Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Related Tests
Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Preferred test to confirm a suspected diagnosis of NF1
Polymerase Chain Reaction/Sequencing
Useful when a pathogenic familial variant identifiable by sequencing is known
Legius syndrome (LS) is a rare genetic disorder characterized primarily by cutaneous findings such as café au lait spots, axillary and intertriginous freckling, and lipomas. Distinguishing LS from neurofibromatosis type 1 (NF1) may be difficult because of overlapping clinical features, especially in younger patients who have not yet developed other clinical features particular to NF1 (eg, neurofibromas and Lisch nodules). SPRED1 molecular testing can help identify patients who do not need routine surveillance for NF1-related tumors and other complications.
Disease Overview
Prevalence
- May represent 0.5% of NF1 diagnoses or 8% of those with isolated café au lait spots
- 3-25% of individuals being evaluated for NF1 who lack variants in the NF1 gene have variants in the SPRED1 gene
Clinical Findings
- Café au lait spots
- Axillary and intertriginous freckling
- Lipomas
- Macrocephaly
- Learning disabilities, attention deficit hyperactivity disorder (ADHD), and developmental delays
Diagnostic Considerations
Diagnosis can be difficult due to clinical overlap with NF1. Patients with LS may have pigmentary symptoms of NF1 (ie, café au lait macules and/or intertriginous freckling); however, they lack the nonpigmentary manifestations (eg, Lisch nodules, neurofibromas).
Identification of a pathogenic SPRED1 gene variant is necessary to make a definitive diagnosis of LS.
Genetics
Gene
SPRED1
Inheritance
De novo variants
Variants
Most variants are of the following types:
- Sequence variants (88% of detected variants in one study )
- Large deletions (multiexonic, or whole gene ; 10% of detected variants in one study )
Test Interpretation
Sensitivity/Specificity
- Clinical sensitivity: unknown
- Analytical sensitivity/specificity: 99%
Results
Results | Result Description | Interpretive Data |
---|---|---|
Positive |
Pathogenic variant detected in SPRED1 gene |
Diagnosis of LS confirmed |
Negative |
No pathogenic variants detected in SPRED1 gene |
Diagnosis of LS less likely, but not excluded |
Inconclusive |
Variant of unknown significance detected |
Inconclusive |
Limitations
- Regulatory region and deep intronic variants will not be detected
- Large deletion/duplication breakpoints will not be determined
- Diagnostic errors can occur due to rare sequence variations
References
-
GeneReviews - Legius Syndrome
Stevenson D, Viskochil D, Mao R. Legius syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews, University of Washington, 1993-2020. [Last update: Aug 2020; Accessed: Feb 2020]
Online -
24334617
Brems H, Legius E. Legius syndrome, an update. Molecular pathology of mutations in SPRED1. Keio J Med. 2013;62(4):107-112.
PubMed -
21548021
Spencer E, Davis J, Mikhail F, et al. Identification of SPRED1 deletions using RT-PCR, multiplex ligation-dependent probe amplification and quantitative PCR. Am J Med Genet A. 2011;155A(6):1352-1359.
PubMed
Use to confirm a suspected diagnosis of Legius syndrome in individuals with a negative NF1 Sequencing and Deletion/Duplication test