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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 an underestimate. There is no apparent prevalence in any particular ethnic group. Several syndromes have overlapping features with NS, including cardiofaciocutaneous (CFC), Costello, Williams, Aarskog, and 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 NS 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 SOS1 gene comprises 23 exons and encodes a 150-kd autoinhibited RAS-specific guanine nucleotide exchange factor. After receptor tyrosine kinase (RTK) stimulation, SOS1 is recruited to the plasma membrane, where it acquires a catalytically active conformation and catalyzes activation of the Ras-MAPK pathway. Reported NS-associated mutations in SOS1 are missense, gain-of-function mutations and are believed to abolish autoinhibition, which leads to increased and prolonged Ras activation.
In addition to NS and related phenotypes, an insertion mutation in SOS1 that creates a premature stop codon at residue 1106 was identified in an extensive Brazilian family with hereditary gingival fibromatosis, an overgrowth condition characterized by a benign, slowly progressive, nonhemorrhagic, fibrous enlargement of maxillary and mandibular keratinized gingiva.
Genetic testing for SOS1 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.
Aiding in the diagnosis of SOS1-associated Noonan syndrome and hereditary gingival fibromatosis
All detected alterations will be evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants will be classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Patients who have received a heterologous blood transfusion within the preceding 6 weeks, or who have received an allogeneic blood or marrow transplant, can have inaccurate genetic test results due to presence of donor DNA.
Related genetic tests available include testing for a specific familial mutation (SOSK / SOS1 Gene, Known Mutation, Blood), which should be used when testing individuals who are at risk for a SOS1 mutation that has been previously identified in the family.
Absence of a mutation does not preclude the diagnosis of Noonan syndrome or another SOS1-related disorder unless a specific mutation has already been identified in an affected family member.
This method will not detect mutations that occur in the introns (except in the splicing regions) and regulatory regions of the gene and large rearrangement-type mutations.
Sometimes a genetic alteration of unknown significance may be identified. In this case, testing of appropriate family members may be useful to determine pathogenicity of the alteration.
An interpretive report will be provided.
1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards of interpretation and reporting of sequence variations: revisions 2007. Genet Med 2008;10(4):294-300
2. Roberts A, Araki T, Swanson K, et al: Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet 2007;39(1):70-74
3. Ferrero G, Baldassarre G, Delmoanco A, et al: Clinical and molecular characterization of 40 patients with Noonan syndrome. Eur J Med Genet 2008;Epub ahead of print:1-7
4. Tartaglia M, Pennachio L, Zhao C, et al: Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet 2007;39(1):75-79
5. Zenker M, Horn D, Wieczorek D, et al: SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. J Med Genet 2007;44:651-656
6. Tartaglia M, Gelb B, Zenker M: Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab 2011;25:161-179