Noonan/LEOPARD Syndrome

Noonan Syndrome and Related Disorders

Gene: PTPN11

Protein: tyrosine-protein phosphatase non-receptor type 11

Gene: SOS1

Protein: son of sevenless homolog 1

Gene: RAF1

Protein: RAF proto-oncogene serine/threonine-protein kinase

Gene: KRAS

Protein: GTPase KRas

Gene: SHOC2

Protein: leucine-rich repeat protein SHOC-2

Gene: BRAF

Protein: serine/threonine-protein kinase B-raf

Gene: MAP2K1/MEK1

Protein: dual specificity mitogen-activated protein kinase kinase 1

Clinical Characteristics

Noonan Syndrome

  • Heart defects including hypertrophic cardiomyopathy and pulmonic valve stenosis
  • Facial dysmorphology
  • Short stature
  • Chest wall deformities
  • Developmental delay

LEOPARD Syndrome

  • Acronym for:
    • Lentigines (multiple)
    • Electrocardiogram abnormalities
    • Ocular hypertelorism
    • Pulmonic valvular stenosis
    • Abnormalities of genitalia
    • Retardation of growth
    • Deafness (sensorineural)
  • Lentigines may or may not be present
  • Heart defects including hypertrophic cardiomyopathy and pulmonic valve stenosis
  • Cryptorchidism
  • Postnatal growth retardation
  • Mild facial dysmorphology
  • Mild mental retardation

Noonan-Like Syndrome With Loose Anagen Hair

  • Features of Noonan syndrome
  • Actively growing hair that is easy to pluck, sparse, thin and slow-growing

Inheritance pattern: Autosomal dominant

What Can Be Learned From This Test

Testing can be performed in tiers, moving to the next tier only if the preceding test is negative. Testing can also be performed concurrently or in any order requested.

The following strategy is suggested for Noonan syndrome testing:

  • Tier 1 and 3 suggested if an individual has findings suggestive of LEOPARD syndrome
  • Tier 5 suggested if an individual has loose anagen hair

Tiered sequencing:

  • Tier 1: entire coding region of PTPN11
  • Tier 2: entire coding region of SOS1
  • Tier 3: exons 7, 14 and 17 of RAF1
  • Tier 4: entire coding region of KRAS
  • Tier 5: part of exon 2 for reported mutation in SHOC2
  • Tier 6: exons 6 and 11 through 16 of BRAF
  • Tier 7: exons 2, 3, 6 and 7 of MAP2K1 (MEK1)

Sequencing tests will detect point mutations, small deletions and small insertions in the regions of the genes that are analyzed. It will not detect a partial or whole gene deletion or duplication.

For Noonan syndrome, mutations are detected in:

  • PTPN11 in about 50% of affected individuals
  • SOS1 in about 10% of affected individuals
  • Exon 7, 12, 14, or 17 of RAF1 in 3-17% of affected individuals
  • KRAS in fewer than 5% of affected individuals
  • Exon 2 of SHOC2 in individuals with Noonan-like syndrome with loose anagen hair
  • BRAF in fewer than 2% of affected individuals
  • MAP2K1 (MEK1) in fewer than 2% of individuals

For LEOPARD syndrome, mutations are detected in:

  • Exon 7, 12, 14, or 17 of RAF1 in about 3% of affected individuals

A negative test does not completely rule out a diagnosis of Noonan syndrome or LEOPARD syndrome, since mutations in these five genes do not account for 100 percent of cases.

Clinical overlap is seen between Noonan syndrome, Costello syndrome and cardiofaciocutaneous (CFC) syndrome. Tests for Costello syndrome and CFC syndrome are also available in our lab and can be requested if clinically indicated.

Sample Requirements

Draw 2ml–4ml of blood in EDTA/purple-top tube (minimum of 1ml–2ml for infants).

Turnaround time: 7-10 business days for each gene; about 4 weeks for all 7 tiers

CPT Codes and Cost

Full Gene Sequencing


  • Code: 81406
  • Cost: $1,400 


  • Code: 81406
  • Cost: $1,500 


  • Code: 81404
  • Cost: $250


  • Code: 81405
  • Cost: $425


  • Code: 81400
  • Cost: $225


  • Code: 81406
  • Cost: $600 


  • Code: 81479
  • Cost: $250

Known Variant Testing

  • Code: 81479
  • Cost: $225 

Additional Information