Noonan Syndrome via the SPRY1 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, MAP3K8, SPRY1, NF1, RRAS, RASA2, and A2ML1 (Human Gene Mutation Database).

To date, three distinct pathogenic variants in the SPRY1 gene have been identified via whole exome sequencing. These cases include one individual with Noonan syndrome, one individual with cardiac and neurodevelopmental abnormalities, and three family members with craniosynostosis (Chen et al. 2014. PubMed ID: 25049390; Jin. 2017. PubMed ID: 28991257; Timberlake et al. 2016. PubMed ID: 27606499). Evidence for pathogenicity include: de novo origin of variants in three sporadic cases and co-segregation of one variant with craniosynostosis in a familial case; and functional studies in mice demonstrating that the conditional expression of SPRY1 in neural crest cells result in craniofacial and cardiac abnormalities, whilst SPRY1-null mice exhibit kidney and urinary tract abnormalities (Yang et al. 2010. PubMed ID: 20459789, Basson et al. 2005. PubMed ID: 15691764).

The SPRY1 gene encodes the sprouty homolog 1 protein, which acts as a negative regulator of Ras/MAPK/RTK signaling across a variety of systems in embryonic and adult tissues (Kim and Bar-Sagi. 2004. PubMed ID: 15173823). It is hypothesized that SPRY1 may regulate signaling pathways that have been implicated in Noonan spectrum disorders, however, the exact molecular mechanism underlying inhibition remain unclear (Tidyman and Rauen. 2016. PubMed ID: 27942422).

Pathogenic variants in the SPRY1 gene appear to be a rare cause of Noonan Syndrome. A whole exome sequencing study of 27 Noonan Syndrome cases lacking a causative variant in a known disease-associated gene identified a single individual carrying a de novo nonsense variant in SPRY1 (Chen et al. 2014. PubMed ID: 25049390).

This test provides full coverage of all coding exons of the SPRY1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.