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Noonan syndrome

 

Noonan syndrome is a genetic disorder characterized by a series of birth defects including dysmorphic facial features, short stature after birth, webbing of the neck, caved-in chestbone, cardiovascular problems such as pulmonic stenosis and hypertrophic cardiomyopathy, bleeding tendency and, in boys, testes that do not descend normally into the scrotum.

NS is an autosomal dominant disorder that carries an elevated risk of developmental and language delay, learning disability, hearing loss, and mild mental retardation. The syndrome is relatively common, with an estimated incidence of 1 in 1,000-2,500 live births. Noonan syndrome is a clinically recognizable and genetically heterogeneous disorder. The common denominator of the various genetic alterations found in patients with Noonan syndrome and related disorders is that they cause dysregulation of RAS-MAPK signaling. Even if strict clinical criteria are applied, the molecular genetic lesion currently remains unidentified in about 10-20% of cases, thus suggesting additional genes for Noonan syndrome.

We provide testing for the genes listed below that are believed to be connected to Noonan syndrome.

Type OMIM Gene Description
NS1 163950 PTPN11 In most of the families with multiple affected members, NS maps to chromosome 12q24.1. In 2001, it was reported that approximately half of a group of patients with Noonan syndrome carried a mutation of the PTPN11 gene at that location, which encodes protein tyrosine phosphatase SHP-2.The SHP2 protein is a component of several intracellular signal transduction pathways involved in embryonic development that modulate cell division, differentiation, and migration, including that mediated by the epidermal growth factor receptor. The latter pathway is important in the formation of the cardiac semilunar valves. Chromosomal abnormalities, such as a duplication of chromosome region 12q24 encompassing gene PTPN11 can result in an apparent Noonan syndrome.
NS3 609942 KRAS Additional mutations in KRAS gene has been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome
NS4 610733 SOS1 It has recently been shown that activating mutations in SOS1 also give rise to NS. Shp2 and SOS1 both have roles as positive regulators of the Ras/MAP kinase pathway suggesting that dysregulation of this pathway may play a major role in the genesis of this syndrome
NS5 611553 RAF1 Additional mutations in RAF1 genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome.
NS6 613224 NRAS NRAS mutations account for less than 1% of cases with Noonan syndrome
NS7 613706 BRAF BRAF mutations account for less than 2% of cases with Noonan syndrome

Methodology: Sequencing analysis of each gene

Purpose: Confirmation of Clinical Diagnosis

ICD-10 Code Q87.1

Test Requisition: Sequencing Requisition

NS1 PTPN11 CPT Code: 81406 Cost: $935.00

NS3 KRAS CPT Code: 81405 Cost: $528.00

NS4 SOS1 CPT Code: 81406 Cost: $935.00

NS5 RAF1 CPT Code: 81406 Cost: $330.00

NS6 NRAS CPT Code: 81404 Cost: $715.00

NS7 BRAF CPT Code: 81406 Cost: $1089.00

Panel CPT Codes: 81405, 81406x4, 81404 Cost: $4532.00

Turn-around-time: 5-6 weeks each test

Specimen Requirements

Shipping Information

References

1. Jamieson CR, van der Burgt I, Brady AF, van Reen M, Elsawi MM, Hol F, Jeffery S, Patton MA, Mariman E (1994). "Mapping a gene for Noonan syndrome to the long arm of chromosome 12". Nat. Genet. 8 (4): 357–60


2. Freeman RM, Plutzky J, Neel BG (1992). "Identification of a human Src homology 2-containing protein-tyrosine-phosphatase: a putative homolog of Drosophila corkscrew". Proc. Natl. Acad. Sci. U.S.A. 89 (23): 11239–43.

3. Tartaglia M, Mehler EL, Goldberg R, et al (2001). "Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome". Nat. Genet. 29 (4): 465–8.

4. Shchelochkov OA et al, Am J Med Genet A, 2008 Apr 15;146A(8):1042-8

5. Van Der Burgt, I.; Brunner, H. (2000). "Genetic heterogeneity in Noonan syndrome: Evidence for an autosomal recessive form". American Journal of Medical Genetics 94 (1): 46–51.

6. Schubbert S, Zenker M, Rowe SL, et al (2006). "Germline KRAS mutations cause Noonan syndrome". Nat. Genet. 38 (3): 331–6

7. Roberts AE, Araki T, Swanson KD, et al (2007). "Germline gain-of-function mutations in SOS1 cause Noonan syndrome". Nat. Genet. 39 (1): 70–4

8. Bentires-Alj M, Kontaridis MI, Neel BG (2006). "Stops along the RAS pathway in human genetic disease". Nat. Med. 12 (3): 283–5..

9. Razzaque MA, Nishizawa T, Komoike Y, et al (2007). "Germline gain-of-function mutations in RAF1 cause Noonan syndrome". Nat. Genet. 39 (8): 1013–7

 

 

 


Contact Information
Genetics Laboratory
University of Oklahoma Health Sciences Center
1122 NE 13 Street, Suite 1400, Oklahoma City, OK 73104
Phone: (405) 271-3589 |Fax: (405) 271-7117 Email: Dr. Shibo Li

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