Noonan Syndrome via the LZTR1 Gene

Noonan Syndrome (NS) 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 prenatal lymphatic abnormalities such as nuchal translucency, cystic hygroma, bilateral chylothorax, pleural effusion and polyhydramnios. 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). The prevalence of NS is estimated at 1 in 1000 to 1 in 2,500 births worldwide (Allanson et al. 1985; Nisbet et al. 1999; van der Burgt 2007; Romano et al. 2010).

NS is caused by gain of function pathogenic variants in various genes within the RAS/MAPK pathway. Several RAS/MAPK genes (PTPN11, SOS1, SOS2, RAF1, KRAS, SHOC2, BRAF, NRAS, MAP2K1, RIT1, and CBL) have been involved in NS. Recently, five different pathogenic missense variants in the LZTR1 gene were reported in 5 patients affected with NS without detectable pathogenic variants in the remaining Noonan-related genes. Three of the variants occurred de novo, and two co-segregated with NS in two families with a history of the disease (Yamamoto et al. 2015).

Somatic LZTR1 pathogenic variants have been reported in patients with glioblastoma multiforme, a malignant central nervous tumor (Frattini et al. 2013).

In addition to Noonan syndrome, heterozygous germline pathogenic variants have been associated with schwannomatosis-2 (Piotrowski et al. 2014; Smith et al. 2015; Paganini et al. 2015). Schwannomatosis (SWNTS) is the third main type of neurofibromatosis (Plotkin et al. 2013).

The LZTR1 gene encodes for leucine zipper-like transcriptional regulator 1 protein, a member of the BTB-kelch superfamily that has not been previously associated with the RAS/MAPK pathway (Aoki et al. 2016). The mechanism by which LZTR1 pathogenic variants lead to NS is unknown at this time.

Pathogenic variants in LZTR1 were detected in ~ 2.5 % of patients with Noonan syndrome (Yamamoto et al. 2015).

This test provides full coverage of all coding exons of the LZTR1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.