Neurofibromatosis Type 1 (NF1) Sequencing and Deletion/Duplication

Background Information for Neurofibromatosis Type 1 (NF1) Sequencing and Deletion/Duplication:
Characteristics: Neurofibromatosis type 1 (NF1) demonstrates extreme clinical variability. Features include: cafe au lait macules, axillary and inguinal freckling, dermal fibromas, Lisch nodules (iris hamartomas), optic glioma, specific osseous lesions such as tibial pseudarthrosis or sphenoid dysplasia, learning disabilities (50 percent), scoliosis, vertebral dysplasia, and somatic overgrowth. Large NF1 locus deletions increase the risk for neurofibroma development, cognitive abnormalities and malignant peripheral nerve sheath tumors (MPNST).
Incidence: 1 in 3000.
Inheritance: Autosomal dominant; de novo mutations occur in 50 percent of cases.
Penetrance: 100 percent by adulthood.
Cause: Pathogenic NF1 mutations.
Clinical Sensitivity: Approximately 84-93 percent; 77-86 percent of causative mutations are detected by sequencing and 7 percent by deletion testing.
Methodology: Bidirectional sequencing of the entire NF1 coding region and intron-exon boundaries; multiplex ligation-dependent probe amplification (MLPA) to detect large NF1 locus and intragenic deletions/duplications.
Analytical Sensitivity and Specificity: 99 percent.
Limitations: Diagnostic errors can occur due to rare sequence variations. Regulatory region mutations and deep intronic mutations will not be detected. Large deletions/duplications of exons 11 and 20 will not be detected. The breakpoints of large deletions/duplications will not be determined. This assay is not designed to detect somatic variants associated with malignancy. Interpretation of this test result may be impacted if the patient has had an allogeneic stem cell transplantation.