Medical Policy

Policy Num:      11.003.102
Policy Name:    Genetic Testing for Neurofibromatosis
Policy ID:          [11.003.102]  [Ac / B / M+ / P+]  [2.04.137]

Last Review:    February 05, 2025
Next Review:    February 20, 2026
 

Related Policies: None

Genetic Testing for Neurofibromatosis

Summary

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.

Summary of Evidence

For individuals who have suspected NF who receive genetic testing for NF1, NF2, or SPRED1 pathogenic variants, the evidence includes clinical validation studies of a multistep diagnostic protocol and genotype-phenotype correlation studies. Relevant outcomes are test accuracy and validity, symptoms, morbid events, and functional outcomes. A multistep variant testing protocol identifies more than 95% of pathogenic variants in NF type 1; for NF type 2, the variant detection rate approaches more than 70% in simplex cases and exceeds 90% for familial cases. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are asymptomatic, with a close relative(s) with an NF diagnosis, who receive genetic testing for NF1, NF2, or SPRED1 pathogenic variants, there is no direct evidence. Relevant outcomes are test accuracy and validity, symptoms, morbid events, and functional outcomes. For individuals with a known pathogenic variant in the family, testing of at-risk relatives will confirm or exclude the variant with high certainty. While direct evidence on the clinical utility of genetic testing for NF is lacking, a definitive diagnosis resulting from genetic testing 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 NF type 2 because early identification of internal lesions by imaging is expected to improve outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Additional Information

Not applicable

Objective

The objective of this evidence review is to determine whether genetic testing for neurofibromatosis type 1 (NF1), neurofibromatosis type 2-related schwannomatosis (formerly NF type 2)(NF2), or SPRED1 pathogenic variants improves the net health outcome in individuals who are suspected of having or who are at risk of developing neurofibromatosis.

Policy Statements

Genetic testing for neurofibromatosis type 1 (NF1) or neurofibromatosis type 2 (NF2) pathogenic variants may be considered medically necessary when a 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, may be considered medically necessary 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.

Genetic testing for neurofibromatosis for all other situations not meeting the criteria outlined above is considered investigational.

Policy Guidelines

Testing Strategy

For evaluation of neurofibromatosis type 1 (NF1), testing for a variety of pathogenic variants of NF1, preferably through a multistep variant detection protocol, is indicated. If no NF1 pathogenic variants are detected in patients with suspected NF1, testing for SPRED1 variants is reasonable.

There are a number of cancer types associated with NF, including breast cancer associating with NF1. While the National Comprehensive Cancer Network's Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic consensus guidelines (version 2.2024 ) addresses the risk of breast cancer with NF1 and has intensified breast cancer screening recommendations, these screening recommendations apply only to individuals with a clinical diagnosis of NF1.^1, Criteria for a clinical diagnosis are included below.

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 (eg, 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 variant. Unlike inherited variants, somatic mosaic variants may affect only a portion of the body and are not transmitted to progeny.

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table PG2). The Society's nomenclature is recommended by the Human Variome Project, the Hu man Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG3 shows the recommended standard terminology- "pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"- to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

   ACMG-AMP: American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Genetic Counseling

Genetic counseling is primarily aimed at patients 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

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

When possible, genetic testing for neurofibromatosis should be performed in an affected family member so that testing in at-risk family members with no signs of disease can be performed for the family-specific variant found in the affected family member. However, coverage for testing of the affected index case (proband) depends on contract benefit language.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage. 

Background

Neurofibromatosis

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-related schwannomatosis (formerly NF type 2)(NF2), and schwannomatosis.

Neurofibromatosis Type 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 macules occur in nearly all affected individuals, and intertriginous freckling occurs in almost 90%. Café-au-lait macules 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 in 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.^2, 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 stabilize throughout adulthood. Plexiform neurofibromas can compress the spinal cord or airway and can transform into malignant peripheral nerve sheath tumors. Malignant peripheral nerve sheath tumors occur in approximately 10% of affected individuals.

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 adulthood. While optic pathway gliomas are particularly associated 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.^3, 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.^4,5,3, Additionally, children with NF1 have long been recognized to carry significantly higher risk of juvenile myelomonocytic leukemia than children who do not have NF1.^6,7,

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.^2,

• 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 including valvar pulmonic stenosis, congenital heart defects, and hypertrophic cardiomyopathy may be especially frequent in individuals with NF1 whole gene deletions.^2, 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.^2,

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 mosaic NF1.^8,9, 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.^2,

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.^2,

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 should be followed clinically as if they do.^10, A definitive diagnosis of NF1 can be made in most children by 4 years of age using the NIH criteria.^2,

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 variant. Penetrance is virtually complete after childhood though expressivity is highly variable.

The variants responsible for NF1 are heterogeneous and include nonsense and missense single nucleotide changes, single-base insertions or 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.^2,

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. ^11,2,12,

After an initial diagnosis of NF1, the extent of the disease should be established, with a 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.^2,

Surveillance recommendations for an individual with NF1 focus on regular annual visits for skin examination for new peripheral neurofibromas, signs of plexiform neurofibroma or progression of existing lesions, checks for hypertension, other studies (eg, 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 include annual ophthalmologic examination in early childhood (less frequently in older children and adults) and regular developmental assessment.

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

It is recommended that radiotherapy is avoided because radiotherapy in individuals with NF1 may be associated with a high-risk of developing a malignant peripheral nerve sheath tumor 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 NF1 might 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. ^13,  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-related Schwannomatosis (Formerly 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.^13,The 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 which rarely progress to visually significant cataracts.

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

Diagnosis

The diagnosis of NF2 is usually based 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 undestanding of genotypic and phenotypic features of NF2, as well as to better delineate between NF2 and schwannomatosis.^15, The new criteria for NF2 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 variant ^14,

Between 25% and 33% of individuals with NF2 caused by a de novo variant 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 also be lower because molecular genetic test results may be normal in unaffected tissue (eg, lymphocytes), and molecular testing of tumor tissue may be necessary to establish the presence of somatic mosaicism.^2,

Management

In an individual diagnosed with NF2, it is recommended that an initial evaluation establishes the extent of the disease, typically using cranial 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 examinations 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. .^14,

Radiotherapy should be avoided, because radiotherapy of NF2-associated tumors, especially in childhood, may induce, accelerate, or transform tumors .^14,

Evaluation of At-Risk Relatives

Early identification of relatives who have inherited the family-specific NF2 variant allows for appropriate screening using MRI for neuroimaging and audiologic evaluation, which results in earlier detection and improved outcomes. .^14,  Identification of at-risk relatives who do not have the family-specific NF2 variant eliminates the need for surveillance.

Schwannomatosis

Schwannomatosis is a rare condition characterized by development of multiple schwannomas and, less frequently, meningiomas.^17, 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. The presentation of schwannomatosis exists on a spectrum with NF2, with certain key distinguishing clinical and more recently-recognized molecular features. SMARCB1 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 of SMARCB1 or LZTR1 pathogenic variants. New diagnostic criteria for molecularly-defined subtypes of schwannomatosis not associated with NF2 pathogenic variants (ie, 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.^16,

Regulatory Status

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

Rationale

This evidence review was created in January 2016 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through December 3, 2024.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Schwannomatosis is rare and far less well-described than neurofibromatosis type 1 (NF1) and neurofibromatosis type 2-related schwannomatosis (formerly NF type 2)(NF2); therefore, this review focuses on NF1 and NF2.

Population reference No. 1

Neurofibromatosis

Clinical Context and Test Purpose

The purpose of genetic testing in patients who have suspected NF is to inform a decision to pursue additional surveillance for comorbid conditions as recommended by well-defined management guidelines if a definitive diagnosis can be made.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with suspected NF1 or NF2, based on clinical symptoms or because a family member has been diagnosed with NF1 or NF2.

Interventions

The genetic tests being considered are those for NF1, NF2, and SPRED1 variants.

These tests would typically be ordered by a specialist. Genetic counseling is an important component of care delivery.

Comparators

The following tool based on clinical evaluations is currently being used to make diagnostic decisions about suspected NF1 and NF2: the National Institutes of Health (NIH) diagnostic criteria.^2,

Outcomes

The potential beneficial outcomes of primary interest include earlier intervention and improved outcomes, and direct clinical management according to accepted guideline recommendations.

Harmful outcomes resulting from a false-positive test result include the potential for unneeded additional tests, while false-negative tests could delay care.

The duration of follow-up is years to assess non-test-related outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess the clinical validity of genetic testing to evaluate neurofibromatosis, studies should report variant detection rates.

• To assess the clinical utility of genetic testing to evaluate neurofibromatosis, studies should demonstrate how results of the genetic tests impact treatment decisions and overall management of the patient.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Neurofibromatosis Type 1

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

A multistep variant detection protocol has identified more than 95% of NF1 pathogenic variants in individuals who fulfill NIH diagnostic criteria.^2, The protocol involves sequencing of both messenger RNA (complementary DNA [cDNA]) and genomic DNA, and testing for whole NF1 deletions (eg, by multiplex ligation-dependent probe amplification [MLPA]) because whole gene deletions cannot be detected by sequencing). Due to the wide variety and rarity of individual pathogenic variants in NF1, sequencing of cDNA increases the detection rate of variants from approximately 61% with genomic DNA sequence analysis alone^17, to greater than 95% with sequencing for both cDNA and genomic DNA and testing for whole gene deletions.

Table 1 summarizes several studies conducted on various populations, using various testing techniques to detect NF1 and SPRED1 variants. Below is a detailed description of 2 of the studies with high variant detection rates.

Sabbagh et al (2013) reported on a comprehensive analysis of constitutional NF1 variants in unrelated, well-phenotyped index cases with typical clinical features of NF1 who enrolled in a French clinical research program.^18, The 565 families in this study (n=1697 individuals) were enrolled between 2002 and 2005; 1083 fulfilled NIH diagnostic criteria for NF1. 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, and 505 were identified using the single cDNA sequencing approach. MLPA detected 12 deletions or duplications that would not have been detected by sequencing. No variant was detected in 19 (3.4%) patients, 2 of whom had a SPRED1 variant, which is frequently confused with NF; the remainder might have been due to an unknown variant of the NF1 locus.

Valero et al (2011) developed a method for detecting NF1 variants by combining an RNA-based cDNA-polymerase chain reaction variant detection method and denaturing high-performance liquid chromatography with MLPA.^19, A variant was identified in 53 cases (95% sensitivity), involving 47 different variants, of which 23 were novel. After validation, the authors implemented the protocol as a routine test and subsequently reported the spectrum of NF1 variants identified in 93 patients from a cohort of 105. The spectrum included a wide variety of variants (nonsense, small deletions or insertions and duplications, splice defects, complete gene deletions, missense, single exon deletions and duplications, and a multi-exon deletion), confirming the heterogeneity of the NF1 gene variants that can cause NF1.

Table 1. Diagnostic Performance of Genetic Testing for Suspected NF1

   aCGH: array comparative genomic hybridization; cDNA: complementary DNA; DHPLC: denaturing high-pressure liquid chromatography; gDNA: genomic DNA; MLPA: multiplex ligation-dependent probe amplification; NF1: neurofibromatosis type 1; NGS: next-generation sequencing; NIH: National Institutes of Health; PCR: polymerase chain reaction; RT-PCR: real-time quantitative PCR.

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. Two clear correlations have been observed between certain NF1 alleles and consistent clinical phenotypes^2,:

1. 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.^2,28,[^29,

2. A 3-base pair inframe deletion of exon 17 is associated with typical pigmentary features of NF1, but no cutaneous or surface plexiform neurofibromas.^30,

Also, missense variants of NF1 p.Arg1809 have been associated with typical NF1 findings of multiple café-au-lait macules and axillary freckling but the reduced frequency of NF1-associated benign or malignant tumors.^31,32, In a cohort of 136 patients, 26.2% of patients had features of Noonan syndrome (ie, short stature, pulmonic stenosis) present in excess.

In the Sabbagh et al (2013) study (described above), authors evaluated genotype-phenotype correlations for a subset of patients.^19, This subset, which included 439 patients harboring a truncating (n=368), inframe splicing (n=36), or missense (n=35) NF1 variant, was evaluated to assess the contribution of intragenic NF1 variants (vs large gene deletions) to the variable expressivity of NF1. Their findings suggested a tendency for truncating variants to be associated with a greater incidence of Lisch nodules and a larger number of café-au-lait spots compared with missense variants.

However, other studies (eg, Zhu et al [2016],^22, shown in Table 1; Hutter et al [2016]^33,; Ko et al [2013]^34,) reported no associations between variant type and phenotype.

Legius Syndrome

Pasmant et al (2009) described a cohort of 61 index cases meeting the NIH clinical diagnosis of NF1 but without an NF1 variant detectable who were screened for germline loss-of-function variants in the SPRED1 gene, located on 15q13.2.^35, 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.

Messiaen et al (2009) described a separate cohort of 22 NF1 variant-negative probands who met NIH clinical criteria for NF1 with a SPRED1 loss-of-function variant and participated in genotype-phenotype testing with their families.^36, Forty patients were found to be SPRED1 variant-positive, 20 (50%, 95% confidence interval [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 a university genomics laboratory for NF1 genetic testing from 2003 to 2007 with a phenotypic checklist of NF-related symptoms filled out by the referring physician. In the anonymous cohort, 26 pathogenic SPRED1 variants 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%).

Neurofibromatosis Type 2-related Schwannomatosis (Formerly NF Type 2)

At least 200 different NF2 variants have been described, most of which are point mutations. Large deletions of NF2 represent 10% to 15% of NF2 variants. When variant scanning is combined with deletion and duplication analysis of single exons, the variant detection rate approaches 72% in simplex cases and exceeds 92% for familial cases.^14, Wallace et al (2004) conducted NF2 variant scanning in 271 patient samples (245 lymphocyte DNA, 26 schwannoma DNA).^37, The overall NF2 variant detection rate was 88% among familial cases and 59% among sporadic cases. Evans et al (2007) analyzed a database of 460 families with NF2 and 704 affected individuals for mosaicism and transmission risks to offspring.^38, 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.^14,

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.^39,

Frameshift or nonsense variants cause truncated protein expression, which has been associated with more severe manifestations of NF2.^39, Missense or inframe deletions have been associated with milder manifestations of the disease.

Selvanathan et al (2010) reported on genotype-phenotype correlations in 268 patients with an NF2 variant.^40, Variants 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. Variants found especially exons 14 and 15 were associated with milder disease and fewer meningiomas.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

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.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Section Summary: Clinically Valid

Studies conducted among multiple cohorts of patients meeting NIH criteria for NF1 reported a high sensitivity of multistep variant testing protocol in identifying pathogenic NF1 variants. On the other hand, studies conducted among familial and sporadic NF2 cases reported a variant detection rate exceeding 90% for familial cases and more than 70% in simplex cases.

Individuals With Suspected Neurofibromatosis

In many cases of suspected NF1, the diagnosis can be made according to clinical criteria, which are both highly sensitive and specific, except in young children. However, there are suspected cases in children and adults that do not meet the original NIH criteria. Given the well-established clinical management criteria and the high detection yield with genetic testing, these patients would benefit from genetic testing to confirm the diagnosis and to direct clinical management according to accepted guideline recommendations.

For NF2, 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.

Subsection Summary: Individuals With Suspected Neurofibromatosis

Currently, there is no direct evidence from studies demonstrating that genetic testing for NF1 and NF2 pathogenic variants results in improved patient outcomes (eg, survival or quality of life) among suspected cases. Suspected cases of NF1 or NF2 among children and adults who do not meet the NIH diagnostic criteria might benefit from genetic testing to confirm the diagnosis and receive earlier treatment, which might result in improved outcomes.

For individuals who have suspected NF who receive genetic testing for NF1, NF2, or SPRED1 pathogenic variants, the evidence includes clinical validation studies of a multistep diagnostic protocol and genotype-phenotype correlation studies. Relevant outcomes are test accuracy and validity, symptoms, morbid events, and functional outcomes. A multistep variant testing protocol identifies more than 95% of pathogenic variants in NF type 1; for NF type 2, the variant detection rate approaches more than 70% in simplex cases and exceeds 90% for familial cases. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population reference No. 2

At-Risk Relatives

Similar to the case for suspected NF1, it is most often the case that clinical diagnosis can be made in an at-risk relative of a proband because 1 of the NIH criteria for diagnosis is having a first-degree relative with NF1 and, therefore, only 1 other clinical sign is necessary to confirm the diagnosis. Cases with 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 variant. Unlike NF1, the age of symptom onset for NF2 is relatively uniform within families. Therefore, it is usually not necessary to offer testing or surveillance to asymptomatic parents of an index case. However, testing of at-risk asymptomatic individuals younger than 18 years of age may help avoid unnecessary procedures in a child who has not inherited the variant.^13,

Subsection Summary: At-Risk Relatives

Currently, there is no direct evidence from studies demonstrating that genetic testing for NF1 and NF2 result in improved outcomes (eg, survival or quality of life) among asymptomatic individuals with a close relative(s) with an NF diagnosis. However, genetic testing of at-risk asymptomatic individuals not fulfilling clinical diagnostic criteria might benefit through diagnosis, clinical management if needed, and avoiding unnecessary procedures in case of individuals who have not inherited the variant.

For individuals who are asymptomatic, with a close relative(s) with an NF diagnosis, who receive genetic testing for NF1, NF2, or SPRED1 pathogenic variants, there is no direct evidence. Relevant outcomes are test accuracy and validity, symptoms, morbid events, and functional outcomes. For individuals with a known pathogenic variant in the family, testing of at-risk relatives will confirm or exclude the variant with high certainty. While direct evidence on the clinical utility of genetic testing for NF is lacking, a definitive diagnosis resulting from genetic testing 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 NF type 2 because early identification of internal lesions by imaging is expected to improve outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Academy of Pediatrics

In 2019, the American Academy of Pediatrics published diagnostic and health supervision guidance for children with neurofibromatosis type 1 (NF1). ^12, 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

National Comprehensive Cancer Network

The National Comprehensive Cancer Network's Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic consensus guidelines (version 2.2025 ) address the association between pathogenic NF1 variants and risk of breast cancer.^1, The panel recommends annual screening mammograms for breast cancer beginning at age 30 years (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-associated cancer 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.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in November 2024 did not identify any ongoing or unpublished trials that would likely influence this review.

References

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, and Prostate. Version 2.2025. Accessed December 3, 2024.
2. Friedman JM. Neurofibromatosis 1. In: Adam MP, Feldman J, Mirzaa GM, et al., eds. GeneReviews. Seattle, WA: University of Washington; 1993-2023. Updated April 21, 2022. Accessed December 2, 2024.
3. Uusitalo E, Rantanen M, Kallionpää RA, et al. Distinctive Cancer Associations in Patients With Neurofibromatosis Type 1. J Clin Oncol. Jun 10 2016; 34(17): 1978-86. PMID 26926675
4. Walker L, Thompson D, Easton D, et al. A prospective study of neurofibromatosis type 1 cancer incidence in the UK. Br J Cancer. Jul 17 2006; 95(2): 233-8. PMID 16786042
5. Nishida T, Tsujimoto M, Takahashi T, et al. Gastrointestinal stromal tumors in Japanese patients with neurofibromatosis type I. J Gastroenterol. Jun 2016; 51(6): 571-8. PMID 26511941
6. Stiller CA, Chessells JM, Fitchett M. Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer. Nov 1994; 70(5): 969-72. PMID 7947106
7. Niemeyer CM, Arico M, Basso G, et al. Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Blood. May 15 1997; 89(10): 3534-43. PMID 9160658
8. Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol. May 1988; 45(5): 575-8. PMID 3128965
9. Legius E, Messiaen L, Wolkenstein P, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med. Aug 2021; 23(8): 1506-1513. PMID 34012067
10. Bernier A, Larbrisseau A, Perreault S. Café-au-lait Macules and Neurofibromatosis Type 1: A Review of the Literature. Pediatr Neurol. Jul 2016; 60: 24-29.e1. PMID 27212418
11. Xu AL, Suresh KV, Gomez JA, et al. Consensus-Based Best Practice Guidelines for the Management of Spinal Deformity and Associated Tumors in Pediatric Neurofibromatosis Type 1: Screening and Surveillance, Surgical Intervention, and Medical Therapy. J Pediatr Orthop. Aug 01 2023; 43(7): e531-e537. PMID 37253707
12. Miller DT, Freedenberg D, Schorry E, et al. Health Supervision for Children With Neurofibromatosis Type 1. Pediatrics. May 2019; 143(5). PMID 31010905
13. Legius E, Stevenson D. Legius Syndrome. In: Adam MP, Feldman J, Mirzaa GM, et al., eds. GeneReviews. Seattle, WA: University of Washington; 1993-2023. Updated August 6, 2020. Accessed December 1, 2024.
14. Evans DG. NF2-Related Schwannomatosis. In: Adam MP, Feldman J, Mirzaa GM, et al., eds. GeneReviews. Seattle, WA: University of Washington; 1993-2024. Updated April 20, 2023. Accessed December 3, 2024.
15. Evans DG, Sainio M, Baser ME. Neurofibromatosis type 2. J Med Genet. Dec 2000; 37(12): 897-904. PMID 11106352
16. Plotkin SR, Messiaen L, Legius E, et al. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation. Genet Med. Sep 2022; 24(9): 1967-1977. PMID 35674741
17. Dhamija R, Plotkin S, Gomes A, Babovic-Vuksanovic D. LZTR1- and SMARCB1-Related Schwannomatosis. In: Adam MP, Feldman J, Mirzaa GM, et al, eds. GeneReviews. Seattle, WA: University of Washington; 1993-2024. Updated April 25, 2024. Accessed December 3, 2024.
18. van Minkelen R, van Bever Y, Kromosoeto JN, et al. A clinical and genetic overview of 18 years neurofibromatosis type 1 molecular diagnostics in the Netherlands. Clin Genet. Apr 2014; 85(4): 318-27. PMID 23656349
19. Sabbagh A, Pasmant E, Imbard A, et al. NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. Hum Mutat. Nov 2013; 34(11): 1510-8. PMID 23913538
20. Valero MC, Martín Y, Hernández-Imaz E, et al. A highly sensitive genetic protocol to detect NF1 mutations. J Mol Diagn. Mar 2011; 13(2): 113-22. PMID 21354044
21. Spurlock G, Bennett E, Chuzhanova N, et al. SPRED1 mutations (Legius syndrome): another clinically useful genotype for dissecting the neurofibromatosis type 1 phenotype. J Med Genet. Jul 2009; 46(7): 431-7. PMID 19443465
22. Zhu L, Zhang Y, Tong H, et al. Clinical and Molecular Characterization of NF1 Patients: Single-Center Experience of 32 Patients From China. Medicine (Baltimore). Mar 2016; 95(10): e3043. PMID 26962827
23. Zhang J, Tong H, Fu X, et al. Molecular Characterization of NF1 and Neurofibromatosis Type 1 Genotype-Phenotype Correlations in a Chinese Population. Sci Rep. Jun 09 2015; 5: 11291. PMID 26056819
24. Bianchessi D, Morosini S, Saletti V, et al. 126 novel mutations in Italian patients with neurofibromatosis type 1. Mol Genet Genomic Med. Nov 2015; 3(6): 513-25. PMID 26740943
25. Calì F, Chiavetta V, Ruggeri G, et al. Mutation spectrum of NF1 gene in Italian patients with neurofibromatosis type 1 using Ion Torrent PGM™ platform. Eur J Med Genet. Feb 2017; 60(2): 93-99. PMID 27838393
26. Giugliano T, Santoro C, Torella A, et al. Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders. Genes (Basel). Jul 31 2019; 10(8). PMID 31370276
27. Angelova-Toshkina D, Holzapfel J, Huber S, et al. Neurofibromatosis type 1: A comparison of the 1997 NIH and the 2021 revised diagnostic criteria in 75 children and adolescents. Genet Med. Sep 2022; 24(9): 1978-1985. PMID 35713653
28. Pasmant E, Sabbagh A, Spurlock G, et al. NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat. Jun 2010; 31(6): E1506-18. PMID 20513137
29. Mautner VF, Kluwe L, Friedrich RE, et al. Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions. J Med Genet. Sep 2010; 47(9): 623-30. PMID 20543202
30. Upadhyaya M, Huson SM, Davies M, et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. Jan 2007; 80(1): 140-51. PMID 17160901
31. Rojnueangnit K, Xie J, Gomes A, et al. High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation. Hum Mutat. Nov 2015; 36(11): 1052-63. PMID 26178382
32. Pinna V, Lanari V, Daniele P, et al. p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas. Eur J Hum Genet. Aug 2015; 23(8): 1068-71. PMID 25370043
33. Hutter S, Piro RM, Waszak SM, et al. No correlation between NF1 mutation position and risk of optic pathway glioma in 77 unrelated NF1 patients. Hum Genet. May 2016; 135(5): 469-475. PMID 26969325
34. Ko JM, Sohn YB, Jeong SY, et al. Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol. Jun 2013; 48(6): 447-53. PMID 23668869
35. Pasmant E, Sabbagh A, Hanna N, et al. SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype. J Med Genet. Jul 2009; 46(7): 425-30. PMID 19366998
36. Messiaen L, Yao S, Brems H, et al. Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome. JAMA. Nov 18 2009; 302(19): 2111-8. PMID 19920235
37. Wallace AJ, Watson CJ, Oward E, et al. Mutation scanning of the NF2 gene: an improved service based on meta-PCR/sequencing, dosage analysis, and loss of heterozygosity analysis. Genet Test. 2004; 8(4): 368-80. PMID 15684865
38. Evans DG, Ramsden RT, Shenton A, et al. Mosaicism in neurofibromatosis type 2: an update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification. J Med Genet. Jul 2007; 44(7): 424-8. PMID 17307835
39. Jordan JT, Evans DG. NF2-related schwannomatosis (formerly neurofibromatosis type 2). In: UpToDate, ed. UpToDate. Waltham, MA: Kluwer Wolters; Updated October 30, 2024. Accessed December 3, 2024.
40. Selvanathan SK, Shenton A, Ferner R, et al. Further genotype--phenotype correlations in neurofibromatosis 2. Clin Genet. Feb 2010; 77(2): 163-70. PMID 19968670

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