Guidelines and Recommendations

Amyotrophic Lateral Sclerosis (ALS)

Italian Amyotrophic Lateral Sclerosis Genetic (ITALSGEN) Consortium

The following guidelines were created as a result from a workshop on ALS genetic testing.

• “All ALS patients who have a first-degree or second-degree relative with ALS, frontotemporal dementia or both, should be offered genetic testing. At present, however, we do not recommend offering genetic testing to sporadic ALS patients, outside research protocols.”
• “Genetic testing at present is not indicated in asymptomatic at-risk subjects and, therefore, should not be proposed.”
• The guidelines also note that “two-thirds of mutations are found in four genes, C9ORF72, SOD1, TARDBP and FUS.” Therefore, they state that these genes should be “considered” for routine diagnostic protocol. Furthermore, they note that C9ORF72 testing is “worthwhile” in sporadic patients. If these 4 genes are negative, other ALS-related genes may be tested. Finally, UBQLN2 is a gene that should be tested if there is suspicion of an X-linked dominant inheritance (Chio et al., 2014).

ALS Association

The ALS Association published information on genetic testing on their website. They state that “Knowing whether your ALS is connected to a specific gene mutation could make you eligible for ongoing clinical trials testing treatments targeted at specific genes.” The guidelines go one to state that “if genetic testing identifies a disease-causing genetic mutation in a person with ALS, their family members generally have the option to pursue testing themselves” but note that this is a personal decision with significant costs and benefits (ALSA, 2023)

Ataxias (including Friedreich ataxia)

European Federation of Neurological Societies (EFNS) and European Neurological Society (ENS)

The EFNS-ENS released joint guidelines on diagnosis and management of chronic ataxias in adulthood. Their genetic testing guidelines are listed below:

“In the case of a family history that is compatible with an autosomal dominant cerebellar ataxia, screening for SCA1, 2, 3, 6, 7 and 17 is recommended (level B). In Asian patients, DRPLA should also be tested for.” “If mutation analysis is negative, we recommend contact with or a referral to a specialized clinic for reviewing the clinical phenotype and further genetic testing (good practice point).”

In the case of a family history compatible with an autosomal recessive cerebellar ataxia, they recommend a three‐ step diagnostic approach.

Step 1 includes mutation analysis of the FRDA gene for Friedreich's ataxia (although one can refrain from this in the case of severe cerebellar atrophy). Step 2 includes mutation analysis of the SACS, POLG, Aprataxin (APTX) and SPG7 genes (taking into account specific phenotypes).

Step 3 includes “referral to a specialized centre, e.g. for skin or muscle biopsy targeted at diagnoses such as Niemann−Pick type C, recessive ataxia with coenzyme Q deficiency [aarF domain containing kinase 3 (ADCK3)/autosomal recessive spinocerebellar ataxia 9 (SCAR9)] and mitochondrial disorders, or for extended genetic screening using gene panel diagnostics.”

“In the case of sporadic ataxia and independent from onset age, we recommend routine testing for SCA1, SCA2, SCA3, SCA6 and DRPLA (in Asian patients) (level B)” (van de Warrenburg et al., 2014).

Friedreich's Ataxia Research Alliance (FARA)

The FARA notes genetic diagnostic information on their website.

They state that in “more than 95% of abnormal alleles, the mutation is expansion of naturally occurring GAA repeat in first intron (non-coding region) of the frataxin or FRDA gene.” “Genetic testing results in ~98% detection in symptomatic individuals. In rare cases, analysis of frataxin protein levels can be helpful to confirming or ruling out a diagnosis…Carrier testing is recommended for anyone with a positive family history of Friedreich ataxia and for partners of known carriers. Presymptomatic testing for at-risk siblings/relatives is available, however genetic counseling is strongly recommended to assist individuals/families in considering the risks vs benefits for testing an untreatable genetic condition” (FARA, 2022).

An expert working group was convened to review and provide guidelines for FA. This working group reviewed guidelines from a variety of different societies, and drafted their own guidelines based off their review. Their genetic testing items are as follows:

“Any individual in whom the diagnosis of FRDA is considered should undergo genetic testing for FRDA.” “Referral to a clinical geneticist or genetic counselor should be considered on diagnosis of FRDA.” “Requests for pre-symptomatic genetic testing are best managed on a case-by-case basis; there is no evidence to support the routine provision or refusal of pre-symptomatic genetic testing for FRDA.” “The committee did not reach consensus on the issue of whether it is appropriate to conduct presymptomatic testing in a minor. Where a request for presymptomatic testing in a minor occurs, the individual/family should be referred to a team with expertise in this field for discussion about pre-symptomatic genetic testing in which the risks and benefits of pre-symptomatic genetic diagnosis are put forward. The risks and benefits from both the child’s and parents’ perspectives should be carefully reviewed during the pre-test assessment.” “All patients identified pre-symptomatically and their families would benefit from immediate post-test counseling and psychosocial support and referral for appropriate neurological and cardiac surveillance.” “Carrier testing should be first undertaken on the closest relative” (Corben et al., 2014).

For Friedreich Ataxia due to compound heterozygosity for a FXN Intron 1 GAA expansion and point mutation/insertion/deletion:

“If a person compound heterozygous for a FXN GAA expansion and a point mutation/insertion/deletion has a similar phenotype to those with FRDA due to homozygosity for GAA expansions, they should be managed as per the guidelines in this document.” “If spastic ataxia is the predominant phenotype, then the main management issue is that of spasticity and the guidelines for management of spasticity should be followed” (Corben et al., 2014).

Ataxia UK

Genetic tests are recommended as part of the secondary care regimen for ataxia. The secondary care is divided into “first line” and “second line” for adults.

The first line genetic tests are for: FRDA, SCA1, 2, 3, 6, 7 (12, 17), and FXTAS. The second line genetic tests are for any remaining genes (de Silva et al., 2019). The guidelines list genes associated with types of ataxia (Bonney et al., 2016).

Spinocerebellar ataxias:

The guidelines note that the clinical validity of genetic testing for SCA8 by CAG repeat sizing has not been determined. Therefore, SCA8 should not be offered as a routine test if family history is unknown. However, testing may be appropriate in “large pedigrees where the expansion has been proven to be segregating with the disease” (Bonney et al., 2016).

SCAs are considered autosomal dominant ataxias. Autosomal dominant ataxias also include GSS, DRPLA, POLG1, and EA types 1 and 2.

Autosomal recessive ataxia genes include FXN (Frederich’s Ataxia), APTX, SETX, SACS, SPG7, ATM, and TTPA (Ataxia with Vitamin E deficiency).

Mitochondrial Ataxias include NARP, MELAS, and MERRF.

X-Linked Ataxias include FXTAS (Fragile X associated Tremor and Ataxia Syndrome).

For children, second-line diagnostic tests for chronic ataxias include DNA testing for the FXN gene is recommended for suspected Frederich’s Ataxia, ATM testing is recommended for suspected ataxia-telangiectasia, and general DNA testing is recommended for “other conditions.” Finally, “genetic testing of asymptomatic ‘atrisk’ minors is not generally recommended, but should be considered on a case-by-case basis” (Bonney et al., 2016).

National Ataxia Foundation (NAF)

The National Ataxia Foundation published a “Frequently Asked Questions” document regarding genetic testing for hereditary ataxias. For diagnostic testing, they noted that in sporadic ataxia cases (no prior family history of ataxia), genetic testing should only be done after non-genetic causes of ataxia have been excluded. For predictive testing, a patient “must” know what type of ataxia is present in their family to be eligible (NAF, 2015).

Dystonias

European Federation of Neurological Societies (EFNS)

The EFNS has released guidelines on the genetic testing of dystonias, which are listed below:

“Genetic testing should be performed after establishing the clinical diagnosis. Genetic testing is not sufficient to make a diagnosis of dystonia without clinical features of dystonia (level B). Genetic counselling is recommended.”

“DYT1 testing is recommended for patients with limb‐onset, primary dystonia with onset before age 30 (level B), as well as in those with onset after age 30 if they have an affected relative with early‐onset dystonia (level B).”

“In dystonia families, DYT1 testing is not recommended in asymptomatic individuals (good practice point).” “DYT6 testing is recommended in early‐onset dystonia or familial dystonia with cranio‐cervical predominance or after exclusion of DYT1 (good practice point).”

“Individuals with early‐onset myoclonus affecting the arms or neck, particularly if positive for autosomal‐ dominant inheritance and if triggered by action, should be tested for the DYT11 gene (good practice point). If direct sequencing of the SGCE gene is negative, gene dosage studies increase the proportion of mutation‐ positives (level C).”

“Diagnostic testing for the PNKD gene (DYT8) is recommended in symptomatic individuals with PNKD (good practice point).”

“Gene testing for mutation in GLUT1 is recommended in patients with paroxysmal exercise‐induced dyskinesias, especially if involvement of GLUT1 is suggested by low CSF/serum glucose ratio, epileptic seizures or haemolytic anaemia (good practice point)” (Albanese et al., 2011).

The EFNS also released guidelines on the diagnosis of Huntington’s Disease. In it, they recommend that “diagnostic testing for HD is recommended (Level B) when a patient presents with an otherwise unexplained clinical syndrome of a progressive choreatic movement disorder and neuropsychiatric disturbances with or without a positive family history of the disease” (Harbo et al., 2009).

Hereditary Spastic Paraplegia (HSP)

National Organization for Rare Disorders (NORD)

NORD has published a webpage on HSP. This page states that “Individuals seeking genetic counseling for HSP are recommended to consult a genetic counselor or medical geneticist for specific information”; further, “Genetic testing is often helpful in confirming the clinical diagnosis of HSP and in determining the genetic type of HSP. Results of genetic testing can be used, together with clinical information, to provide genetic counseling” (NORD, 2017).

Regarding genetic testing for a HSP diagnosis, NORD states that “Testing for HSP genes is available and performed for individual HSP genes, for panels containing dozens of HSP genes, and by analysis of all genes (whole exome and whole genome analysis). Genetic testing is often helpful to confirm the clinical diagnosis of HSP. Genetic testing is most often able to find causative gene mutations for subjects with HSP who have a family history of a similarly affected first-degree relative. Despite discovery of more than 60 genes in which mutations cause various types of HSP, many individuals with HSP do not have an identified gene mutation… at present, genetic testing results very rarely influence treatment which is largely directed toward reducing symptoms” (NORD, 2017).

Huntington Disease (HD)

Working Group on Genetic Counselling and Testing of the European Huntington’s Disease Network (EHDN)

This Working Group was convened to provide guidelines for diagnostic genetic testing for HD. The guidelines list four groups that “should be considered” for genetic testing.

• The first group is “the patient with a positive family history and specific motor symptoms.” The authors note that diagnosis of this group is “not difficult” and that the test may be “little more than a formality.”
• The second group is “the patient with no family history, but specific symptoms likely to be HD.” The authors consider diagnostic testing of this group to be “most clinically useful.”
• The third group is “the patient with a positive family history and prodromal symptoms, which suggest the impending onset of HD.” The authors state that the motor abnormalities are part of the diagnostic criteria, but other symptoms such as behavioral changes or other mental conditions may present in HD.
• The fourth group is “the child with a family history of HD and features of juvenile HD.” The authors note this group as challenging to diagnose, and alludes to diagnostic criteria set forth by Nance, which are as follows:
  • “a known family history of HD (often, but not exclusively, the father)
  • and two or more of
    • declining school performance
    • Seizures
    • oral motor dysfunction
    • Rigidity
    • gait disturbance” (Craufurd et al., 2015)

Another Working Group was convened to evaluate the predictive testing guidelines for HD in 2013. In those guidelines, they noted that HD testing should not be part of routine blood work and that patients under 18 should not be tested. However, they state that genetic counseling should be offered to those desiring to take the test (MacLeod et al., 2013). MacLeod et al. (2013) was affirmed by the American Association of Neurology on January 14, 2014 (AAN, 2014).

The EDHN performed a literature review of scientific and consensual guidelines in 2019. The only major change had to do with deutetrabenazine (Grade A) as a treatment. Other studies were in agreement with previously noted guidelines and recommendations (Bachoud-Lévi et al., 2019).

Parkinsonism (Parkinson Disease, PD)

European Federation of Neurological Societies (EFNS) and Movement Disorder Society–European Section (MDS-ES)

These guidelines were created by a Task Force comprised of members from both societies. Their genetic testing recommendations for Parkinson disease are listed below:

• “Testing for SNCA point mutations and gene multiplications is recommended only in families with multiple affected members in more than one generation suggestive of dominant inheritance, with early‐ or late‐onset PD.”
• “LRRK2 genetic testing for counselling purposes, specifically directed at known pathogenic variants is recommended in patients with a clinical picture of typical PD and a positive family history suggestive of dominant inheritance.”
• “In sporadic patients, genetic testing should be limited to the search for known LRRK2 founder mutations in the appropriate populations (i.e. with known high mutation frequencies).”
• “Genetic testing for GBA gene mutations is recommended in patients with typical PD with or without a positive family history, limited to the known founder mutations of established pathogenic role in the appropriate populations.”
• “Genetic testing of the parkin, PINK1 and DJ‐1 genes for counselling purposes is recommended in patients with typical PD and positive family history compatible with recessive inheritance, particularly when the disease onset is before the age of 50 years. For sporadic cases, parkin, PINK1 and DJ‐1 genetic testing is recommended when onset is very early, particularly before the age of 40.”
• “Testing of the ATP13A2, PLA2G6 and FBXO7 genes might be considered in cases with very‐early‐ onset PD, if no mutation in parkin, PINK1 and DJ‐1 gene has been found.”

For recommendation III, the guideline lists Ashkenazi Jews, North African Arabs, and Basques as examples of high mutation frequency populations (Berardelli et al., 2013).

Spinal Muscular Atrophies (SMA)

218th European Neuromuscular Centre (ENMC) International Workshop

Researchers, industry representatives, and other representatives from SMA Europe convened to review the current knowledge on the standards of care for SMA. Regarding genetic testing, they noted that “there was consensus that genetic testing is the first line investigation when this condition is suspected in a typical case and that muscle biopsy or electromyography should not be performed in a typical presentation. There was also consensus that, at variance with previous recommendations, the current gold standard is SMN1 deletion/mutation and SMN2 copy number testing, with a minimal standard of SMN1 deletion testing. Other areas concerning the value of SMN2 copy number were more controversial and a further Delphi round was planned to complete the task” (Finkel et al., 2017).

“Diagnostic testing for HD is recommended (Level B) when a patient presents with an otherwise unexplained clinical syndrome of a progressive choreatic movement disorder and neuropsychiatric disturbances with or without a positive family history of the disease” (Finkel et al., 2017).

American College of Obstetricians and Gynecologists (ACOG)

ACOG recommended SMA screening for all individuals “considering pregnancy or are currently pregnant.” ACOG also noted that if one parent had a family history of SMA, the other parent should be tested for SMN1 deletion if molecular reports for the first parent were not available. These guidelines were reaffirmed in 2021 (ACOG, 2017).

Wilson Disease (WD)

Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)

ESPGHAN has published a position paper regarding Wilson disease in children. The genetic testing-relevant items are listed below:

The paper stated that the scoring system used for diagnosis of Wilson’s Disease included identification of a pathogenic mutation, which was considered one point (the scoring system is as follows: 0-1: unlikely, 2-3: probable, 4+, highly likely). The paper also notes that if biochemical and clinical symptoms are present, only one mutation needs to be identified to diagnose Wilson disease. If the patient is asymptomatic, two mutations must be identified to diagnose “with certainty.” The diagnostic protocol calls for biochemical (copper metabolism testing), liver (ALT/AST, bilirubin, et al), and clinical evaluation before proceeding to molecular testing, and ATP7B is the primary gene mutation mentioned in evaluation of Wilson disease.

“Genetic counseling is essential for families of patients with WD, and screening first-degree relatives is recommended by both European and American guidelines.”

“It is essential to screen siblings of any patient newly diagnosed with WD because the chance of being a homozygote and developing clinical disease is 25%. Assessment should include physical examination, serum ceruloplasmin, liver function tests, and molecular testing for ATP7B mutations or haplotype studies if not available. Newborn screening is not warranted and screening may be delayed until 1 to 2 years of age” (Socha et al., 2018).

State and Federal Regulations, as applicable

Food and Drug Administration (FDA)

Many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). LDTs are not approved or cleared by the U. S. Food and Drug Administration; however, FDA clearance or approval is not currently required for clinical use.

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81177, 81178, 81179, 81180, 81181, 81182, 81183, 81184, 81185, 81186, 81243, 81244, 81271, 81274, 81284, 81285, 81286, 81289, 81329, 81343, 81344, 81400, 81401, 81403, 81404, 81405, 81406, 81407, 81408, 81479, 0136U, 0231U, 0233U, 0236U

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

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Policy Implementation/Update Information

11/10/20 New policy developed. Genetic testing for neurodegenerative disorders is covered when coverage criteria are met. Notification given 11/10/2020 for policy effective date 01/12/2021. (sk)

12/13/22 Reviewed by Avalon 3rd Quarter 2022 CAB. When Covered section updated. Table of Terminology added. Codes 81177, 81186, 96040, 0231U, 0233U, 0236U, and S0265 added to Billing/Coding section. Policy Guidelines updated. References updated. (sk)

10/24/23 Wording in Policy Statement, When Covered, and/or Not Covered section(s) changed from Reimbursement to Medical Necessity. (ldh)

12/05/23 Reviewed by Avalon 3rd Quarter 2023 CAB. Policy Guidelines and References updated. When Covered section edited for clarity. Added Note 1. Removed Table of Terminology. No change to policy statement. Removed CPT code 96040 and HCPCS code S0265 from the Billing/Coding section. Medical Director review 11/2023. (ldh)

12/17/24 Reviewed by Avalon 3rd Quarter 2024 CAB. Updated Description and Reference sections. Added the following statement to the When Covered Section, “Genetic counseling is required for individuals prior to and after undergoing genetic testing for diagnostic, carrier, and/or risk assessment purposes” and removed reference to genetic counseling from any disease-specific sections. Moved the following statement, “For guidance on preconception screening for spinal muscular atrophies, please refer to Prenatal Screening (Genetic) AHS-M2179” from the SMA section of When Covered to the Related Policies for clarity. Updated Note 2 in When Covered section. No change to policy statement. Medical Director review 10/2024. (ldh)