Noonan-Like Syndrome via the RRAS 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; Allanson and Roberts. 2016. PubMed ID: 20301303).

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, RASA2, SPRY1, NF1 , and RRAS (Human Gene Mutation Database).

Pathogenic variants in the RRAS gene have been identified in patients presenting with features within the Noonan-spectrum disorders. Clinical features include a triangular face, downslanting palpebral fissures, congenital ptosis, low-set ears, thick lips, low posterior hairline, pulmonic stenosis, broad chest, crowded teeth, pyloric stenosis, glomerulonephritis, arthritis, and delayed acquisition of walking. Prenatal polyhydramnios has also been reported (Flex et al. 2014. PubMed ID: 24705357).

To date, two activating germline pathogenic variants in the RARS gene have been reported in two cases. These include a missense variant in a familial case and a de novo duplication of a single residue in a sporadic case. Evidence for pathogenicity include: (1) de novo occurrence of one of the identified variants; (2) localization of the identified variants in a known oncogene hotspot of the RRAS gene; and (3) positive modulatory role of the mutated RRAS proteins, reavealed by expression studies of the mutant proteins in a cell-model and in an experimental model (Flex et al. 2014. PubMed ID: 24705357).

The RRAS gene encodes a small monomeric GTPase, that has been involved in the control of cell adhesion and neurite outfrowth (Zhang et al. 1996. PubMed ID: 8620538; Keely et al. 1999. PubMed ID: 10352023).

Pathogenic variants in the RRAS gene appear to be a rare cause of Noonan syndrome. They have been identified in two individuals from a cohort of 504 patients presenting with phenotypes that overlap with features within Noonan spectrum disorders (Flex et al. 2014. PubMed ID: 24705357).

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