPCTAC Definitions, Clinical Background Information, 12/19/13: QIC and References sections. Revised criteria in Medical Policy Statement section. Revised language in Applicable Coding section and revised applicable code list. 01/30/14 Review for effective date 04/01/14. Added 04/01/14 01/27/14: MPCTAC ICD10 diagnosis code equivalents of existing Version 8 01/30/14: QIC ICD9 diagnosis codes. 07/01/14 Review for effective date 10/01/14. Updated 10/01/14 07/21/14: MPCTAC Summary section and introductory paragraph Version 9 (electronic vote) in the Applicable Coding section. Added CPT 07/24/14: QIC codes 81404, 81405, and 88248 to the (electronic vote) applicable code list. 11/01/14 Review for effective date 03/01/15. Added 03/01/15 11/19/14: MPCTAC CPT code 81401 as an applicable code. Version 10 12/10/14: QIC Updated criteria in the Medical Policy Statement and Limitations sections. Revised Summary, Definitions, Clinical Background Information, and References sections. Changed review calendar. 11/25/15 Review for effective date 01/01/16. Updated 01/01/16 11/18/15: MPCTAC template with list of applicable products and Version 11 11/25/15: MPCTAC Genetic Testing for Fragile X-Associated Disorders

Policy Revisions History notes. Revised language in the Applicable (electronic vote) Coding section. 12/09/15: QIC 01/01/16 Review for effective date 05/01/16. Revised 05/01/16 01/20/16: MPCTAC language in the Applicable Coding section Version 12 02/10/16: QIC and updated list of waived pregnancy diagnosis codes and corresponding procedure codes. Updated Summary, Definitions, Clinical Background Information, and References sections. Revised criteria in the Medical Policy Statement and Limitations sections. 09/28/16 Review for effective date 11/01/16. 11/01/16 09/30/16: MPCTAC Administrative changes made to clarify Version 13 (electronic vote) language related to gender. Added 10/12/16: QIC definitions. 01/01/17 Review for effective date 05/01/17. Revised 05/01/17 01/18/17: MPCTAC ICD-10 pregnancy diagnosis codes in the Version 14 02/08/17: QIC Applicable Coding section. Updated criteria in the Limitations section. Revised Summary, Definitions, Clinical Background Information, References, and Reference to Applicable Laws and Regulations sections. Administrative changes made to the Medical Policy Statement section. 08/09/17 Revision effective 10/01/17. Industry-wide 10/01/17 Not applicable updates to the ICD-10 diagnosis codes Version 15 because industry-wide included in the Applicable Coding section. updates to ICD-10 diagnosis codes. 01/01/18 Review for effective date 02/01/18. Updated 02/01/18 01/17/18: MPCTAC Summary, References, and Reference to Version 16 Applicable Laws and Regulations sections. Administrative changes made to the Medical Policy Statement and Applicable Coding sections. 01/01/19 Review for effective date 04/01/19. Industry- 04/01/19 01/16/19: MPCTAC wide code updates made in the Applicable Version 17 Coding section with revised Plan notes. Administrative changes made to the Policy Summary, Limitations, Definitions, Clinical Background Information, References, Other Applicable Policies, and Reference to Applicable Laws and Regulations sections. Criteria revised in the Medical Policy Statement section. Genetic Testing for Fragile X-Associated Disorders

Policy Revisions History 02/01/19 Review fore effective date 04/01/19. 04/01/19 02/20/19: MPCTAC Administrative changes made to the Medical Version 18 Policy Statement section to clarify guidelines. Updated Plan notes in the Applicable Coding section (without revising the applicable code list). Revised the Policy Summary and Other Applicable Policies sections. 06/01/19 Review for effective date 07/01/19. Revised 07/01/19 06/19/19: MPCTAC language in the Policy Summary, Medical Version 19 Policy Statement, and Applicable Coding section to clarify that the prior authorization waiver for the specified primary pregnancy diagnosis codes only applies to genetic tests ordered, administered, and processed by participating providers and participating laboratories. 07/01/19 Review for effective date 10/01/19. Medical 10/01/19 07/17/19: MPCTAC policy criteria retired and applicable Version 20 InterQual® criteria adopted. Administrative changes made to the Policy Summary, Description of Item or Service, and Other Applicable Policies sections. Updated Plan notes in the Applicable Coding section. Maintained diagnosis code list for prior authorization pregnancy waiver and updated corresponding procedure code list. 09/01/19 Review for effective date 12/01/19. Added 12/01/19 09/18/19: MPCTAC high-risk diagnosis code in the Applicable Version 21 Coding section. 01/01/20 Review for effective date 02/01/20. 02/01/20 01/15/20: MPCTAC Administrative changes made to the Version 22 References and Reference to Applicable Laws and Regulations sections. 02/01/21 Review for effective date 03/01/21. Updated 03/01/21 02/17/21: MPCTAC the Policy Statement and References Version 23 sections. Administrative changes made to the Applicable Coding section.

Last Review Date 02/01/21

Genetic Testing for Fragile X-Associated Disorders

Next Review Date 01/01/22

Authorizing Entity MPCTAC

Other Applicable Policies Medical Policy - Chromosomal Microarray Analysis for Unexplained Intellectual Disabilities and/or Multiple Congenital Anomalies, policy number OCA 3.573 Medical Policy - Drug Screening/Testing for Drugs of Abuse and/or Controlled Substances, policy number OCA 3.98 Medical Policy - Experimental and Investigational Treatment, policy number OCA 3.12 Medical Policy - Genetic Testing for Hereditary Thrombophilia, policy number OCA 3.728 Medical Policy - Genetic/Genomic Testing and Pharmacogenetics, policy number OCA 3.727 Medical Policy - Medically Necessary, policy number OCA 3.14 Medical Policy - Preimplantation Genetic Testing, policy number OCA 3.726 Reimbursement Policy - General Billing and Coding Guidelines, policy number 4.31 Reimbursement Policy - General Billing and Coding Guidelines, policy number SCO 4.31 Reimbursement Policy - General Billing and Coding Guidelines, policy number WS 4.17 Reimbursement Policy - General Clinical Editing and Payment Accuracy Review Guidelines, policy number 4.108 Reimbursement Policy - General Clinical Editing and Payment Accuracy Review Guidelines, policy number SCO 4.108 Reimbursement Policy - General Clinical Editing and Payment Accuracy Review Guidelines, policy number WS 4.18 Reimbursement Policy - Hospital, policy number WS 4.21 Reimbursement Policy - Inpatient Hospital, policy number 4.110 Reimbursement Policy - Inpatient Hospital, policy number SCO 4.110 Reimbursement Policy - Non-Participating Provider, policy number WS 4.5 Reimbursement Policy - Non-Reimbursed Codes, policy number 4.38 Reimbursement Policy - Non-Reimbursed Codes, policy number WS 4.38 Reimbursement Policy - Outpatient Hospital, policy number 4.17 Reimbursement Policy - Outpatient Hospital, policy number SCO 4.17 Reimbursement Policy - Physician and Non Physician Practitioner Services, policy number 4.608 Reimbursement Policy - Physician and Non Physician Practitioner Services, policy number SCO 4.608 Reimbursement Policy - Physician and Non Physician Practitioner Services, policy number WS 4.28

Genetic Testing for Fragile X-Associated Disorders

Reference to Applicable Laws and Regulations 42 CFR 438.210. Code of Federal Regulations. Public Health. Medical Assistance Programs. Managed Care Access Standards. Coverage and Authorization of Services.

78 FR 46499. Social Security Administration. Change in Terminology: "Mental Retardation" to "Intellectual Disability."

78 FR 48164-69. Centers for Medicare & Medicaid Services (CMS). Medicare Program. Revised Process for Making National Coverage Determinations. 2013 Aug 7.

114.3 CMR 17.00. Code of Massachusetts Regulations. Division of Health Care Finance and Policy. Medicine.

130 CMR. Code of Massachusetts Regulations. Division of Medical Assistance.

Affordable Care Act, 42 USC § 300gg-8.

Commonwealth of Massachusetts. Chapter 207 of the Acts of 2010 - An Act Relative to Insurance Coverage for Autism.

Commonwealth of Massachusetts. General Laws. Accessed at: https://malegislature.gov/Laws/GeneralLaws

Commonwealth of Massachusetts. Massachusetts General Laws Mandating that Certain Health Benefits Be Provided By Commercial Insurers, Blue Cross and Blue Shield and Health Maintenance Organizations. Regulatory Citations. 2017 Oct 24. Accessed at: https://www.mass.gov/files/documents/2017/10/27/mndatben.pdf

Developmental Disabilities Assistance and Bill of Rights Act of 2000, Public Law 106-402.

He-W 500. New Hampshire Code of Administrative Rules. Medical Assistance.

He-W 530.01(e). New Hampshire Code of Administrative Rules. Medical Assistance. Service Limits, Co- Payments, and Non-Covered Services. Definitions. Medically Necessary.

He-W 531. New Hampshire Code of Administrative Rules. Medical Assistance. Physician Services.

He-W 543. New Hampshire Code of Administrative Rules. Medical Assistance. Hospital Services.

MGL c 111 § 70G. Massachusetts General Law. Genetic information and reports protected as private information; prior written consent for genetic testing.

Genetic Testing for Fragile X-Associated Disorders

MGL c 1760. Massachusetts General Laws. Health Insurance Consumer Protections.

New Hampshire Department of Health and Human Services (DHHS). Certified Administrative Rules. Accessed at: https://www.dhhs.nh.gov/oos/bhfa/rules.htm

RSA Chapter 326-K. New Hampshire Revised Statutes. Genetic Counselors.

RSA Chapter 420-E. New Hampshire Revised Statutes. Insurance. Licensure of Medical Utilization Review Entitles.

Disclaimer Information: + Medical Policies are the Plan’s guidelines for determining the medical necessity of certain services or supplies for purposes of determining coverage. These Policies may also describe when a service or supply is considered experimental or investigational, or cosmetic. In making coverage decisions, the Plan uses these guidelines and other Plan Policies, as well as the Member’s benefit document, and when appropriate, coordinates with the Member’s health care Providers to consider the individual Member’s health care needs. Plan Policies are developed in accordance with applicable state and federal laws and regulations, and accrediting organization standards (including NCQA). Medical Policies are also developed, as appropriate, with consideration of the medical necessity definitions in various Plan products, review of current literature, consultation with practicing Providers in the Plan’s service area who are medical experts in the particular field, and adherence to FDA and other government agency policies. Applicable state or federal mandates, as well as the Member’s benefit document, take precedence over these guidelines. Policies are reviewed and updated on an annual basis, or more frequently as needed. Treating providers are solely responsible for the medical advice and treatment of Members. The use of this Policy is neither a guarantee of payment nor a final prediction of how a specific claim(s) will be adjudicated. Reimbursement is based on many factors, including member eligibility and benefits on the date of service; medical necessity; utilization management guidelines (when applicable); coordination of benefits; adherence with applicable Plan policies and procedures; clinical coding criteria; claim editing logic; and the applicable Plan – Provider agreement.

Genetic Testing for Fragile X-Associated Disorders