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Neurofibromatosis type 1 (NF1) Gene Analysis
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Genetic testing for NF1 mutation.
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Neurofibromatosis type 1 (NF1) Gene Analysis
- Why is it done?
- Test Purpose: This test detects mutations in the NF1 gene located on chromosome 17, which causes neurofibromatosis type 1, an autosomal dominant genetic disorder characterized by the development of benign tumors of the nervous system (neurofibromas) and increased cancer risk.
- Clinical Indications: Confirmation of clinical diagnosis in individuals with typical NF1 features such as café-au-lait spots, neurofibromas, optic nerve gliomas, or characteristic skeletal abnormalities; identification of NF1 carriers in families with known mutations; prenatal or carrier testing in at-risk family members; and assessment of disease severity.
- Timing and Circumstances: Testing is performed when NF1 is clinically suspected based on diagnostic criteria; during childhood or adolescence for diagnostic confirmation; in adulthood for carrier identification or family planning; and upon identification of NF1 in a family member to determine inheritance patterns.
- Normal Range
- Normal Result: No mutations detected in the NF1 gene; reported as 'wild-type' or 'normal' sequence. This indicates the individual does not carry a pathogenic NF1 mutation.
- Abnormal Result: Presence of a pathogenic mutation in the NF1 gene; mutations may include deletions, insertions, point mutations, splice site mutations, or gross rearrangements affecting the NF1 locus.
- Variant Classification: Variants are classified as pathogenic, likely pathogenic, uncertain significance, likely benign, or benign based on established criteria and databases (ClinVar, LOVD, literature review).
- Interpretation Categories: Positive (mutation confirmed) indicates NF1 diagnosis; negative (no mutation detected) may indicate non-NF1 condition or segmental NF1; and variants of uncertain significance require further investigation or specialized interpretation.
- Interpretation
- Pathogenic Mutation Detected: Confirms diagnosis of neurofibromatosis type 1; establishes autosomal dominant inheritance pattern; indicates 50% transmission risk to offspring; warrants comprehensive clinical surveillance, ophthalmological and dermatological evaluation, and monitoring for malignant transformation.
- No Mutation Detected: May indicate individual does not have NF1; could suggest segmental NF1 (mutations present in limited cell populations); possibility of mosaicism in a parent; or technical limitations of testing method (large deletions/rearrangements may be missed by sequencing alone).
- Variant of Uncertain Significance (VUS): Variant classification remains unclear; requires additional evidence, segregation analysis, or functional studies; may be reclassified with time as new evidence emerges; genetic counseling recommended to discuss management pending additional testing.
- Likely Benign or Benign Variant: Variant is unlikely to cause NF1; does not explain clinical phenotype; additional evaluation needed to identify actual cause of clinical features if clinical suspicion remains high.
- Factors Affecting Test Interpretation: Testing methodology (DNA sequencing alone may miss large deletions; fluorescence in situ hybridization FISH or array CGH may be needed); germline vs. somatic mutations; mosaicism in parents; ethnicity-specific variant frequencies; and phenotypic variability even within same mutations.
- Clinical Correlation: Results should be interpreted within clinical context; diagnostic criteria (NIH criteria) require combination of clinical features; approximately 5% of clinically diagnosed NF1 patients show no detectable NF1 mutation (segmental NF1 or other diagnoses).
- Associated Organs
- Nervous System: Primary organ system affected; neurofibromas develop along peripheral nerves; optic nerve gliomas occur in 15-20% of patients; risk of malignant peripheral nerve sheath tumors (MPNST); spinal neurofibromas may cause myelopathy.
- Skin: Café-au-lait spots (hyperpigmented macules) present in >99% of NF1 patients; neurofibromas and subcutaneous nodules; freckling in intertriginous areas; increased risk of melanoma and other cutaneous malignancies.
- Skeletal System: Bone dysplasia, scoliosis (severe in 10-15% of patients), short stature, tibial pseudoarthrosis, segmental overgrowth, and increased fracture risk; dysplasia of long bones, ribs, and vertebrae common.
- Cardiovascular System: Increased risk of hypertension; pulmonary artery stenosis; increased incidence of congenital heart defects; vasculopathy secondary to neurofibromas affecting vessels.
- Endocrine System: Pheochromocytoma risk (5% of NF1 patients); increased risk of thyroid carcinoma; growth hormone abnormalities; precocious or delayed puberty possible.
- Gastrointestinal System: Gastrointestinal stromal tumors (GISTs); increased cancer risk; neurofibromas of GI tract; intestinal pseudoobstruction.
- Eyes: Optic nerve gliomas (asymptomatic in most); Lisch nodules (iris hamartomas, hallmark of NF1); iris nodules; vision problems; glaucoma.
- Associated Malignancies: Significantly increased lifetime cancer risk (approximately 24-50%); common malignancies include MPNST, optic pathway glioma, breast cancer (5-fold increase in females), pheochromocytoma, GISTs, and increased risk of various other cancers.
- Follow-up Tests
- Confirmatory Testing: FISH or array CGH if large deletions suspected; repeat sequencing or alternative sequencing methods if results inconclusive; functional studies for variants of uncertain significance.
- Clinical Surveillance Imaging: Annual ophthalmologic examination for optic nerve gliomas; MRI of brain and spine for assessment of tumors; baseline and periodic imaging of suspicious lesions; PET scan if malignancy suspected.
- Biochemical Testing: 24-hour urine metanephrine and catecholamines to screen for pheochromocytoma; thyroid function tests; blood pressure monitoring for hypertension screening.
- Cancer Surveillance: Annual clinical breast examination starting in childhood; mammography beginning in 20s (earlier and more frequent than general population); skin cancer surveillance; consideration of other cancer screening protocols.
- Family Testing: Genetic testing of first-degree relatives carrying identified pathogenic mutation; testing of parents if proband has de novo mutation; genetic counseling for family members regarding inheritance and cancer risk.
- Prenatal/Preimplantation Diagnosis: NF1 gene analysis on amniotic fluid or chorionic villus samples for prenatal diagnosis; preimplantation genetic diagnosis (PGD) for in vitro fertilization in affected couples.
- Monitoring Frequency: Lifelong surveillance recommended; annual comprehensive NF1 assessments advised; more frequent monitoring if tumors develop or concerning features emerge; increased surveillance in adulthood for malignancy screening.
- Fasting Required?
- Fasting Status: No - Fasting is not required for NF1 gene analysis testing.
- Sample Collection Requirements: Blood sample collection (usually 5-10 mL of peripheral blood in EDTA tube); saliva sample collection (alternative for some laboratories); tissue biopsy if analyzing tumor tissue or somatic mutations; amniotic fluid or chorionic villus sample for prenatal testing.
- Medication Considerations: No medications need to be discontinued for this genetic test; current medications do not affect test results; continue all prescribed medications as directed by physician.
- Pre-test Preparation: No special preparation required; patient may eat and drink normally; maintain regular daily routine; genetic counseling is recommended before testing to discuss implications, inheritance patterns, and test limitations.
- Informed Consent: Informed consent should be obtained before testing; discussion of test purpose, benefits, risks, limitations, and implications should occur; counseling about potential incidental findings or uncertain results recommended.
How our test process works!
