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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 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 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 with NS. 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 30% to 75% of families.
The RAF1 gene comprises 17 exons and encodes the Raf-1 protein, which is 648 amino acids and has 3 domains: CR1, CR2, and CR3. Reported mutations in RAF1 are missense mutations, and cluster within the CR2 and CR3 domains. NS-associated RAF1 mutations are predicted to cause a gain-of-function of the protein.
Some studies have shown that there is a genotype-phenotype correlation associated with NS. RAF1 mutations appear to be correlated with hypertrophic cardiomyopathy (HCM). In a study by Pandit et al(1), 18 of 19 (95%) subjects with NS or LEOPARD syndrome with a RAF1 mutation showed HCM, compared with the 18% prevalence of HCM among individuals with NS in general. In contrast, PTPN11 mutations are rarely associated with HCM, but are frequently associated with pulmonary stenosis.
Mutations in RAF1 have also been associated with LEOPARD syndrome, an autosomal dominant disorder sharing several clinical features with NS characterized by lentigines and cafe-au-lait spots, facial anomalies, and cardiac defects. Additionally, a RAF1 mutation was identified in 1 case of nonsyndromic hypertrophic cardiomyopathy.(1)
Genetic testing for RAF1 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 RAF1-associated Noonan syndrome and LEOPARD syndrome
All detected alterations will be evaluated according to American College of Medical Genetics and Genomics recommendations.(2) 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 RAF1 genetic tests available include testing for a specific familial variant (RAFK / RAF1 Gene, Known Mutation, Blood), which should be used when testing individuals who are at risk for a RAF1 variant that has been previously identified in the family.
Absence of a mutation does not preclude the diagnosis of NS or another RAF1-related disorder unless a specific mutation has already been identified in an affected family member.
This method will not detect mutations that occur deep 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. Pandit B, Sarkozy A, Pennacchio L, et al: Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet 2007;39:1007-1012
2. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300
3. Razzaque M, Nishizawa T, Komoike Y, et al: Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet 2007;39:1013-1017