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
PTPN11
- Code: 81406
- Cost: $1,400
SOS1
- Code: 81406
- Cost: $1,500
RAF1
- Code: 81404
- Cost: $250
KRAS
- Code: 81405
- Cost: $425
SHOC2
- Code: 81400
- Cost: $225
BRAF
- Code: 81406
- Cost: $600
MAP2K1
- Code: 81479
- Cost: $250
Known Variant Testing
- Code: 81479
- Cost: $225
Additional Information
- GeneReview:
- OMIM entries