Invitae RASopathies Comprehensive Panel
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
Order test
Primary panel (18 genes)
Customized gene selection (0 included, 0 excluded)
A2ML1 BRAF CBL HRAS KRAS MAP2K1 MAP2K2 NF1 NRAS PTPN11 RAF1 RASA1 RIT1 RRAS SHOC2 SOS1 SOS2 SPRED1
Clinical information
Disorders tested
- 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
Clinical description
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.
| Disorder | Main 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 |
Clinical sensitivity
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.
| Gene | Noonan | NSML | CFC | Costello | Legius | NF1 | CM-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% |
Inheritance
All RASopathy conditions have an autosomal dominant inheritance pattern.
Penetrance
The RASopathies are highly penetrant conditions whose clinical expression is widely variable, even among family members.
Prevalence/Incidence
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.
Considerations for testing
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.
References
- 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
- 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
- Smpokou, P, et al. Malignancy in Noonan syndrome and related disorders. Clin. Genet. 2015; :None. doi: 10.1111/cge.12568. PMID: 25683281
- 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
- Rauen, KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013; 14:355-69. doi: 10.1146/annurev-genom-091212-153523. PMID: 23875798
- 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
- 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
- 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
- Niemeyer, CM. RAS diseases in children. Haematologica. 2014; 99(11):1653-62. doi: 10.3324/haematol.2014.114595. PMID: 25420281
- 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
- Aoki, Y, et al. Recent advances in RASopathies. J. Hum. Genet. 2016; 61(1):33-9. PMID: 26446362
- Yamamoto, GL, et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J. Med. Genet. 2015; :None. PMID: 25795793
- Cordeddu, V, et al. Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome. Hum. Mutat. 2015; :None. PMID: 26173643
Assay
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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
| 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 |
NF1: Sequencing analysis for exons 41, 48 includes only cds +/- 10 bp.
Resources
Clinical resources
Cardiology management guidelines Cardiology requisition form and gene list Invitae brochure Pediatric genetics requisition form and gene list Why is cardiology genetic testing important?References
- 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
- Aoki, Y, et al. Recent advances in RASopathies. J. Hum. Genet. 2016; 61(1):33-9. PMID: 26446362
- 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
- Cordeddu, V, et al. Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome. Hum. Mutat. 2015; :None. PMID: 26173643
- 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
- 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
- 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
- Niemeyer, CM. RAS diseases in children. Haematologica. 2014; 99(11):1653-62. doi: 10.3324/haematol.2014.114595. PMID: 25420281
- 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
- Rauen, KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013; 14:355-69. doi: 10.1146/annurev-genom-091212-153523. PMID: 23875798
- Smpokou, P, et al. Malignancy in Noonan syndrome and related disorders. Clin. Genet. 2015; :None. doi: 10.1111/cge.12568. PMID: 25683281
- 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
- Yamamoto, GL, et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J. Med. Genet. 2015; :None. PMID: 25795793
