Noonan Spectrum Disorders/RASopathies Panel

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesCPT Code Copy CPT Codes
1309 A2ML1 81479,81479 Add to Order
BRAF 81406,81479
CBL 81479,81479
HRAS 81404,81479
KRAS 81405,81479
LZTR1 81479,81479
MAP2K1 81406,81479
MAP2K2 81406,81479
MAP3K8 81479,81479
NF1 81408,81479
NRAS 81479,81479
PTPN11 81406,81479
RAF1 81406,81479
RASA2 81479,81479
RIT1 81479,81479
RRAS 81479,81479
SHOC2 81405,81479
SOS1 81406,81479
SOS2 81479,81479
SPRY1 81479,81479
Full Panel Price* $640
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
1309 Genes x (20) $640 81404, 81405(x2), 81406(x6), 81408, 81479(x30) Add to Order

Pricing Comments

CPT code 81442 can be used if analysis includes BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, RIT1, SHOC2, and SOS1.

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available.

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.

Deletion and duplication testing for NF1 is performed using NGS, but CNVs detected in this gene are usually confirmed via multiplex ligation-dependent probe amplification (MLPA). Please see limitations for CNV detection via NGS.

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

The Noonan Spectrum Disorders, also known as RASopathies, are a group of developmental syndromes characterized by extensive clinical and genetic heterogeneity. They include:

1- Noonan syndrome

2- Cardiofaciocutaneous syndrome

3- Noonan syndrome with multiple lentigines, previously known as LEOPARD syndrome

4- Costello syndrome

Although there is a considerable phenotypic overlap among the various syndromes, each syndrome is characterized by distinct clinical features.

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).

Cardio-Facio-Cutaneous Syndrome (CFCS) is characterized by distinctive facial appearance, congenital cardiac and ectodermal abnormalities, postnatal growth failure, feeding difficulties with failure to thrive and neurological findings. Facial features include high forehead, short, upturned nose with a low nasal bridge, prominent external ears that are posteriorly angulated and ocular hypertelorism. The most common cardiac abnormalities include pulmonic stenosis and atrial septal defects. Ectodermal abnormalities are heterogeneous in features and severity. They include café au lait spots, erythema, keratosis, ichthyosis, eczema, sparse and brittle hair, and nail dystrophy. The neurological findings include seizures, hypotonia, macrocephaly and various degrees of mental and cognitive delay (Reynolds et al. 1986. PubMed ID: 3789005).

Noonan syndrome with multiple lentigines (NSML), previously known as LEOPARD syndrome (multiple Lentigines, Electrocardiographic-conduction abnormalities, Ocular hyperterlorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness) is 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. 2002. PubMed ID: 12161596; Sarkozy et al. 2004. PubMed ID: 15121796).

Costello Syndrome (CS) is characterized by coarse facial features with wide forehead, depressed nasal bridge and full cheeks; thick and loose skin of the hands and feet; papillomata; heart defects, mainly pulmonary valve stenosis, rhythm disturbances and hypertrophic cardiomyopathy; increased growth at the prenatal stage followed by postnatal growth retardation; short stature; relative macrocephaly and mild to moderate mental retardation (van Eeghen et al. 1999. PubMed ID: 9934987; Lin et al. 2002. PubMed ID: 12210337). Patients with CS are at risk of developing benign and malignant tumors, most commonly rhabdomyosarcoma. Neuroblastoma and bladder carcinoma have also been reported (Gripp et al. 2006. PubMed ID: 16969868).

Genetics

Noonan spectrum disorders are caused by dysregulation of the RAS/mitogen-activated protein kinase (Ras/MAPK) signaling pathway (Tidyman and Rauen. 2009. PubMed ID: 19467855; Wright and Kerr. 2010. PubMed ID: 20371595; Allanson and Roberts. 2016. PubMedID: 20301303).

Heterozygous germline pathogenic variants in the following genes have been reported in patients with Noonan spectrum disorders: PTPN11, SOS1, SOS2, RAF1, KRAS, HRAS, SHOC2, BRAF, NRAS, MAP2K1, MAP2K1, MAP3K8, A2ML1, RASA2, RRAS, SPRY1, NF1, CBL, RIT1, and LZTR1 (Rauen. 2013. PubMed ID: 23875798; Martinelli et al. 2010. PubMed ID: 20619386; Niemeyer et al. 2010. PubMed ID: 20694012; Aoki et al. 2013. PubMed ID: 23791108; Vissers et al. 2015. PubMed ID: 24939586).

Noonan and Noonan-like syndromes are caused by pathogenic variants in PTPN11, SOS1, RAF1, KRAS, SHOC2, BRAF, NRAS, CBL, RIT1, SOS2, LZTR1, A2ML1, MAP3K8, RASA2, RRAS, SPRY1, and NF1. Over 330 pathogenic variants have been reported in these genes. They account for up to 80% of all cases genotyped (Romano et al. 2010. PubMed ID: 20876176; Tartaglia et al. 2010. PubMed ID: 20648242; Aoki et al. 2013. PubMed ID: 23791108; Chen. 2014. PubMed ID: 25049390; Cordeddu. 2015. PubMed ID: 26173643; Yamamoto et al. 2015. PubMed ID: 25795793). The vast majority are missense, although a few small deletions or insertions, and indels have been reported, which are all predicted to result in in-frame alterations of the translated protein. To date, three large genomic duplications have been reported in patients with clinical features suggestive of NS. Two of these duplications include the PTPN11, TBX3 and TBX5 genes (Shchelochkov et al. 2008. PubMed ID: 18348260; Graham et al. 2009. PubMed ID: 19760651), while the third includes PTPN11 and TBX3 only (Chen et al. 2014. PubMed ID: 24739123). These three duplications occurred de novo and represent an uncommon cause of NS (Tartaglia et al. 2010. PubMed ID: 20648242).

Although most causative NS pathogenic variants occur de novo, familial cases have been reported. In these families, NS is inherited in an autosomal dominant manner with complete penetrance and variable expressivity (Romano et al. 2010. PubMed ID: 20876176).

CFCS is caused by defects in the following RAS/MAPK genes: BRAF, HRAS, KRAS, MAP2K1, MAP2K2, and NRAS. To date, over 100 heterozygous pathogenic variants have been detected (Rodriguez-Viciana et al. 2006. PubMed ID: 16439621; Niihori et al. 2006. PubMed ID: 16474404; Schubbert et al. 2006. PubMed ID: 16474405; Tumurkhuu et al. 2010. PubMed ID: 20030748; Narumi et al. 2008. PubMed ID: 18651097). The vast majority of variants have been reported in the HRAS gene. They affect codons Gly12 and Gly13. Although most CFCS causative variants are missense, small deletions and duplications have been documented. These are all predicted to result in in-frame alterations of the translated protein. More recently, four different indels that are predicted to result in substitutions of codon Gly12 have been identified in patients with Costello syndrome. No complex rearrangements have been reported. Most patients with CFCS do not reproduce. With one exception, all causative variants reported to date occurred de novo. The exception consists of a familial c.383C>A (p.Pro128Gln) variant in the MAP2K2 gene that was shown to be transmitted through four generations (Rauen et al. 2010. PubMed ID: 20358587). In this family, CFCS is inherited in an autosomal dominant manner.

NSML, previously known as LEOPARD syndrome is caused by defects in PTPN11 and RAF1 (Digilio et al. 2006. PubMed ID: 16733669; Pandit et al. 2007. PubMed ID: 17603483). NSML-causative variants in the PTPN11 gene act through a dominant negative effect, which appears to disrupt the function of the wild-type gene product (SHP2 protein) (Jopling et al. 2007. PubMed ID: 18159945). PTPN11 pathogenic variants are the most common cause of NSML and account for over 90% of all cases genotyped. Ten different PTPN11 pathogenic variants, all missense, have been reported in patients with NSML (Human Gene Mutation Database). RAF1 pathogenic variants appear to be a rare cause of NSML. Parents of NSML patients are often asymptomatic, and de novo pathogenic 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. 2006. PubMed ID: 16987887).

CS syndrome is caused by pathogenic variants in the HRAS gene (Aoki et al. 2005. PubMed ID: 16170316). To date, 20 heterozygous activating germline variants have been reported in patients with clinical features of CS. Most of these are missense. A few indels, which are expected to result in amino acid substitutions; and a 21-bp duplication that is predicted to result in an inframe insertion of seven residues was reported in a patient with mild clinical features suggestive of CS (Lorenz et al. 2013. PubMed ID: 23335589). The majority of variants affect codons G12 and G13. However, variants affecting other codons have been reported. Most CS cases are sporadic resulting from de novo HRAS pathogenic variants.

Somatic mosaicism has been reported for several RAS/MAPK genes. Non-syndromic Juvenile Myelomonocytic Leukemia (JMML) involves somatic PTPN11 pathogenic variants in about 34% of all cases genotyped (Tartaglia et al. 2003. PubMed ID: 12717436). Somatic RAF1 pathogenic variants have been implicated in several human cancers (Pandit et al. 2007. PubMed ID: 17603483; Sarkozy et al. 2009. PubMed ID: 19206169). Somatic KRAS pathogenic variants have been implicated in several human cancers, including JMML (Reimann et al. 2006. PubMed ID: 16826224) and colon cancer (Edkins et al. 2006. PubMed ID: 16969076). Somatic NRAS pathogenic variants were detected in patients with JMML (Flotho et al. 1999. PubMed ID: 10049057). Somatic recurrent MAP2K1 pathogenic variants have been implicated in several human cancers including melanoma (Nikolaev et al. 2011. PubMed ID: 22197931). Somatic HRAS pathogenic variants have been reported in patients with Costello syndrome (Gripp et al. 2006. PubMed ID: 16329078; Sol-Church et al. 2009. PubMed ID: 19206176).

Testing Strategy

This panel provides 100% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

Deletion and duplication testing for NF1 is performed using NGS, but CNVs detected in this gene are usually confirmed via multiplex ligation-dependent probe amplification (MLPA). Please see limitations for CNV detection via NGS.

Clinical Sensitivity - Sequencing and CNV

Clinical Sensitivity for Noonan Syndrome (Aoki et al. 2016. PubMed ID: 26446362)

Gene Sensitivity (%)
PTPN11 50
SOS1 11
RAF1 5
KRAS 1.5
SHOC2 2
BRAF 0.8
NRAS 0.2
RIT1 5
CBL Rare
LZTR1 2.5
SOS2 1
NF1 Rare
A2ML1 3 cases
RASA2 3 cases
RRAS 2 cases
MAP3K8 One case
SPRY1 One case

Clinical Sensitivity for CFC Syndrome (Rauen et al. 2016. PubMed ID: 20301365)

Gene Sensitivity (%)
BRAF 75
MAP2K1 12.5
MAP2K2 12.5
KRAS < 2%
SOS1 Rare

Clinical Sensitivity for NSML/LEOPARD Syndrome: ~90% (PTPN11, RAF1) (Gelb and Tartaglia 2015. PubMed ID: 20301557)

Clinical Sensitivity Costello Syndrome: ~ 80-90% (HRAS) (Gripp and Lin 2012. PubMed ID: 20301680)

Sensitivity corresponds to the percentage of all genotyped patients with a clinical diagnosis of the listed phenotype, except for RIT1, where sensitivity corresponds to the percentage of patients with no detectable pathogenic variants in the remaining Noonan-associated genes.

Only two large genomic duplications that span the PTPN11, TBX3 and TBX5 genes have been reported in patients with NS clinical features (Shchelochkov et al. 2008. PubMed ID: 18348260; Graham et al. 2009. PubMed ID: 19760651). The frequency of these duplications is currently unknown, but appears to be quite low.

Indications for Test

Candidates for this NGS RASopathies panel are: patients with clinical features suggestive of Noonan syndrome, Cardio-Facio-Cutaneous Syndrome, or Noonan syndrome with multiple lentigines, also known as LEOPARD syndrome, patients with a clinical diagnosis of these syndromes that previously tested negative in a subset of genes included in this panel, patients with a clinical diagnosis of Costello syndrome and no pathogenic variants in HRAS, and patients with Noonan syndrome-like clinical features.

Genes

Official Gene Symbol OMIM ID
A2ML1 610627
BRAF 164757
CBL 165360
HRAS 190020
KRAS 190070
LZTR1 600574
MAP2K1 176872
MAP2K2 601263
MAP3K8 191195
NF1 613113
NRAS 164790
PTPN11 176876
RAF1 164760
RASA2 601589
RIT1 609591
RRAS 165090
SHOC2 602775
SOS1 182530
SOS2 601247
SPRY1 602465
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
PGxome®
BRAF-Related Disorders via the BRAF Gene
PTPN11-Related Disorders via the PTPN11 Gene
RAF1-Related Disorders via the RAF1 Gene
Cardio-Facio-Cutaneous Syndrome via the MAP2K1 Gene
Noonan Syndrome via the SOS1 Gene

Citations

  • Allanson and Roberts. 2016. PubMed ID: 20301303
  • Allanson. 1987. PubMed ID: 3543368
  • Aoki et al. 2005. PubMed ID: 16170316
  • Aoki et al. 2013. PubMed ID: 23791108
  • Aoki et al. 2016. PubMed ID: 26446362
  • Cao et al. 2017. PubMed ID: 28643916
  • Chen et al. 2014. PubMed ID: 24739123
  • Chen et al. 2014. PubMed ID: 25049390
  • Cordeddu et al. 2015. PubMed ID: 26173643
  • Digilio et al. 2006. PubMed ID: 16733669
  • Edkins et al. 2006. PubMed ID: 16969076
  • Flotho et al. 1999. PubMed ID: 10049057
  • Gelb and Tartaglia. 2006. PubMed ID: 16987887
  • Gelb and Tartaglia. 2015. PubMed ID: 20301557
  • Graham et al. 2009. PubMed ID: 19760651
  • Gripp and Lin. 2012. PubMed ID: 20301680
  • Gripp et al. 2006. PubMed ID: 16329078
  • Gripp et al. 2006. PubMed ID: 16969868
  • Human Gene Mutation Database (Bio-base).
  • Jopling et al. 2007. PubMed ID: 18159945
  • Legius et al. 2002. PubMed ID: 12161596
  • Lin et al. 2002. PubMed ID: 12210337
  • Lorenz et al. 2013. PubMed ID: 23335589
  • Martinelli et al. 2010. PubMed ID: 20619386
  • Narumi et al. 2008. PubMed ID: 18651097
  • Niemeyer et al. 2010. PubMed ID: 20694012
  • Niihori et al. 2006. PubMed ID: 16474404
  • Nikolaev et al. 2011. PubMed ID: 22197931
  • Pandit et al. 2007. PubMed ID: 17603483
  • Rauen et al. 2010. PubMed ID: 20358587
  • Rauen. 2013. PubMed ID: 23875798
  • Rauen. 2016. PubMed ID: 20301365
  • Reimann et al. 2006. PubMed ID: 16826224
  • Reynolds et al. 1986. PubMed ID: 3789005
  • Rodriguez-Viciana et al. 2006. PubMed ID: 16439621
  • Romano et al. 2010. PubMed ID: 20876176
  • Sarkozy et al. 2004. PubMed ID: 15121796
  • Sarkozy et al. 2009. PubMed ID: 19206169
  • Schubbert et al. 2006. PubMed ID: 16474405
  • Shchelochkov et al. 2008. PubMed ID: 18348260
  • Smpokou et al. 2012. PubMed ID: 23165751
  • Sol-Church et al. 2009. PubMed ID: 19206176
  • Tartaglia et al. 2003. PubMed ID: 12717436
  • Tartaglia et al. 2010. PubMed ID: 20648242
  • Tidyman and Rauen. 2009. PubMed ID: 19467855
  • Tumurkhuu et al. 2010. PubMed ID: 20030748
  • van Eeghen et al. 1999. PubMed ID: 9934987
  • Vissers et al. 2015. PubMed ID: 24939586
  • Wright and Kerr. 2010. PubMed ID: 20371595
  • Yamamoto et al. 2015. PubMed ID: 25795793

Ordering/Specimens

Ordering Options

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.

Specimen Types

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