Noonan Syndrome via the MAP3K8 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, one pathogenic missense variant in the MAP3K8 gene has been identified via whole exome sequencing in a three-year-old male patient who presented with short stature, typical facies and mild aortic stenosis, consistent with Noonan syndrome (Chen et al. 2014. PubMed ID: 25049390). Evidence for pathogenicity includes: de novo origin of a variant in an individual with clinical features consistent with Noonan syndrome; and functional studies in cell lines suggesting that MAP3K8 is an agonist of the MAPK pathway (Hagemann et al. 1999. PubMed ID: 10050876, Johannessen et al. 2010. PubMed ID: 21107320). These studies have primarily used cancer and non-human cell-lines and, as such, may have limited application to Noonan syndrome.

MAP3K8 is an oncogene that encodes mitogen activated protein kinase kinase kinase 8, a member of the serine/threonine protein kinase family that activates MAPK and JNK pathways through MEK-dependent mechanisms (Aoki et al. 1993. PubMed ID: 8226782, Hagemann et al. 1999, PubMed ID: 10050876, Clark et al. 2004. PubMed ID: 15287022, Johannessen et al. PubMed ID: 21107320). The MAP3K8 gene, also known as COT and TPL2, has been implicated in inflammation and tumorigenesis (Vougioukalaki et al. 2011. PubMed ID: 21377269).

Pathogenic variants in the MAP3K8 gene appear to be a rare cause of Noonan Syndrome. A whole exome sequencing study of 27 individuals with Noonan Syndrome lacking a causative variant in a known disease-associated gene identified a single individual carrying a de novo missense variant in MAP3K8 (Chen et al. 2014. PubMed ID: 25049390).

This test provides full coverage of all coding exons of the MAP3K8 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.