PT1K - Clinical: PTPN11 Gene, Known Mutation, Blood

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Test ID: PT1K    
PTPN11 Gene, Known Mutation, Blood

Useful For Suggests clinical disorders or settings where the test may be helpful

Genetic testing of individuals at risk for a known PTPN11

Genetics Test Information Provides information that may help with selection of the correct test or proper submission of the test request

Documentation of the specific familial mutation must be provided with the specimen in order to perform this test.

Testing Algorithm Delineates situation(s) when tests are added to the initial order. This includes reflex and additional tests.


Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Noonan syndrome (NS) is an autosomal dominant disorder of variable expressivity characterized by short stature, congenital heart defects, characteristic facial dysmorphology, unusual chest shape, developmental delay of varying degree, cryptorchidism, and coagulation defects, among other features. Heart defects include pulmonary valve stenosis (20%-50%), hypertrophic cardiomyopathy (20%-30%), atrial septal defects (6%-10%), ventricular septal defects (approximately 5%), and patent ductus arteriosus (approximately 3%). Facial features, which tend to change with age, may include hypertelorism, downward slanting eyes, epicanthal folds, and low-set and posteriorly rotated ears. Mild mental retardation is seen in up to one-third of adults.


The incidence of NS is estimated to be between 1 in 1,000 and 1 in 2,500, although subtle expression in adulthood may cause this number to be underestimated. There is no apparent prevalence in any particular ethnic group. Several syndromes have overlapping features with NS, including cardiofaciocutaneous (CFC), Costello, Williams, Aarskog, and multiple lentigines (LEOPARD: lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and deafness) syndromes.


NS is genetically heterogeneous, with 4 genes currently associated with the majority of cases: PTPN11, RAF1, SOS1, and KRAS. Heterozygous mutations in NRAS, HRAS, BRAF, SHOC2, MAP2K1, MAP2K2, and CBL have also been associated with a smaller percentage of Noonan syndrome and related phenotypes. All of these genes are involved in a common signal transduction pathway, the Ras-MAPK pathway, which is important for cell growth, differentiation, senescence, and death. Molecular genetic testing identifies PTPN11 mutations in 50% of individuals. Mutations in RAF1 are identified in approximately 3% to 17%, SOS1 approximately 10%, and KRAS less than 5% of affected individuals. NS can be sporadic and due to new mutations; however, an affected parent can be recognized in up to 30% to 75% of families.


The PTPN11 gene comprises 15 exons and encodes the Src homology-2 domain-containing phosphatase (SHP-2), a widely expressed extracellular protein. SHP-2 is a key molecule in the cellular response to growth factors, hormones, cytokines, and cell adhesion molecules. It is required in several intracellular signal transduction pathways that control diverse developmental processes. Most reported mutations in PTPN11 are missense mutations, although small deletions as well as whole gene duplications have been reported to cause NS. Most mutations associated with NS destabilize the catalytically inactive conformation of the protein, causing a gain of function of SHP-2.


Some studies have shown that there is a genotype-phenotype correlation associated with NS. An analysis of a large cohort of individuals with NS has suggested that PTPN11 mutations are more likely to be found when pulmonary stenosis is present, while hypertrophic cardiomyopathy (HCM) is commonly associated with RAF1 mutations but rarely associated with PTPN11.


Mutations in PTPN11 have also been identified in individuals with a variety of other disorders that overlap phenotypically with NS. PTPN11 has been associated with LEOPARD syndrome, an autosomal dominant disorder sharing several clinical features with NS and characterized by multiple lentigines and cafe-au-lait spots, facial anomalies, and cardiac defects. Two mutations, p.Tyr279Cys and p.Thr468Met, represent the most common PTPN11 mutations found in LEOPARD syndrome, although other mutations have been described. Mutations in PTPN11 have also been identified in patients who have clinical features of NS along with features of CFC syndrome, a condition involving congenital heart defects, cutaneous abnormalities, Noonan-like facial features, and severe psychomotor developmental delay.


Genetic testing for PTPN11 mutations can allow for the confirmation of a suspected genetic disease. Confirmation of NS or other associated phenotypes allows for proper treatment and management of the disease and preconception, prenatal, and family counseling.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Blood samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic blood or marrow transplantation. Results from samples obtained under these circumstances may not accurately reflect the recipient's genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. For individuals who have received allogeneic blood or marrow transplantation, a pretransplant DNA specimen is recommended for testing.


This test is for individuals who are at risk for a PTPN11 variant that has been previously identified in the family. If the familial variant is not known, the familial proband should be screened for a PTPN11 mutation using the full gene sequence assay (PT11 / PTPN11, Full Gene Sequence, Blood).

Clinical Reference Provides recommendations for further in-depth reading of a clinical nature

1. Tartaglia M, Mehler E, Goldberg R, et al: Mutations in PTPN11, encoding the protein tyrosine phophatase SHP-2, cause Noonan syndrome. Nat Genet 2001;29:465-468

2. Tartaglia M, Kalidas K, Shaw A, et al: PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 2002;70:1555-1563

3. Musante L, Kehl H, Majewski F, et al: Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and 5 patients with cardio-facio-cutaneous syndrome. Eur J Hum Genet 2002;11:201-206

4. Kontaridis M, Swanson K, David F, et al: PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem 2006;281(10):6785-6792

5. Cohen MM, Gorlin RJ: Noonan-like/multiple giant cell lesion syndrome. Am J Med Genet 1991;40:159

6. Lee JS, Tartaglia M, Gelb BD, et al: Phenotypic and genotypic characterization of Noonan-like/multiple giant cell lesion syndrome. J Med Genet 2005;42(2):e11

7. Tartaglia M, Gelb B, Zenker M: Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab 2011 Feb;25(1):161-179

Special Instructions and Forms Describes specimen collection and preparation information, test algorithms, and other information pertinent to test. Also includes pertinent information and consent forms to be used when requesting a particular test