Noonan Syndrome via the RIT1 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8585 RIT1 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8585RIT181479 81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

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 OMIM 607785). 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).

Genetics

NS is caused by gain of function mutations in various genes within the RAS/MAPK pathway, including RIT1. Several RAS/MAPK genes (PTPN11, SOS1, RAF1, KRAS, SHOC2, BRAF, NRAS, MAP2K1 and CBL) have been involved in NS. Recently, nine different pathogenic missense variants in the RIT1 gene were reported in 17 patients affected with NS or a related disorder without detectable mutations in the remaining Noonan-related genes. Perinatal and neonatal abnormalities were found in nine patients and include polyhydramnios, nuchal translucency, placental abruption, pleural effusion, and chylothorax. Features characteristic of cardiofaciocutaneous syndrome (CFCS), including sparse and curly hair and a high cranial vault, were detected in two patients who were initially diagnosed with CFCS. The remaining patients have features characteristic of NS. Although pathogenic variants occurred apparently de novo in most cases where parental testing was performed, one patient inherited the variant from the affected mother (Aoki et al., 2013).

Somatic RIT1 mutations have been reported in several cancers (http://cancer.sanger.ac.uk/cosmic). Lymphoblastic leukemia occurred in one of the 17 patients described by Aoki et al.

Clinical Sensitivity - Sequencing with CNV PG-Select

Pathogenic variants in RIT1 were detected in ~ 9% of NS patients without detectable pathogenic variants in the remaining Noonan-related genes (Aoki et al., 2013).

Testing Strategy

This test provides full coverage of all coding exons of the RIT1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Candidates for this test are patients with a clinical diagnosis of NS without PTPN11 or SOS1 mutations. Symptoms of NS patients overlap with those for Cardio-Facio-Cutaneous Syndrome (CFCS) and Costello Syndrome (CS) patients. NS patients who test negative for mutations in (PTPN11, SOS1, RIT1, RAF1, KRAS, SHOC2, BRAF, NRAS, CLB, and KAT6B may be candidates for CFCS (MAP2K1 and MAP2K2 genes) or CS (HRAS gene) testing. Conversely, CFCS or CS Syndrome patients who test negative for BRAF, MAP2K1, MAP2K2 and KRAS genes or HRAS, respectively, may be candidates for all or a portion of our NS testing.

Gene

Official Gene Symbol OMIM ID
RIT1 609591
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Noonan Syndrome 8 AD 615355

Related Test

Name
Fetal Concerns Panel

Citations

  • Allanson JE, Hall JG, Hughes HE, Preus M, Witt RD. 1985. Noonan syndrome: the changing phenotype. Am. J. Med. Genet. 21: 507-514. PubMed ID: 4025385
  • Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, Takada F, Yano M, Ando T, Hoshika T, Barnett C, Ohashi H, Kawame H, Hasegawa T, Okutani T, Nagashima T, Hasegawa S, Funayama R, Nagashima T, Nakayama K, Inoue S, Watanabe Y, Ogura T, Matsubara Y. 2013. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am. J. Hum. Genet. 93:173-180.
    PubMed ID: 23791108
  • COSMIC: Catalogue of Somatic Mutations in Cancer. Wellcome Trust Sanger Institute, Genome Research Limited.
  • Nisbet DL, Griffin DR, Chitty LS. 1999. Prenatal features of Noonan syndrome. Prenat. Diagn. 19:642-647. PubMed ID: 10419612.
  • Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. 2010. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics 126: 746-759. PubMed ID: 20876176
  • van der Burgt I 2007. Noonan syndrome. Orphanet J. Rare Dis. 2:4. PubMed ID: 17222357

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

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