PTPN11-Related Disorders via the PTPN11 Gene

Noonan syndrome (NS, OMIM 163950) 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 lymphatic findings. 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 OMIM 607785). The prevalence of NS is estimated at 1 in 1000-2500 births worldwide (Allanson et al. Am J Med Genet 21:507-514, 1985; Romano et al. Pediatrics 126:746-759, 2010).

LEOPARD syndrome (multiple lentigines, electrocardiographic-conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, sensorineural deafness, OMIM 151100) is a rare congenital developmental disorder characterized by skin pigmentation anomalies including multiple lentigines and café au lait spots, hypertrophic cardiomyopathy, pulmonary valve stenosis, and deafness. Other less common features include short stature, mild mental retardation, and abnormal genitalia (Legius et al. J Med Genet 39:571-574, 2002; Sarkozy et al. J Med Genet 41:e68, 2004; see also Gelb and Tartaglia, GeneReviews, 2010).

Metachondromatosis (MC OMIM 156250) is a rare skeletal dysplasia characterized by multiple exostoses mainly in the hands and feet. Additional features include enchondromas of the iliac crest and metaphyseal region of the long bones of the lower extremities and periarticular calcifications. The exostoses may result in peroneal-nerve symptoms, which are relieved by surgery. The original exostoses may regress spontaneously with age, while new ones may develop. Although skeletal radiological findings of MC resemble those of multiple enchondromatosis (OMIM 166000), the two conditions can be easily distinguished. In MC, the exostoses point toward the nearby joints. In addition, they do not result in shortening of affected long bones, bowing, joint deformity, or joint dislocation, as is the case in multiple enchondromatosis (Kennedy Radiology 48:117-118, 1983; Bassett et al. J Bone Joint Surg Am 67:811-814, 1985).

Noonan syndrome (NS) is caused by gain of function variants in various genes within the RAS/MAPK pathway, including PTPN11. These variants appear to activate the gene product (SHP2 protein). To date, seven RAS/MAPK genes (PTPN11, SOS1, RAF1, KRAS, SHOC2, BRAF, and NRAS) have been associated with NS. PTPN11 variants are the most common cause of NS, and account for ~ 50% of all cases genotyped (Allanson and Roberts, GeneReviews, 2011). Over 70 variants were reported. Most causative variants are missense. A few small deletion or insertion variants have been reported (Tartaglia et al. Am J Hum Genet 78:279-290, 2006). Except for two large genomic duplications that included the entire PTPN11 gene (Shchelochkov et al. Am J Med Genet 146A:1042-1048, 2008; Graham et al. Am J Med Genet 149A:2122-2128, 2009), no gross defects or rearrangements in PTPN11 have been reported in patients with NS. Although de novo variants are found in a substantial fraction of patients, familial cases have been reported. In these families, NS is inherited in an autosomal dominant manner with variable expressivity (Romano et al. Pediatrics 126:746-759, 2010).

Genotype-phenotype correlations are slowly being made. In particular, several groups have shown that pulmonary stenosis is more common in NS patients with PTPN11 variants, while hypertrophic cardiomyopathy is more common in patients without PTPN11 variants (Romano et al. 2010).

LEOPARD syndrome is caused by defects in three genes within the RAS/MAPK: PTPN11, RAF1 and BRAF (Digilio et al. Am J Hum Genet 71:389-394, 2002; Pandit et al. Nat Genet 39:1007-1012, 2007; Sarkozy et al. Hum Mutat 30:695-702, 2009). Unlike NS, LEOPARD syndrome variants act through a dominant negative effect, which appears to disrupt the function of the wild-type gene product (SHP2 protein) (Jopling et al. PLOS Genetics 3:e225, 2007). Ten different PTPN11 variants, all missense, have been reported in patients with LEOPARD. PTPN11 variants are the most common cause of LEOPARD syndrome, and account for over 90% of all cases genotyped. Parents of patients with LEOPARD syndrome are often asymptomatic, and de novo variants are common. However, familial cases have been reported. In these families, affected relatives are diagnosed only after the birth of a visibly affected child, and the disease is transmitted in an autosomal dominant manner with variable penetrance and expressivity (Gelb and Tartaglia, GeneReviews, 2010). Genotype-phenotype correlations have been proposed (see for example Limongelli et al. Am J Med Genet A 146:620-628, 2008).

Metachondromatosis (MC) is caused by loss-of-function variants in PTPN11. Recently, 13 heterozygous PTPN11 variants were reported. At this time, PTPN11 variants are the only known cause of MC. Variants were found in ~ 60% if the MC families that have been studied, suggesting that PTPN11 variants are a common cause of the disorder and that MC is genetically heterogeneous (Sobreira et al. PLoS Genet 6:e1000991, 2010; Bowen et al. PLoS Genet 7:e1002050, 2011). Variants are distributed along the entire coding region of the gene and include missense, splicing, small deletions, and complex rearrangements. MC is inherited in an autosomal dominant manner with incomplete penetrance.

Somatic PTPN11 variants account for ~ 34% of non-syndromic juvenile myelomonocytic leukemia (JMML) (Tartaglia et al. Nat Genet 34:148-150, 2003).

This test will detect causative variants in ~50% of NS patients, ~90% of LS patients, and ~60% of MC patients.

This test provides full coverage of all coding exons of the PTPN11 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.