Invitae RASopathies Comprehensive Panel


Test description

The Invitae RASopathies Comprehensive Panel analyzes 16 genes that are members of the mitogen-activated protein kinase (Ras/MAPK) pathway, which is associated with a class of pediatric disorders termed “RASopathies” (also known as Noonan Spectrum Disorders). These disorders include:

  • capillary malformation–arteriovenous malformation (CM-AVM) syndrome
  • cardio-facio-cutaneous (CFC) syndrome
  • Costello syndrome
  • Legius syndrome
  • neurofibromatosis type 1 (NF1)
  • Noonan syndrome
  • Noonan syndrome with multiple lentigines (NSML)

The Ras/MAPK pathway is involved in a signal transduction cascade that is necessary for the proper formation of several types of tissue during embryonic and postnatal development. The RASopathies have several overlapping phenotypic features due to their common underlying Ras/MAPK pathway dysregulation; these features include distinctive facial characteristics, cardiac defects, cutaneous abnormalities, neurocognitive delay, and a predisposition to malignancies.

The RASopathies are multisystemic disorders whose expression is highly variable, even among family members. Many of the clinical features that can differentiate RASopathy conditions from each other manifest later in childhood or change with age, making accurate clinical diagnosis difficult. The phenotypes of many RASopathy conditions are expanding: Individuals are being discovered with a molecular genetic finding in a RASopathy gene but clinical findings that are not typically described in the specific condition associated with that gene. Additionally, some genes are associated with more than one RASopathy syndrome.

Proper management by specialists across a variety of disciplines is critical because it is essential that the different disorders be correctly identified and appropriately managed. The Invitae RASopathies Comprehensive panel provides a comprehensive approach to testing individuals who have features that fall within the RASopathies spectrum.

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Primary panel (16 genes)


  • capillary malformation-arteriovenous malformation syndrome (CM-AVM)
  • cardio-facio-cutaneous syndrome (CFC)
  • Costello syndrome
  • Legius syndrome
  • Neurofibromatosis type 1 (NF1)
  • Noonan syndrome
  • Noonan syndrome with multiple lentigines (NSML, formerly known as LEOPARD syndrome)

RASopathies are a class of pediatric developmental disorders that share a common spectrum of symptoms, including congenital heart defects, short stature, distinctive craniofacial features, cutaneous abnormalities affecting the skin and hair, varying degrees of developmental delay, and development of tumors, both benign and cancerous. Additional information about each disorder is available by following the links below to their respective condition’s page.

DisorderMain clinical features
Noonan syndrome Characteristic facial features, short stature, congenital heart defects (pulmonary valve stenosis), chest deformities, coagulation and lymphatic deficiencies
Noonan syndrome with multiple lentigines (formerly known as LEOPARD syndrome)Lentigines and café-au-lait macules, hearing loss, congenital heart defects (pulmonary valve stenosis), short stature, increased risk of malignancies
Cardio-facio-cutaneous syndrome Failure to thrive and feeding difficulties, congenital heart defects, characteristic facial features, curly sparse hair and skin rashes, neurologic complications (e.g., hypotonia, motor delay), developmental delay
Costello syndrome Coarse facial features, congenital heart defects, failure to thrive and feeding difficulties, developmental delay and intellectual disability, deep palmar and plantar creases, increased risk of malignancies
Legius syndrome Café-au-lait macules, axillary and inguinal freckling, macrocephaly, lipomas
Neurofibromatosis type 1 Café-au-lait macules, axillary and inguinal freckling, neurofibromas, short stature, macrocephaly
Capillary malformation-arteriovenous malformation syndrome Capillary malformations

The clinical sensitivity of this test is dependent on the patient’s underlying genetic condition. For each condition, the chart below shows the percentage of clinical cases in which a pathogenic variant is expected to be identified through analysis of the genes on this panel.

A2ML1 unknown
BRAF <2% rare 75%
CBL <1%
HRAS 80%-90%
KRAS <5% <2%
MAP2K1 <2% 10%-15%
MAP2K2 rare 10%-15%
NF1 ~95%
NRAS rare
PTPN11 50% 90%
RAF1 5%-10% 5%
RASA1 ~70%
RIT1 <2%
SHOC2 <1% unknown
SOS1 10%-15% unknown
SPRED1 >99%

All RASopathy conditions have an autosomal dominant inheritance pattern.

The RASopathies are highly penetrant conditions whose clinical expression is widely variable, even among family members.

The RASopathies represent one of the largest groups of genetic syndromes, with incidences ranging from a few hundred cases worldwide to approximately 1 in 1,000 individuals.

Estimated prevalence for each syndrome is:

  • Noonan syndrome: 1 in 1000 to 1 in 2500
  • NF1: 1 in 3000
  • CFC: ~1 in 810,000 to 1 in 150,000
  • CM-AVM: ~1 in 100,000
  • Noonan syndrome with multiple lentigines (NSML), Costello syndrome, and Legius syndrome are reportedly rare and their prevalence is currently unknown.

This test may be considered for individuals with:

  • a clinical diagnosis or suspicion of any of the RASopathy disorders
  • a family history of a RASopathy disorder
  • features that are consistent with a RASopathy disorder and negative results from previous molecular testing of select genes

Clinical findings suggestive of RASopathies include short stature, congenital heart defects, developmental delay, broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, characteristic facies, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities.

  1. Allanson, JE, Roberts, AE. Noonan Syndrome. 2001 Nov 15. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: PMID: 20301303
  2. Cizmarova, M, et al. Rasopathies - dysmorphic syndromes with short stature and risk of malignancy. Endocr Regul. 2013; 47(4):217-22. doi: 10.4149/endo_2013_04_217. PMID: 24156711
  3. Digilio, MC, et al. RASopathies: Clinical Diagnosis in the First Year of Life. Mol Syndromol. 2011; 1(6):282-289. doi: 10.1159/000331266. PMID: 22190897
  4. Kratz, CP, et al. Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes. Br. J. Cancer. 2015; 112(8):1392-7. doi: 10.1038/bjc.2015.75. PMID: 25742478
  5. Niemeyer, CM. RAS diseases in children. Haematologica. 2014; 99(11):1653-62. doi: 10.3324/haematol.2014.114595. PMID: 25420281
  6. Rauen, KA, et al. Recent developments in neurofibromatoses and RASopathies: management, diagnosis and current and future therapeutic avenues. Am. J. Med. Genet. A. 2015; 167A(1):1-10. doi: 10.1002/ajmg.a.36793. PMID: 25393061
  7. Rauen, KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013; 14:355-69. doi: 10.1146/annurev-genom-091212-153523. PMID: 23875798
  8. Smpokou, P, et al. Malignancy in Noonan syndrome and related disorders. Clin. Genet. 2015; :None. doi: 10.1111/cge.12568. PMID: 25683281
  9. Tidyman, WE, Rauen, KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr. Opin. Genet. Dev. 2009; 19(3):230-6. doi: 10.1016/j.gde.2009.04.001. PMID: 19467855

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
A2ML1 NM_144670.4
BRAF NM_004333.4
CBL NM_005188.3
HRAS NM_005343.2
KRAS NM_004985.4
MAP2K1 NM_002755.3
MAP2K2 NM_030662.3
NF1 NM_000267.3
NRAS NM_002524.4
PTPN11 NM_002834.3
RAF1 NM_002880.3
RASA1 NM_002890.2
RIT1 NM_006912.5
SHOC2 NM_007373.3
SOS1 NM_005633.3
SPRED1 NM_152594.2