Noonan Syndrome via the SOS1 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).

NS is caused by gain of function variants in various genes within the RAS/MAPK pathway, including SOS1. To date, seven RAS/MAPK genes (PTPN11, SOS1, RAF1, KRAS, SHOC2, BRAF, and NRAS) have been involved in NS. SOS1 variants are the second most common cause of NS, and account for 10-13% of all cases genotyped (Roberts et al. Nat Genet 39:70-74, 2007; Tartaglia et al. Nat Genet 39:75-79, 2007; Zenker et al. J Med Genet 44:651-656, 2007; Allanson and Roberts,GeneReviews, 2011). About 50 missense variants and a few small deletions, insertions and indels were reported. Although de novo variants are found in a substantial fraction of patients, familial cases have been reported. In these families, NS is inherited in an autosomal dominant manner with variable expressivity (Romano et al. Pediatrics 126:746-759, 2010).

This test will detect causative variants in ~ 16-20% of NS patients without PTPN11 variants (Roberts et al. Nat Genet 39:70-74, 2007; Tartaglia et al. Nat Genet 39:75-79, 2007).

This test provides full coverage of all coding exons of the SOS1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.