Legius Syndrome (SPRED1)

  • Preferred test to confirm LS for symptomatic individuals
  • Use to rule out NF1 in patients with cutaneous findings only

Acceptable diagnostic test for LS for symptomatic individuals

Related Tests

Preferred test to confirm a suspected diagnosis of NF1

  • Use to confirm a suspected clinical diagnosis of Noonan syndrome, cardiofacial cutaneous syndrome, costello syndrome, LS, Noonan syndrome with multiple lentigines (LEOPARD syndrome), Noonan-like syndrome, and Noonan-like syndrome with loose anagen hair (NS/LAH)
  • For additional test information, refer to the Noonan Spectrum Disorders Panel Test Fact Sheet

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 inguinal 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

Unknown

  • 2% of individuals meeting the NIH diagnostic criteria for NF1 have an identifiable variant in the SPRED1 gene 
  • 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 inguinal freckling 
  • Lipomas 
  • Macrocephaly 
  • Learning disabilities 
  • Attention deficit hyperactivity disorder (ADHD 

Diagnostic Considerations

Diagnosis can be difficult due to clinical overlap with NF1; patients with Legius syndrome may meet clinical criteria for an NF1 diagnosis without a pathogenic variant in NF1. However, the following manifestations of NF1 have not been reported in LS: 

  • Neurofibromas
  • Lisch nodules (iris hamartomas)
  • Central nervous system (CNS) tumors

Identification of a pathogenic SPRED1 gene variant is necessary to make definitive diagnosis of Legius syndrome. 

Genetics

Gene

SPRED1

Inheritance

Autosomal dominant 

De novo variants

Approximately 39% 

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

  1. 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 updated: Jan 2015; Accessed: Feb 2020]

    Online