KRAS-Related Disorders via the KRAS Gene

Noonan syndrome (NS, OMIM 163950) is a relatively common developmental disorder that is characterized by dysmorphic facial features, growth and congenital heart defects, and musculoskeletal abnormalities. Cardiac abnormalities are found in up to 80% of patients and include pulmonary valve stenosis, atrial septal defect, atrioventricular canal defect, and hypertrophic cardiomyopathy. Musculoskeletal abnormalities include short stature, chest deformity with sunken or raised sternum, and short webbed neck. Several additional abnormalities have been described and include renal, genital, hematological, neurologic, cognitive, behavioral, gastrointestinal, dental, and lymphatic findings. Intelligence is usually normal; however, learning disabilities may be present. NS is characterized by an extensive clinical heterogeneity, even among members of the same family. Diagnosis is often made in infancy or early childhood. Symptoms often change and lessen with advancing age. Infants with NS are at risk of developing juvenile myelomonocytic leukemia (JMML OMIM 607785). The prevalence of NS is estimated at 1 in 1000-2500 births worldwide (Allanson et al. Am J Med Genet 21:507-514, 1985; Romano et al. Pediatrics 126:746-759, 2010).

Cardio-facio-cutaneous syndrome (CFCS, OMIM 115150) is a rare developmental disorder characterized by distinctive facial appearance, congenital cardiac and ectodermal abnormalities, postnatal growth failure, feeding difficulties with failure to thrive, and neurological findings. Facial features include high forehead; short, upturned nose with a low nasal bridge; prominent external ears that are posteriorly angulated; and ocular hypertelorism. The most common cardiac abnormalities include pulmonic stenosis and atrial septal defects. Ectodermal abnormalities are heterogeneous in features and severity. They include café au lait spots, erythema, keratosis, ichthyosis, eczema, sparse and brittle hair, and nail dystrophy. The neurological findings include seizures, hypotonia, macrocephaly, and various degrees of mental and cognitive delay (Reynolds et al. Am J Med Genet 25:413-427, 1986).

NS is caused by gain of function variants in various genes within the RAS/MAPK pathway, including KRAS. To date, seven RAS/MAPK genes (PTPN11, SOS1, RAF1, KRAS, SHOC2, BRAF, and NRAS) have been involved in patients with NS. KRAS variants account for less than 5% of all cases genotyped (Schubbert et al. Nat Genet 38:331-336, 2006). To date, thirteen variants, all missense, were reported. Although de novo KRAS variants are found in most NS patients, familial cases have been reported. In these families, NS is inherited as an autosomal dominant trait.

Genotype-phenotype correlations are slowly being made. Mild to moderate mental retardation appears to be more common in NS patients with KRAS variants compared to other NS patients (Zenker et al. J Med Genet 44:131-135, 2007; Allanson et al. J Med Genet 24:9-13, 1987). Craniosynostosis has been documented in a few unrelated NS patients with KRAS variants (Kratz et al. Am J Med Genet A 149A:1036-40, 2009; Brasil et al. Am J Med Genet A 158A:1178-1184, 2012).

CFCS is caused by variants in four genes within the RAS/MAPK pathway: BRAF, MAP2K1, MAP2K1, and KRAS (Rodriguez-Viciana et al. Science 311:1287-1290, 2006; Niihori et al. Nat Genet 38:294-296, 2006). To date, only four KRAS variants were detected in patients with CFCS. All four variants are missense and account for a small fraction of all cases genotyped. All CFCS with KRAS variants are sporadic resulting from de novo dominant KRAS variants. To date, no mosaicism in the KRAS gene has been reported in CFCS patients (Rauen, GeneReviews, 2010).

Somatic KRAS variants have been implicated in several human cancers, including juvenile myelomonocytic leukemia (JMML OMIM 607785) (Reimann et al. Leukemia 20:1637-1638, 2006) and colon cancer (Edkins et al. Cancer Biol Ther 5:928-932, 2006).

This test will detect causative KRAS variants in less than 5% of NS patients (Allanson and Roberts 2011) and in ~ 2-3 % of CFCS patients (Rauen 2010).

This test provides full coverage of all coding exons of the KRAS gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.