Noonan Syndrome via the RASA2 Gene

Noonan Syndrome (NS) 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 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). The prevalence of NS is estimated at 1 in 1,000 to 1 in 2,500 births worldwide (Allanson. 1987. PubMed ID: 3543368; Romano et al. 2010. PubMed ID: 20876176; Smpokou et al. 2012. PubMed ID: 23165751; Cao et al. 2017. PubMed ID: 28643916).

Clinical features of Noonan syndrome overlap with those of Cardio-Facio-Cutaneous Syndrome (Gripp et al. 2007. PubMed ID: 17551924; Rauen 2016. PubMed ID: 20301365), and Costello Syndrome (Gripp and Lin. 2012. PubMed ID: 20301680).

Noonan and Noonan-like syndromes are caused by pathogenic variants in PTPN11, SOS1, RAF1, KRAS, SHOC2, BRAF, NRAS, CBL, KAT6B, RIT1, SOS2, LZTR1, A2ML1, MAP3K8, SPRY1, NF1, RRAS, and RASA2 (Human Gene Mutation Database).

Pathogenic variants in the RASA2 gene have been identified in patients diagnosed clinically with Noonan syndrome. Clinical features include short stature, typical facies, developmental delay, and cardiovascular abnormalities in the form of pulmonary valve stenosis, dysplastic pulmonary valve, atrial septal defect, branch pulmonary artery stenosis, patent ductus arteriosus, and dilated main pulmonary artery (Chen et al. 2014. PubMed ID: 25049390).

To date, three loss-of function missense variants affecting two residues in the RASA2 gene have been reported in three sporadic cases. It is, however, not clear if the variants were de novo because the parents were not available for testing. Evidence for pathogenicity include: (1) localization of the identified variants in highly conserved amino acids in the GAP domain of the protein; and (2) increased ERK activation as a result of decreased RASA2 levels in cells expressing the mutant proteins (Chen et al. 2014. PubMed ID: 25049390). In addition, recurrent inactivating RASA2 variants have been implicated in several cancers (Arafeh et al. 2015. PubMed ID: 26502337).

The RASA2 gene encodes RAS p21 protein activator 2, a member of the GAP1 family of GTPase-activating proteins. It is involved in the control of cellular proliferation and differentiation (Li et al. 1996. PubMed ID: 8812506).

Pathogenic variants in the RASA2 gene appear to be a rare cause of Noonan syndrome. They have been identified in 3 individuals from a cohort of 27 patients diagnosed clinically with Noonan syndrome, with no pathogenic variants in the known Noonan syndrome genes (Chen et al. 2014. PubMed ID: 25049390).

This test provides full coverage of all coding exons of the RASA2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.