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Aiding in the diagnosis of KRAS-associated Noonan syndrome, cardiofaciocutaneous syndrome, and Costello syndrome
This test aids in the diagnosis of KRAS-associated Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, and clinically related disorders.
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 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 NS and related phenotypes. All of these genes are involved in a common signal transduction pathway, the Ras-mitogen-activated protein kinase (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 in approximately 10%, and KRAS in 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 KRAS gene has been shown to have a total of 6 exons that are alternatively spliced into K-Ras isoforms A and B. Exon 1 is noncoding. Exons 2, 3, and 4 are invariant coding exons, whereas exon 5 undergoes alternative splicing. K-Ras isoform B results from exon 5 skipping. In K-Ras isoform A mRNA, exon 6 encodes the 3-prime untranslated region, whereas in K-Ras isoform B mRNA, exon 6 encodes the C-terminal region. Reported mutations in KRAS associated with NS are missense mutations. It has been proposed that all reported mutations lead to stabilization of K-Ras in the active conformation, most likely by different gain of function mechanisms.
Mutations in KRAS have been identified in individuals with other disorders that overlap phenotypically with NS, including CFC syndrome, a condition involving congenital heart defects, cutaneous abnormalities, Noonan-like facial features, and severe psychomotor developmental delay. KRAS mutations have also been associated with Costello syndrome, which is characterized by coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, failure to thrive, cardiac anomalies, and developmental disability.
Genetic testing for KRAS 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.
An interpretive report will be provided.
All detected alterations will be evaluated according to American College of Medical Genetics and Genomics (ACMG) 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.
Absence of a mutation does not preclude the diagnosis of Noonan syndrome or another KRAS-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.
1. 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
2. Schubbert S, Zenker M, Rowe S, et al: Germline KRAS mutations cause Noonan syndrome. Nat Genet 2006;38(3):331-336
3. Zenker M, Lehmann K, Schulz A, et al: Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet 2007;44(2):131-135
4. Nava C, Hanna N, Michot C, et al: Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationship and overlap with Costello syndrome. J Med Genet 2007;44:763-771
5. Niihori T, Aoki Y, Narumi Y, et al: Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet 2006;38(3):294-296
6. Carta C, Pantaleoni F, Bocchinfuso G, et al: Germline missense mutations affecting KRAS isoform B are associated with a severe form of Noonan syndrome. Am J Hum Genet 2006;79(1):129-135
7. Tartaglia M, Gelb B, Zenker M: Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab 2011;25:161-179