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Invitae RASopathies Comprehensive Panel

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  2. Invitae RASopathies Comprehensive Panel
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  • Test code: 04151
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Overview

Test description

The Invitae RASopathies Comprehensive Panel analyzes 18 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). RASopathies are a class of pediatric disorders whose spectrum of symptoms include distinctive facial features, heart defects, developmental delay, and an increased risk of malignancies.

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.

Genes tested

A2ML1 BRAF CBL HRAS KRAS MAP2K1 MAP2K2 NF1 NRAS PTPN11 RAF1 RASA1 RIT1 RRAS SHOC2 SOS1 SOS2 SPRED1

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Primary panel (18 genes)

A2ML1 BRAF CBL HRAS KRAS MAP2K1 MAP2K2 NF1 NRAS PTPN11 RAF1 RASA1 RIT1 RRAS SHOC2 SOS1 SOS2 SPRED1

Clinical information

  • 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.

GeneNoonanNSMLCFCCostelloLegiusNF1CM-AVM
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%
RRAS unknown
SHOC2 <1% unknown
SOS1 10%-15% unknown
SOS2 rare
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: http://www.ncbi.nlm.nih.gov/books/NBK1124/ PMID: 20301303
  2. Aoki, Y, et al. Recent advances in RASopathies. J. Hum. Genet. 2016; 61(1):33-9. PMID: 26446362
  3. 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
  4. Cordeddu, V, et al. Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome. Hum. Mutat. 2015; :None. PMID: 26173643
  5. 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
  6. Flex, E, et al. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. Hum. Mol. Genet. 2014; 23(16):4315-27. PMID: 24705357
  7. 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
  8. Niemeyer, CM. RAS diseases in children. Haematologica. 2014; 99(11):1653-62. doi: 10.3324/haematol.2014.114595. PMID: 25420281
  9. 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
  10. Rauen, KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013; 14:355-69. doi: 10.1146/annurev-genom-091212-153523. PMID: 23875798
  11. Smpokou, P, et al. Malignancy in Noonan syndrome and related disorders. Clin. Genet. 2015; :None. doi: 10.1111/cge.12568. PMID: 25683281
  12. 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
  13. Yamamoto, GL, et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J. Med. Genet. 2015; :None. PMID: 25795793

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
RRAS NM_006270.4
SHOC2 NM_007373.3
SOS1 NM_005633.3
SOS2 NM_006939.2
SPRED1 NM_152594.2

Clinical resources
Cardiology gene list Cardiology management guidelines Invitae brochure Pediatric genetics gene list Why is cardiology genetic testing important?
Patient resources
Patient guide: Genetic testing simplified Patient guide: Hereditary heart conditions
Test information
Forms page Specimen requirements page

References

  1. Allanson, JE, Roberts, AE. Noonan Syndrome. 2001 Nov 15. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1124/ PMID: 20301303
  2. Aoki, Y, et al. Recent advances in RASopathies. J. Hum. Genet. 2016; 61(1):33-9. PMID: 26446362
  3. 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
  4. Cordeddu, V, et al. Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome. Hum. Mutat. 2015; :None. PMID: 26173643
  5. 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
  6. Flex, E, et al. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. Hum. Mol. Genet. 2014; 23(16):4315-27. PMID: 24705357
  7. 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
  8. Niemeyer, CM. RAS diseases in children. Haematologica. 2014; 99(11):1653-62. doi: 10.3324/haematol.2014.114595. PMID: 25420281
  9. 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
  10. Rauen, KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013; 14:355-69. doi: 10.1146/annurev-genom-091212-153523. PMID: 23875798
  11. Smpokou, P, et al. Malignancy in Noonan syndrome and related disorders. Clin. Genet. 2015; :None. doi: 10.1111/cge.12568. PMID: 25683281
  12. 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
  13. Yamamoto, GL, et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J. Med. Genet. 2015; :None. PMID: 25795793

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