Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Genetic Test: Neurofibromatosis

Description:

Neurofibromatoses are autosomal dominant genetic disorders associated with tumors of the peripheral and central nervous systems. There are 3 clinically and genetically distinct forms: neurofibromatosis (NF) type 1, NF type 2, and schwannomatosis. The potential benefit of genetic testing for NF type 1 (NF1), neurofibromatosis type 2 (NF2), or SPRED1 pathogenic variants is to confirm the diagnosis in an individual with suspected NF who does not fulfill clinical diagnostic criteria or to determine future risk of NF in asymptomatic at-risk relatives.

There are 3 major clinically and genetically distinct forms of neurofibromatosis (NF): NF type 1 (NF1; also known as von Recklinghausen disease), NF type 2 (NF2), and schwannomatosis.

Neurofibromatosis 1

NF1 is one of the most common dominantly inherited genetic disorders, with an incidence at birth of 1 in 3000 individuals.

Clinical Characteristics

The clinical manifestations of NF1 show extreme variability, between unrelated individuals, among affected individuals within a single family, and within a single person at different times in life. NF1 is characterized by multiple café-au-lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, and iris Lisch nodules. Segmental NF1 is limited to 1 area of the body. Many individuals with NF1 only develop cutaneous manifestations of the disease and Lisch nodules.

Cutaneous Manifestations

Café-au-lait spots occur in nearly all affected individuals and intertriginous freckling occurs in almost 90%. Café-au-lait spots are common in the general population, but when more than 6 are present, NF1 should be suspected. Café-au-lait spots are often present at birth and increase in number during the first few years of life.

Neurofibromas

Neurofibromas are benign tumors of Schwann cells that affect virtually any nerve in the body and develop most people with NF1. They are divided into cutaneous and plexiform types. Cutaneous neurofibromas, which develop in almost all people with NF1, are discrete, soft, sessile, or pedunculated tumors. Discrete cutaneous and subcutaneous neurofibromas are rare before late childhood. They may vary from a few to hundreds or thousands, and the rate of development may vary greatly from year to year. Cutaneous neurofibromas do not carry a risk of malignant transformation but may be a major cosmetic problem in adults.

Plexiform neurofibromas, which occur in about half of individuals with NF1, are more diffuse growths that may be locally invasive. They can be superficial or deep and, therefore, the extent cannot be determined by clinical examination alone; magnetic resonance imaging (MRI) is the method of choice for imaging plexiform neurofibromas (Friedman, 1993). Plexiform neurofibromas represent a major cause of morbidity and disfigurement in individuals with NF1. They tend to develop and grow in childhood and adolescence and then stabilize throughout adulthood (Friedman, 1993). Plexiform neurofibromas can compress the spinal cord or airway and can transform into malignant peripheral nerve sheath tumors (MPNST). MPNST occur in approximately 10% of affected individuals (Friedman, 1993).

Other Tumors

Optic gliomas, which can lead to blindness, develop in the first 6 years of life. Symptomatic optic gliomas usually present before 6 years of age with loss of visual acuity or proptosis, but they may not become symptomatic until later in childhood or in adulthood. While optic pathway gliomas are particularly with NF1, other central nervous system tumors occur at higher frequency in NF1, including astrocytomas and brainstem gliomas.

Patients with NF1 have a high lifetime risk of cancer, including solid tumors not described above, with excess risk appearing to manifest prior to age 50 years (Uusitalo, 2016). Particularly strong links have been identified between pathogenic and likely pathogenic NF1 variants and risks of breast cancer and gastrointestinal stromal tumors, and 5-year overall survival is significantly worse for patients with NF1 and non-central nervous system cancers compared to similar patients without NF1 (Walker, 2006; Nishida, 2016; Uusitalo, 2016). Additionally, children with NF1have long been recognized to carry significantly higher risk of juvenile myelomonocytic leukemia than children who do not have NF1 (Stiller, 1994; Niemeyer, 1997).

Other Findings

Other findings in NF1 include:

Intellectual disability occurs at a frequency of about twice that in the general population and features of autism spectrum disorder occur in up to 30% of children with NF1.
Musculoskeletal features include dysplasia of the long bones, most often the tibia and fibula, which is almost always unilateral. Generalized osteopenia is more common in people with NF1 and osteoporosis is more common and occurs at a younger age than in the general population (Friedman, 1993)
Cardiovascular involvement includes the common occurrence of hypertension. Vasculopathies may involve major arteries or arteries of the heart or brain and can have serious or fatal consequences. Cardiac issues include valvar pulmonic stenosis, and congenital heart defects and hypertrophic cardiomyopathy may be especially frequent in individuals with NF1 whole gene deletions (Friedman, 1993). Adults may develop pulmonary hypertension, often in association with parenchymal lung disease.
Lisch nodules are innocuous hamartomas of the iris.

Diagnosis

Although the clinical manifestations of NF1 are extremely variable and some are age-dependent, the diagnosis can be made clinically or with the use of combined clinical and genetic findings (Friedman, 1993).

The clinical diagnosis of NF1 should be suspected in individuals with the diagnostic criteria for NF1 developed by the National Institute of Health (NIH) in 1988. These clinical criteria were revised in 2021 by an international expert consensus panel to account for advances in understanding of genotypic and phenotypic features of NF1 and mosaicNF1 (Neurofibromatosis, 1988; Legius, 2021). The criteria are met when an individual has:

Two or more of the following features for diagnosis of NF1:

Is the child of a parent who meets NF1 diagnostic criteria (does not contribute to diagnosis of mosaic NF1; see below)
Germline heterozygous NF1 pathogenic variant with allele fraction of 50%
Six or more café-au-lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in postpubertal individuals
Two or more neurofibromas of any type or one plexiform neurofibroma
Freckling in the axillary or inguinal regions
Optic glioma
Two or more Lisch nodules (raised, tan-colored hamartomas of the iris) or 2 or more choroidal abnormalities
A distinctive osseous lesion such as sphenoid dysplasia, anterolateral bowing of the tibia, or tibial pseudarthrosis

Any of the following features for diagnosis of mosaic NF1:

Germline heterozygous NF1 pathogenic variant with allele fraction significantly less than 50% plus one or more of the criteria for NF1 above (except for being the child of a parent meeting NF1 diagnostic criteria)
Identical somatic heterozygous NF1 pathogenic variant identified in 2 anatomically independent affected tissues
Clearly segmental distribution of café-au-lait macules or cutaneous neurofibromas plus either one or more of the criteria for NF1 above (except for being the child of a parent meeting NF1 diagnostic criteria) or is the parent of a child who meets NF1 diagnostic criteria
Is the parent of a child who meets NF1 diagnostic criteria plus has 2 or more neurofibromas or one plexiform neurofibroma, freckling in the axillary or inguinal region, optic glioma, 2 or more Lisch nodules or 2 or more choroidal abnormalities, or a distinctive osseous lesion

In adults, the diagnostic criteria are highly specific and sensitive for a diagnosis of NF1 (Friedman, 1993).

Approximately half of children with NF1 and no known family history of NF1 meet NIH criteria for the clinical diagnosis by age 1 year. By 8 years of age, most meet NIH criteria because many features of NF1 increase in frequency with age. Children who have inherited NF1 from an affected parent can usually be diagnosed within the first year of life because the diagnosis requires 1 diagnostic clinical feature in addition to a family history of the disease. This feature is usually multiple café-au-lait spots, present in infancy in more than 95% of individuals with NF1 (Friedman, 1993).

Young children with multiple café-au-lait spots and no other features of NF1 who do not have a parent with signs of NF1 should be suspected of having NF1, and followed clinically as if they do (Bernier, 2016). A definitive diagnosis of NF1 can be made in most children by 4 years of age using NIH criteria (Friedman, 1993).

Genetics

NF1 is caused by dominant loss-of-function variants in the NF1 gene, which is a tumor suppressor gene located at chromosome 17q11.2 that encodes neurofibromin, a negative regulator of RAS activity. About half of affected individuals have a de novo NF1 mutation. Penetrance is virtually complete after childhood, however, expressivity is highly variable.

The variants responsible for NF1 are heterogeneous, and include nonsense and missense single nucleotide changes, single base insertions/deletions, splicing variants (»30% of cases), whole gene deletions (»5% of cases), intragenic copy number variants, and other structural rearrangements. Several thousand pathogenic NF1 variants have been identified and none is frequent (Friedman, 1993).

Management

Patient management guidelines for NF1 have been developed by the American Academy of Pediatrics, the National Society of Genetic Counselors and other expert groups (Friedman, 1993; Hersh, 2008).

After an initial diagnosis of NF1, the extent of the disease should be established, with personal medical history and physical examination and particular attention to features of NF1, ophthalmologic evaluation including slit lamp examination of the irides, developmental assessment in children, and other studies as indicated on the basis of clinically apparent signs or symptoms (Friedman, 1993).

Surveillance recommendations for an individual with NF1 are for regular annual visits for skin examination for new peripheral neurofibromas, signs of plexiform neurofibroma or progression of existing lesions, checks for hypertension, other studies (e.g., MRI) as indicated based on clinically apparent signs or symptoms, and monitoring of abnormalities of the central nervous system, skeletal system, or cardiovascular system by an appropriate specialist. In children, recommendations are for annual ophthalmologic examination in early childhood (less frequently in older children and adults), and regular developmental assessment.

Long-term care for individuals with NF1 aims at early detection and symptomatic treatment of complications.

It is recommended that radiotherapy be avoided, if possible, because radiotherapy in individuals with NF1 appears to be associated with a high risk of developing MPNST within the field of treatment.

Legius Syndrome

Clinical Characteristics

A few clinical syndromes may overlap clinically with NF1. In most cases, including Proteus syndrome, Noonan syndrome, McCune-Albright syndrome, and LEOPARD syndrome, patients will be missing key features or will have features of the other disorder. However, Legius syndrome is a rare autosomal-dominant disorder characterized by multiple café-au-lait macules, intertriginous freckling, macrocephaly, lipomas, and potential attention-deficit/hyperactivity disorder. Misdiagnosis of Legius syndrome as NF1might result in overtreatment and psychological burden on families about potential serious NF-related complications.

Genetics

Legius syndrome is associated with pathogenic loss-of-function variants in the SPRED1 gene on chromosome 15, which is the only known gene associated with Legius syndrome.

Diagnosis

The 2021 revision to the NIH diagnostic criteria for NF1 included new criteria for Legius syndrome and mosaic Legius syndrome. The criteria are met when an individual has:

Any of the following features for diagnosis of Legius syndrome:

Both of the following in an individual who is not the child of a parent diagnosed with Legius syndrome:

Six or more café-au-lait macules, with or without axillary or inguinal freckling, and no other features diagnostic of NF1
Germline heterozygous SPRED1 pathogenic variant with allele fraction of 50%

Either of the above criteria for Legius syndrome in an individual who is the child of a parent diagnosed with Legius syndrome

Any of the following features for diagnosis of mosaic Legius syndrome:

Germline heterozygous SPRED1 pathogenic variant with allele fraction significantly less than 50% plus 6 or more café-au-lait macules
Identical somatic heterozygous SPRED1 pathogenic variant identified in 2 independent affected tissues
Clearly segmental distribution of café-au-lait macules plus is the parent of a child who meets Legius syndrome diagnostic criteria

Management

Legius syndrome typically follows a benign course and management generally focuses on the treatment of manifestations and prevention of secondary complications (Legius, 2020). Treatment of manifestations include behavioral modification and/or pharmacologic therapy for those with attention-deficit/hyperactivity disorder; physical, speech, and occupational therapy for those with identified developmental delays; and individualized education plans for those with learning disorders.

Neurofibromatosis Type 2

NF2 (also known as bilateral acoustic neurofibromatosis and central neurofibromatosis) is estimated to occur in 1 in 33,000 individuals.

Clinical Characteristics

NF2 is characterized by bilateral vestibular schwannomas and associated symptoms of tinnitus, hearing loss, and balance dysfunction (Evans, 2018). Average age of onset is 18 to 24 years, and almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Affected individuals may also develop schwannomas of other cranial and peripheral nerves, ependymomas, meningiomas, and, rarely, astrocytomas. The most common ocular finding, which may be the first sign of NF2, is posterior subcapsular lens opacities; they rarely progress to visually significant cataracts.

Most patients with NF2 present with hearing loss, which is usually unilateral at onset. Hearing loss may be accompanied or preceded by tinnitus. Occasionally, features such as dizziness or imbalance are the first symptom (Evans, 2000). A significant proportion of cases (20%-30%) present with an intracranial meningioma, spinal, or cutaneous tumor. The presentation in pediatric populations may differ from adult population as vestibular schwannomas may account for only 15% to 30% of initial symptoms (Evans, 2000).

Diagnosis

The diagnosis of NF2 is usually made on clinical findings and more recently-identified molecular findings. Historically, diagnosis of NF2 was based on modified NIH diagnostic criteria. In 2022, revised diagnostic criteria were introduced by an international expert consensus panel to incorporate advances in understanding of genotypic and phenotypic features of NF2, as well as to better delineate between NF2 and schwannomatosis (Plotkin, 2022). The new criteria forNF2 are met when an individual has one of the following:

Bilateral vestibular schwannomas
Identical somatic NF2 pathogenic variant identified in at least 2 anatomically distinct NF2-related tumors
Either 2 major criteria below or 1 major plus 2 minor criteria below:

Major criteria:

Unilateral vestibular schwannoma
First-degree non-sibling relative with NF2
Two or more meningiomas
Germline NF2 pathogenic variant (considered mosaic NF2 if variant allele fraction is significantly less than 50%)

Minor criteria:

Single meningioma
Ependymoma or schwannoma (each distinct tumor counts as one minor criterion)
Juvenile subcapsular or cortical cataract
Retinal hamartoma
Epiretinal membrane in an individual age < 40 years

Genetics

NF2 is inherited in an autosomal dominant manner; approximately 50% of individuals have an affected parent and the other 50% have NF2 as a result of a de novo mutation (Evans, 2018).

Between 25% and 33% of individuals with NF2 caused by a de novo mutation have somatic mosaicism. Variant detection rates are lower in simplex cases and in an individual in the first generation of a family to have NF2 because they are more likely to have somatic mosaicism. Somatic mosaicism can make clinical recognition of NF2 difficult and results in lower variant detection rates. Clinical recognition of NF2 in these patients may be more difficult because these individuals may not have bilateral vestibular schwannomas. Variant detection rates may be lower because molecular genetic testing may be normal in unaffected tissue (e.g., lymphocytes), and molecular testing of tumor tissue may be necessary to establish the presence of somatic mosaicism (Friedman, 1993).

Management

In an individual diagnosed with NF2, it is recommended that an initial evaluation establish the extent of the disease, typically using head MRI, hearing evaluation, and ophthalmologic and cutaneous examinations. Counseling is recommended for insidious problems with balance and underwater disorientation, which can result in drowning. Hearing preservation and augmentation are part of the management of NF2, as is early recognition and management of visual impairment from other manifestations of NF2. Therefore, routine hearing and eye examination should be conducted. Surveillance measures for affected or at-risk individuals include annual MRI beginning at around age 10 and continuing until at least the fourth decade of life.

Treatment of manifestations includes surgical resection of small vestibular schwannomas, which may often be completely resected with preservation of hearing and facial nerve function. Larger tumors are often managed expectantly with debulking or decompression when brain stem compression, deterioration of hearing, and/or facial nerve dysfunction occur (Evans, 2018).

Radiotherapy should be avoided, because radiotherapy of NF2-associated tumors, especially in childhood, may induce, accelerate, or transform tumors (Evans, 2018).

Evaluation of At-Risk Relatives

Early identification of relatives who have inherited the family-specific NF2 mutation allows for appropriate screening using MRI for neuroimaging and audiologic evaluation, which result in earlier detection and improved outcomes (Evans, 2018). Identification of at-risk relatives who do not have the family-specific NF2 mutation eliminates the need for surveillance.

Schwannomatosis

Schwannomatosis is a rare condition characterized by development of multiple schwannomas and, less frequently, meningiomas (Dhamija, 2018). Individuals with schwannomatosis may develop intracranial, spinal nerve root, or peripheral nerve tumors. Familial cases are inherited in an autosomal dominant manner, with highly variable expressivity and incomplete penetrance, and LZTR1 variants have been shown to cause most cases of familial schwannomatosis but account for a lesser proportion of simplex disease. Some cases are also characterized by chromosome 22 abnormalities, typically involving the 22q region encompassing SMARCB1, LZTR1, and NF2, without identification ofSMARCB1 or LZTR1 pathogenic variants. New diagnostic criteria for molecularly-defined subtypes of schwannomatosis not associated with NF2 pathogenic variants (i.e., with germline or somatic pathogenic variants of SMARCB1 or LZTR1, or with loss of heterozygosity of chromosome 22q) were proposed alongside the 2022 NF2 diagnostic criteria, with cases not meeting these definitions categorized as schwannomatosis-not elsewhere classified (Plotkin, 2022).

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Lab tests for neurofibromatosis are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Definitions

Mutation Scanning

Mutation scanning is a process by which a particular segment of DNA is screened to identify sequence variants. Variant gene regions are then further analyzed (e.g., by sequencing) to identify the sequence alteration. Mutation scanning allows for screening of large genes and novel sequence variants.

Schwann Cells

Schwann cells cover the nerve fibers in the peripheral nervous system and form the myelin sheath.

Simplex Disease

Simplex disease is a single occurrence of a disease in a family.

Somatic Mosaicism

Somatic mosaicism is the occurrence of 2 genetically distinct populations of cells within an individual, derived from a postzygotic mutation. Unlike inherited mutations, somatic mosaic mutations may affect only a portion of the body and are not transmitted to progeny.

Genetic Counseling

Genetic counseling is primarily aimed at individuals who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Coding

CPT code 81405 includes the following test:

NF2 (neurofibromin 2 [merlin]) (e.g., neurofibromatosis, type 2), duplication/deletion analysis

CPT code 81406 includes the following test:

NF2 (neurofibromin 2 [merlin]) (e.g., neurofibromatosis, type 2), full gene sequence

CPT code 81408 includes the following test:

NF1 (neurofibromin 1) (e.g., neurofibromatosis, type 1), full gene sequence

Policy/
Coverage:

Effective February 2024

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Genetic testing for neurofibromatosis type 1 (NF1) or neurofibromatosis type 2 – related schwannomatosis (formerly NF type 2) (NF2) pathogenic variants meets member benefit certificate primary coverage criteria and is covered when the diagnosis of neurofibromatosis is clinically suspected due to signs of disease, but a definitive diagnosis cannot be made without genetic testing.

Genetic testing for NF1 or NF2 pathogenic variants in at-risk relatives with no signs of disease meets member benefit certificate primary coverage criteria and is covered when a definitive diagnosis cannot be made without genetic testing AND at least one of the following criteria is met:

A close relative (ie, first-, second-, or third-degree relative) has a known NF1 or NF2 variant; or
A close relative has been diagnosed with neurofibromatosis but whose genetic status is unavailable

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Genetic testing for neurofibromatosis for all other situations not meeting the criteria outlined above does not meet member benefit certificate primary coverage criteria and is not covered.

For members with contracts without primary coverage criteria, genetic testing for neurofibromatosis for all other situations not meeting the criteria outlined above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective January 2021 - January 2024

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Genetic testing for neurofibromatosis type 1 (NF1) or neurofibromatosis type 2 (NF2) pathogenic variants meets member benefit certificate primary coverage criteria and is covered when the diagnosis of neurofibromatosis is clinically suspected due to signs of disease, but a definitive diagnosis cannot be made without genetic testing.

A close relative (ie, first-, second-, or third-degree relative) has a known NF1 or NF2 variant; or
A close relative has been diagnosed with neurofibromatosis but whose genetic status is unavailable

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Genetic testing for neurofibromatosis for all other situations not meeting the criteria outlined above does not meet member benefit certificate primary coverage criteria and is not covered.

Effective prior to January 2021

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Genetic testing for neurofibromatosis meets member benefit certificate primary coverage criteria and is covered when the diagnosis is clinically suspected due to signs of disease, but a definitive diagnosis cannot be made without genetic testing.

Genetic testing for neurofibromatosis in at-risk relatives with no signs of disease meets member benefit certificate primary coverage criteria and is covered when a definitive diagnosis cannot be made without genetic testing AND at least one of the following criteria is met:

· A close relative (ie, first-, second-, or third-degree relative) has a known NF mutation; or

· A close relative has been diagnosed with neurofibromatosis but whose genetic status is unavailable

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Genetic testing for neurofibromatosis for all other situations not meeting the criteria outlined above does not meet member benefit certificate primary coverage criteria and is not covered.

Rationale:

Schwannomatosis is rare, and far less well-described than neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2); therefore, this review will focus on NF1 and NF2.

Validation of the clinical use of any genetic test focuses on 3 main principles: (1) analytic validity, which refers to the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent; (2) clinical validity, which refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease; and (3) clinical utility, ie, how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes.

Clinical Validity

Neurofibromatosis 1

Detecting mutation in the NF1 gene is challenging because of the gene’s large size, the lack of mutation hotspots, and the wide variety of possible lesions.

A multistep mutation testing protocol identifies more than 95% of NF1 pathogenic variants in individuals who fulfill the National Institutes of Health (NIH) diagnostic criteria (Friedman, 1993). The protocol involves sequencing of both mRNA (cDNA) and genomic DNA, and testing for whole NF1 deletions (eg, by MLPA) because whole gene deletions cannot be detected by sequencing. Due to the wide variety and rarity of individual pathogenic mutation variants in NF1, sequencing of cDNA increases the detection rate of mutations from approximately 61% with genomic DNA sequence analysis alone (van Minkelen, 2014) to greater than 95% with sequencing for both cDNA and genomic DNA and testing for whole gene deletions. This latter method is known as the multistep mutation detection protocol.

Sensitivity rates of more than 95% for detecting a mutation using the multistep protocol have been reported (Sabbagh, 2013; Valero, 2011).

Sabbagh et al reported a comprehensive mutation analysis of constitutional NF1 mutations in unrelated, well-phenotyped index cases with typical clinical features of NF1 who enrolled in a French clinical research program (Sabbagh, 2013). The 565 families for this study (N=1697 individuals) were enrolled between 2002 and 2005; 1083 fulfilled NIH diagnostic criteria for NF1. A comprehensive NF1 mutation screening (sequencing of both cDNA and genomic DNA, as well as large deletion testing by MLPA) was performed in 565 individuals, one from each family, who had a sporadic mutation or who represented the familial index case. A NF1 mutation was identified in 546, a mutation detection rate of 97%. A total of 507 alterations were identified at the cDNA and genomic DNA levels. Among these 507 alterations, 487 were identified using only the genomic DNA sequencing approach. Among these 507 alterations, 505 would have been identified if the single cDNA sequencing approach were used. MLPA detected 12 deletions/duplications that would not have been detected by sequencing. No mutation was detected in 19 patients (3.4%), 2 of whom had a SPRED1 mutation, which is frequently confused with NF; the remainder may have been due to an unknown mutation of the NF1 locus.

The authors then statistically evaluated the genotype-phenotype correlation in 439 of these patients harboring a truncating (n=368), in-frame splicing (n=36), or missense (n=35) NF1 mutation to assess the contribution of intragenic NF1 mutations (vs large gene deletions) to the variable expressivity of NF1. Their findings suggested a tendency for truncating mutations to be associated with a greater incidence of Lisch nodules and a larger number of café-au-lait spots compared with missense mutations.

Valero et al developed a method for detecting NF1 mutations by combining an RNA-based cDNA-polymerase chain reaction mutation detection method and denaturing high-performance liquid chromatography with MLPA (Valero, 2011). Their protocol was validated in a cohort of 56 patients with NF1 (46 sporadic cases, 10 familial cases) who fulfilled NIH diagnostic criteria. A mutation was identified in 53 cases (95% sensitivity), involving 47 different mutations, of which 23 were novel. After validation, the authors implemented the protocol as a routine test and subsequently reported the spectrum of NF1 mutations identified in 93 patients in a cohort of 105. The spectrum included a wide variety of mutations (nonsense, small deletions or insertions/duplications, splice defects, complete gene deletions, missense, single exon deletions and duplications, and a multiexon deletion), confirming the heterogeneity of the NF1 gene mutations that can cause NF1.

Genotype-Phenotype Correlations

NF1 is characterized by extreme clinical variability between unrelated individuals, among affected individuals within a single family and even within a single person with NF1 at different times in life. Only 2 clear correlations have been observed between certain NF1 alleles and consistent clinical phenotypes (Friedman, 1993):

A deletion of the entire NF1 gene is associated with large numbers and early appearance of cutaneous neurofibromas, more frequent and severe cognitive abnormalities, somatic overgrowth, large hands and feet, and dysmorphic facial features (Friedman, 1992; Pasmant, 2010; Mautner, 2010).
A 3-base pair inframe deletion of exon 17 is associated with typical pigmentary features of NF1, but no cutaneous or surface plexiform neurofibromas (Upadhyaya, 2007).

Multigene Panel Testing

Multigene panel testing typically includes the NF1 gene and other genes associated within the differential diagnosis of NF1. The detection frequency of pathogenic variants in the NF1 gene on a panel performed by genomic DNA sequencing will be much lower than that obtained by using the multistep protocol described above (Friedman, 1993).

Neurofibromatosis 2

Genotype-Phenotype Correlations

Intrafamilial variability is much lower than interfamilial variability, and the phenotypic expression and natural history of the disease are similar within families with multiple members with NF2 (Evans, 2015).

Unlike NF1, large deletions of NF2 have been associated with a mild phenotype.

Frameshift or nonsense mutations cause truncated protein expression, which has been associated with more severe manifestations of NF2 (Evans, 2015). Missense or inframe deletions have been associated with milder manifestations of the disease (Evans, 2015).

Selvanathan et al reported on genotype-phenotype correlations in 268 patients with an NF2 mutation (Selvanathan, 2010). Mutations that resulted in a truncated protein were associated with statistically significant younger age at diagnosis, higher prevalence and proportion of meningiomas, spinal tumors and tumors of cranial nerves other than VIII, vestibular schwannomas at a younger age, and more cutaneous tumors. Mutations found in the later part of the gene, especially exons 14 and 15, were associated with milder disease and fewer meningiomas.

Clinical Utility

The clinical utility of genetic testing for NF depends on how the results can be used to improve patient management.

Clinical Utility for Individuals With Suspected NF

The clinical utility of genetic testing for NF1 in adults is limited because most cases of NF1 can be diagnosed clinically with the NIH diagnostic criteria, which are both highly sensitive and specific in all but the youngest of children. Rare cases in adults who do not fulfill the NIH diagnostic criteria may benefit from genetic testing to confirm the diagnosis and to direct clinical management according to accepted guideline recommendations.

The clinical utility of genetic testing for NF2 is higher than in NF1, in that affected individuals may have little in the way of external manifestations and the onset of symptoms may be due to tumors other than vestibular schwannomas, particularly in children. Early identification of patients with NF2 can lead to earlier intervention and improved outcomes, and direct clinical management according to accepted guideline recommendations.

Clinical Utility for At-Risk Relatives

Genetic testing in at-risk relatives of a patient with a diagnosis of NF1 is rarely necessary, in that one of the NIH criterion for diagnosis is having a first-degree relative with NF1 and, therefore, only 1 other clinical sign is necessary for diagnosis. Rare cases in at-risk relatives who do not fulfill the NIH diagnostic criteria may benefit from genetic testing to direct clinical management according to accepted guideline recommendations.

Testing for NF2 may be useful to identify at-risk relatives of patients with an established diagnosis of NF2, allowing for appropriate surveillance, earlier detection, and treatment of disease manifestations, and avoiding unnecessary surveillance in an individual who does not have the family-specific mutation. Unlike NF1, the age of onset of symptoms of NF2 is relatively uniform within families. Therefore, it is usually not necessary to offer testing or surveillance to asymptomatic parents of a proband. However, testing of at-risk asymptomatic individuals younger than 18 years of age may be particularly useful, especially in children, to avoid unnecessary procedures in a child who has not inherited the mutation (Evans, 1993).

Summary of Evidence

The evidence for genetic testing in individuals who have suspected neurofibromatosis (NF) who do not fulfill diagnostic clinical criteria or who are asymptomatic, do not meet diagnostic clinical criteria, but have close relative(s) with neurofibromatosis diagnosis, includes clinical validation studies of a multistep diagnostic protocol and genotype-phenotype correlation studies. Relevant outcomes are test accuracy and validity, symptoms, change in disease status, morbid events, and functional outcomes. Published data on the analytic validity of genetic testing for NF is lacking. A multistep mutation testing protocol identifies more than 95% of pathogenic variants in NF type 1 (NF1), and, for NF type 2 (NF2), the mutation detection rate approaches 72% in simplex cases and exceeds 92% for familial cases. For individuals with a known pathogenic mutation in the family, testing of at-risk relatives will confirm or exclude the mutation with high certainty. Published evidence on the clinical utility of genetic testing for NF is lacking, but a definitive diagnosis can direct patient care according to established clinical management guidelines, including referrals to the proper specialists, treatment of manifestations, and surveillance. Testing of at-risk relatives will lead to initiation or avoidance of management and/or surveillance. Early surveillance may be particularly important for patients with NF2, because early identification of internal lesions by imaging is expected to improve outcomes. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

Practice Guidelines and Position Statements

An expert panel and the Genetics Committee of the American Academy of Pediatrics have published diagnostic and health supervision guidelines for children with NF1 (Hersh, 2008).

2017 Update

A literature search conducted through January 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

Legius Syndrome

In 2009, Pasmant and colleagues described a cohort of 61 index cases meeting the NIH clinical diagnosis of NF1 but without an identifiable NF1 variant detectable who were screened for germline loss-of-function variants in the SPRED1 gene, located on 15q13.2 (Pasmant, 2009). SPRED1 variants were detected in 5% of patients with NF1 features, which were characterized by café-au-lait macules and axillary and groin freckling but not neurofibromas and Lisch nodules. The authors characterized a new syndrome,”Legius syndrome,” based on the presence of a heterozygous SPRED1 variant.

Also in 2009, Messian and colleagues described a separate cohort of 22 NF1-variant negative probands who met NIH clinical criteria for NF1 with a SPRED1 loss-of-function variant who participated in genotype-phenotype testing with their families (Messian, 2009). Forty patients were found to be SPRED1 variant positive, 20 (50%, 95% CI 34% to 66%) met NIH clinical criteria for NF1, although none had cutaneous or plexiform neurofibromas, typical NF osseous lesions, or symptomatic optic pathway gliomas. The authors also reported on an anonymous cohort of 1318 samples received at the UAB Genomics Laboratory for NF1 genetic testing from 2003 to 2007 if a phenotypic checklist of NF-related symptoms had been filled out by the referring physician. In the anonymous cohort, 26 pathogenic SPRED1 mutations in 33 probands were identified. Of 1086 patients fulfilling NIH criteria for a clinical diagnosis of NF1, a SPRED1 variant was identified in 21 (1.9%, 95% CI 1.2% to 2.9%).

Missense mutations of NF1 p.Arg1809 have been associated typical NF1 findings of multiple café-au-lait macules and axillary freckling but reduced frequency of NF1-associated benign or malignant tumors (Rojnueangnit, 2015; Pinna, 2015). In one cohort of 136 patients, patients had features of Noonan syndrome (ie, short stature, pulmonic stenosis) present in excess (26.2%).

CLINICAL UTILITY

The clinical utility of genetic testing for NF depends on how the results can be used to improve patient management. No direct evidence was identified reporting on outcomes for genetic testing of individuals with suspected NF or at-risk relatives with a proband with NF. In the absence of direct evidence, a chain of evidence based on clinical validity may be used to demonstrate clinical utility, if all of the links in the chain are strong.

Clinical Utility for Individuals with Suspected NF

In many cases of suspected NF1, the diagnosis will be able to be made clinically based on the NIH criteria, which are both highly sensitive and specific, except in young children. However, there are suspected cases in children and adults who do not fulfill the NIH diagnostic criteria. Given the well-established clinical management criteria, these patients benefit from genetic testing to confirm the diagnosis and to direct clinical management according to accepted guideline recommendations.

2018 Update

Neurofibromatosis 2

At least 200 different NF2 mutations have been described, most of which are point mutations. Large deletions of NF2 represent 10% to 15% of NF2 mutations. When mutation scanning is combined with deletion/duplication analysis of single exons, the mutation detection rate approaches 72% in simplex cases and exceeds 92% for familial cases (Evans, 1993). One study was identified. Wallace et al (2005) applied neurofibromatosis type 2 mutation scanning for the NF2 gene to 271 patient samples (245 lymphocyte DNA, 26 schwannoma DNA). The overall NF2 variant detection rate was 88% among familial cases and 59% among sporadic cases (Wallace, 2004). Evans et al (2007) analyzed database of 460 families with NF2 and 704 affected individuals for mosaicism and transmission risks to offspring (Evans, 2007). The authors identified a variant in 84 (91%) of 92 second-generation families, with a sensitivity of greater than 90%. Other studies have reported lower variant detection rates, which likely reflects the inclusion of more mildly affected individuals with somatic mosaicism (Evans, 1993).

Ongoing and Unpublished Clinical Trials

One ongoing, unpublished clinical trial that might influence this policy is listed below:

NCT03210285 Whole Exome Sequencing (WES) of NF2-associated in Comparison to Sporadic Vestibular Schwannomas-Correlation With Clinical Data

Planned Enrollment 100

Expected Completion Date September 2021

2019 Update

Annual policy review completed with a literature search using the MEDLINE database through December 2018. No new literature was identified that would prompt a change in the coverage statement.

2020 Update

Annual policy review completed with a literature search using the MEDLINE database through December 2019. No new literature was identified that would prompt a change in the coverage statement.

2021 Update

Annual policy review completed with a literature search using the MEDLINE database through December 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

The American Academy of Pediatrics (2019) published diagnostic and health supervision guidance for children with neurofibromatosis type 1 (NF1) (Miller, 2019). The guidance makes the following statements related to genetic testing:

"NF1 genetic testing may be performed for purposes of diagnosis or to assist in genetic counseling and family planning. If a child fulfills diagnostic criteria for NF1, molecular genetic confirmation is usually unnecessary. For a young child who presents only with [café-au-lait macules], NF1 genetic testing can confirm a suspected diagnosis before a second feature, such as skinfold freckling, appears. Some families may wish to establish a definitive diagnosis as soon as possible and not wait for this second feature, and genetic testing can usually resolve the issue" and "Knowledge of the NF1 [pathogenic sequence variant] can enable testing of other family members and prenatal diagnostic testing."

The guidance includes the following summary and recommendations about genetic testing:

can confirm a suspected diagnosis before a clinical diagnosis is possible;
can differentiate NF1 from Legius syndrome;
may be helpful in children who present with atypical features;
usually does not predict future complications; and
may not detect all cases of NF1; a negative genetic test rules out a diagnosis of NF1 with 95% (but not 100%) sensitivity

2022 Update

Annual policy review completed with a literature search using the MEDLINE database through December 2021. No new literature was identified that would prompt a change in the coverage statement.

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through December 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

The National Comprehensive Cancer Network's Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic consensus guidelines (version 1.2023) address the association between pathogenic NF1 variants and risk of breast cancer (NCCN, 2022). The panel recommends annual screening mammograms for breast cancer beginning at age 30years (or younger, if indicated according to family history of breast cancer) in patients with such NF1 variants, with consideration for screening via breast magnetic resonance imaging (MRI) through age 50 due to excess risk between the ages of 30 and 50, and referral to an NF1 specialist for evaluation and management of other NF1-associatedcancer risks. The guidelines state that studies show that beginning at age 50 breast cancer risk in women with NF1 may not significantly differ from that of women in the general population; and, therefore, breast MRI screening in patients with NF1 may be discontinued at 50 years of age. Note that these screening recommendations apply only to individuals with a clinical diagnosis of NF1.

Giugliano et al conducted a study with 245 participants (150 participants with clinical diagnosis of NF1 and 95 participants with suspected NF1 with only pigmentary features not fulfilling NIH criteria) (Giugliano, 2019). The test consisted of gDNA and cDNA analysis via targeted NGS using HaloPlex Target Enrichment System, MLPA, and RT-PCR, with variant validation via Sanger sequencing. In patients with clinical NF1diagnosis, causativeNF1 variant identified in 98%. In patients not meeting NIH criteria for NF1 diagnosis, causative NF1 variant identified in 69.5%.

Angelova-Toshkina et al conducted a study on 75 children with suspected or clinically diagnosed NF1 (Angelova-Toshkina, 2022). It consisted of retrospective chart review. Genetic testing was performed by varying methods and was not described. At initial suspicion ofNF1, 59% met 1988 NIH diagnostic criteria. At initial suspicion ofNF1, 75% met revised 2021diagnostic criteria (12 additional individuals, all of whom met revised criteria due to finding of a pathogenic NF1 variant).

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

81405	Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) Cytogenomic constitutional targeted microarray analysis of chromosome 22q13 by interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities (When performing cytogenomic [genome-wide] analysis, for constitutional chromosomal abnormalities. See 81228, 81229, 81349)
81406	Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons) ACADVL (acyl-CoA dehydrogenase, very long chain) (eg, very long chain acyl-coenzyme A dehydrogenase deficiency), full gene sequence ACTN4 (actinin, alpha 4) (eg, focal segmental glomerulosclerosis), full gene sequence AFG3L2 (AFG3 ATPase family gene 3-like 2 [S. cerevisiae]) (eg, spinocerebellar ataxia), full gene sequence AIRE (autoimmune regulator) (eg, autoimmune polyendocrinopathy syndrome type 1), full gene sequence ALDH7A1 (aldehyde dehydrogenase 7 family, member A1) (eg, pyridoxine-dependent epilepsy), full gene sequence ANO5 (anoctamin 5) (eg, limb-girdle muscular dystrophy), full gene sequence ANOS1 (anosmin-1) (eg, Kallmann syndrome 1), full gene sequence APP (amyloid beta [A4] precursor protein) (eg, Alzheimer disease), full gene sequence ASS1 (argininosuccinate synthase 1) (eg, citrullinemia type I), full gene sequence ATL1 (atlastin GTPase 1) (eg, spastic paraplegia), full gene sequence ATP1A2 (ATPase, Na+/K+ transporting, alpha 2 polypeptide) (eg, familial hemiplegic migraine), full gene sequence ATP7B (ATPase, Cu++ transporting, beta polypeptide) (eg, Wilson disease), full gene sequence BBS1 (Bardet-Biedl syndrome 1) (eg, Bardet-Biedl syndrome), full gene sequence BBS2 (Bardet-Biedl syndrome 2) (eg, Bardet-Biedl syndrome), full gene sequence BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (eg, maple syrup urine disease, type 1B), full gene sequence BEST1 (bestrophin 1) (eg, vitelliform macular dystrophy), full gene sequence BMPR2 (bone morphogenetic protein receptor, type II [serine/threonine kinase]) (eg, heritable pulmonary arterial hypertension), full gene sequence BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, Noonan syndrome), full gene sequence BSCL2 (Berardinelli-Seip congenital lipodystrophy 2 [seipin]) (eg, Berardinelli-Seip congenital lipodystrophy), full gene sequence BTK (Bruton agammaglobulinemia tyrosine kinase) (eg, X-linked agammaglobulinemia), full gene sequence CACNB2 (calcium channel, voltage-dependent, beta 2 subunit) (eg, Brugada syndrome), full gene sequence CAPN3 (calpain 3) (eg, limb-girdle muscular dystrophy [LGMD] type 2A, calpainopathy), full gene sequence CBS (cystathionine-beta-synthase) (eg, homocystinuria, cystathionine beta-synthase deficiency), full gene sequence CDH1 (cadherin 1, type 1, E-cadherin [epithelial]) (eg, hereditary diffuse gastric cancer), full gene sequence CDKL5 (cyclin-dependent kinase-like 5) (eg, early infantile epileptic encephalopathy), full gene sequence CLCN1 (chloride channel 1, skeletal muscle) (eg, myotonia congenita), full gene sequence CLCNKB (chloride channel, voltage-sensitive Kb) (eg, Bartter syndrome 3 and 4b), full gene sequence CNTNAP2 (contactin-associated protein-like 2) (eg, Pitt-Hopkins-like syndrome 1), full gene sequence COL6A2 (collagen, type VI, alpha 2) (eg, collagen type VI-related disorders), duplication/deletion analysis CPT1A (carnitine palmitoyltransferase 1A [liver]) (eg, carnitine palmitoyltransferase 1A [CPT1A] deficiency), full gene sequence CRB1 (crumbs homolog 1 [Drosophila]) (eg, Leber congenital amaurosis), full gene sequence CREBBP (CREB binding protein) (eg, Rubinstein-Taybi syndrome), duplication/deletion analysis DBT (dihydrolipoamide branched chain transacylase E2) (eg, maple syrup urine disease, type 2), full gene sequence DLAT (dihydrolipoamide S-acetyltransferase) (eg, pyruvate dehydrogenase E2 deficiency), full gene sequence DLD (dihydrolipoamide dehydrogenase) (eg, maple syrup urine disease, type III), full gene sequence DSC2 (desmocollin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 11), full gene sequence DSG2 (desmoglein 2) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 10), full gene sequence DSP (desmoplakin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 8), full gene sequence EFHC1 (EF-hand domain [C-terminal] containing 1) (eg, juvenile myoclonic epilepsy), full gene sequence EIF2B3 (eukaryotic translation initiation factor 2B, subunit 3 gamma, 58kDa) (eg, leukoencephalopathy with vanishing white matter), full gene sequence EIF2B4 (eukaryotic translation initiation factor 2B, subunit 4 delta, 67kDa) (eg, leukoencephalopathy with vanishing white matter), full gene sequence EIF2B5 (eukaryotic translation initiation factor 2B, subunit 5 epsilon, 82kDa) (eg, childhood ataxia with central nervous system hypomyelination/vanishing white matter), full gene sequence ENG (endoglin) (eg, hereditary hemorrhagic telangiectasia, type 1), full gene sequence EYA1 (eyes absent homolog 1 [Drosophila]) (eg, branchio-oto-renal [BOR] spectrum disorders), full gene sequence F8 (coagulation factor VIII) (eg, hemophilia A), duplication/deletion analysis FAH (fumarylacetoacetate hydrolase [fumarylacetoacetase]) (eg, tyrosinemia, type 1), full gene sequence FASTKD2 (FAST kinase domains 2) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence FIG4 (FIG4 homolog, SAC1 lipid phosphatase domain containing [S. cerevisiae]) (eg, Charcot-Marie-Tooth disease), full gene sequence FTSJ1 (FtsJ RNA methyltransferase homolog 1 [E. coli]) (eg, X-linked mental retardation 9), full gene sequence FUS (fused in sarcoma) (eg, amyotrophic lateral sclerosis), full gene sequence GAA (glucosidase, alpha; acid) (eg, glycogen storage disease type II [Pompe disease]), full gene sequence GALC (galactosylceramidase) (eg, Krabbe disease), full gene sequence GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), full gene sequence GARS (glycyl-tRNA synthetase) (eg, Charcot-Marie-Tooth disease), full gene sequence GCDH (glutaryl-CoA dehydrogenase) (eg, glutaricacidemia type 1), full gene sequence GCK (glucokinase [hexokinase 4]) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence GLUD1 (glutamate dehydrogenase 1) (eg, familial hyperinsulinism), full gene sequence GNE (glucosamine [UDP-N-acetyl]-2-epimerase/N-acetylmannosamine kinase) (eg, inclusion body myopathy 2 [IBM2], Nonaka myopathy), full gene sequence GRN (granulin) (eg, frontotemporal dementia), full gene sequence HADHA (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase [trifunctional protein] alpha subunit) (eg, long chain acyl-coenzyme A dehydrogenase deficiency), full gene sequence HADHB (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase [trifunctional protein], beta subunit) (eg, trifunctional protein deficiency), full gene sequence HEXA (hexosaminidase A, alpha polypeptide) (eg, Tay-Sachs disease), full gene sequence HLCS (HLCS holocarboxylase synthetase) (eg, holocarboxylase synthetase deficiency), full gene sequence HMBS (hydroxymethylbilane synthase) (eg, acute intermittent porphyria), full gene sequence HNF4A (hepatocyte nuclear factor 4, alpha) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence IDUA (iduronidase, alpha-L-) (eg, mucopolysaccharidosis type I), full gene sequence INF2 (inverted formin, FH2 and WH2 domain containing) (eg, focal segmental glomerulosclerosis), full gene sequence IVD (isovaleryl-CoA dehydrogenase) (eg, isovaleric acidemia), full gene sequence JAG1 (jagged 1) (eg, Alagille syndrome), duplication/deletion analysis JUP (junction plakoglobin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 11), full gene sequence KCNH2 (potassium voltage-gated channel, subfamily H [eag-related], member 2) (eg, short QT syndrome, long QT syndrome), full gene sequence KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) (eg, short QT syndrome, long QT syndrome), full gene sequence KCNQ2 (potassium voltage-gated channel, KQT-like subfamily, member 2) (eg, epileptic encephalopathy), full gene sequence LDB3 (LIM domain binding 3) (eg, familial dilated cardiomyopathy, myofibrillar myopathy), full gene sequence LDLR (low den
81408	Molecular pathology procedure, Level 9 (eg, analysis of >50 exons in a single gene by DNA sequence analysis)

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Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association.