Noonan Syndrome via the RIT1 Gene

Noonan Syndrome (NS) 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 prenatal lymphatic abnormalities such as nuchal translucency, cystic hygroma, bilateral chylothorax, pleural effusion and polyhydramnios. 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 to 1 in 2,500 births worldwide (Allanson et al., 1985; Nisbet et al., 1999; van der Burgt, 2007; Romano et al., 2010).

NS is caused by gain of function mutations in various genes within the RAS/MAPK pathway, including RIT1. Several RAS/MAPK genes (PTPN11, SOS1, RAF1, KRAS, SHOC2, BRAF, NRAS, MAP2K1 and CBL) have been involved in NS. Recently, nine different pathogenic missense variants in the RIT1 gene were reported in 17 patients affected with NS or a related disorder without detectable mutations in the remaining Noonan-related genes. Perinatal and neonatal abnormalities were found in nine patients and include polyhydramnios, nuchal translucency, placental abruption, pleural effusion, and chylothorax. Features characteristic of cardiofaciocutaneous syndrome (CFCS), including sparse and curly hair and a high cranial vault, were detected in two patients who were initially diagnosed with CFCS. The remaining patients have features characteristic of NS. Although pathogenic variants occurred apparently de novo in most cases where parental testing was performed, one patient inherited the variant from the affected mother (Aoki et al., 2013).

Somatic RIT1 mutations have been reported in several cancers (http://cancer.sanger.ac.uk/cosmic). Lymphoblastic leukemia occurred in one of the 17 patients described by Aoki et al.

Pathogenic variants in RIT1 were detected in ~ 9% of NS patients without detectable pathogenic variants in the remaining Noonan-related genes (Aoki et al., 2013).

This test provides full coverage of all coding exons of the RIT1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.