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  • Test code: 04161
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
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  1. Test Catalog
  2. Invitae Noonan Syndrome Panel

Invitae Noonan Syndrome Panel

Test description

The Invitae Noonan Syndrome Panel analyzes up to 16 genes that are associated with Noonan syndrome (NS). NS is one of the RASopathies, which are a class of pediatric disorders associated with genes that are members of the mitogen-activated protein kinase (Ras/MAPK) pathway. This 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.

Noonan syndrome is characterized by distinctive facial features, short stature, congenital heart defects (pulmonary valve stenosis), chest deformities, and coagulation and lymphatic deficiencies; however, the RASopathies have several overlapping phenotypic features due to their common underlying Ras/MAPK pathway dysregulation. Distinguishing Noonan syndrome from other phenotypically similar syndromes is important for proper medical management.

Genes tested

Primary panel

A2ML1 BRAF CBL KRAS MAP2K1 MAP2K2 NRAS PTPN11 RAF1 RIT1 RRAS SHOC2 SOS1 SOS2

Add-on Baraitser-Winter Syndrome Gene

ACTB ACTG1

Some clinical features of Noonan syndrome overlap with Baraitser-Winter Cerebrofrontofacial (BWCFF) syndrome, a rare autosomal dominant developmental disorder characterized by multiple congenital anomalies and intellectual disability. If analysis for Baraitser Winter Cerebrofrontofacial syndrome has not been performed previously, adding this panel to this analysis may be considered. This panel can be ordered at no additional cost.

Order test

Primary panel (14 genes)

A2ML1 BRAF CBL KRAS MAP2K1 MAP2K2 NRAS PTPN11 RAF1 RIT1 RRAS SHOC2 SOS1 SOS2

Panel details and technical assay limitations
Add-on Baraitser-Winter Syndrome Gene (2 genes)

Some clinical features of Noonan syndrome overlap with Baraitser-Winter Cerebrofrontofacial (BWCFF) syndrome, a rare autosomal dominant developmental disorder characterized by multiple congenital anomalies and intellectual disability. If analysis for Baraitser Winter Cerebrofrontofacial syndrome has not been performed previously, adding this panel to this analysis may be considered. This panel can be ordered at no additional cost.

ACTB ACTG1

Panel details and technical assay limitations

Alternative tests to consider

Testing for Noonan syndrome is also included in the broader Invitae RASopathies Comprehensive Panel. Depending on the individual’s clinical and family history, this broader panel may be appropriate. This broader panel can be ordered at no additional charge.

Clinical information

  • Noonan syndrome
  • Noonan syndrome with loose anagen hair

Noonan syndrome is a multisystemic pediatric developmental syndrome with variable expressivity. It is a member of a class of disorders known as the RASopathies.

Characteristic clinical features include:

  • distinctive facial dysmorphology that is most pronounced in infancy and childhood (broad forehead, hypertelorism, downslanting palpebral fissures, and low-set and posteriorly rotated ears)
  • short stature during childhood (generally normal birth parameters and less evident in adulthood)
  • chest deformities (superior pectus carinatum with inferior pectus excavatum and widely spaced nipples)
  • congenital heart disease in 50%-80% of patients (commonly pulmonary valve stenosis, hypertrophic cardiomyopathy, and atrial septal defects)
  • visual disturbances (strabismus, nystagmus, myopia, or hyermetropia)

Additional clinical features observed in affected individuals include but are not limited to:

  • webbed neck
  • low posterior hairline
  • light blue-green irises
  • failure to thrive in infancy, sometimes requiring tube feeding
  • thin hair that becomes wooly and curly with age
  • abnormal pigmentation
  • males with uni- or bilateral cryptorchidism (up to 80%)
  • renal anomalies (dilation of renal pelvis)
  • hearing impairments
  • cleft palate
  • delayed psychomotor development with generally normal intelligence (20% risk of intellectual impairment)
  • lymphatic abnormalities
  • cerebrovascular anomalies

Noonan syndrome patients are also at increased risk for hematologic abnormalities, including malignancies. The most common hematologic conditions are coagulopathies and factor deficiencies—platelet defects that occur in about one-third of patients. Malignancies including juvenile myelomonocytic leukemia (JMML), acute myelogenous leukemia (AML), and B-cell acute lymphoblastic leukemia are observed more frequently than in the general population. Rhabdomyosarcoma and neuroblastoma have also been described in individual patients.

Pathogenic variants in PTPN11, SOS1, and RAF1 account for the majority (65%-75%) of clinically diagnosed cases of Noonan syndrome. The remaining genes on this panel account for approximately another 10% of cases. See the table below for details.

GeneProportion of NS attributed to pathogenic variants in this gene
A2ML1 unknown
BRAF <2%
CBL <1%
KRAS <5%
MAP2K1 <2%
MAP2K2 rare
NRAS rare
PTPN11 50%
RAF1 5%-10%
RIT1 <2%
RRAS unknown
SHOC2 <1%
SOS1 10%-15%
SOS2 rare

Noonan syndrome is inherited in an autosomal dominant pattern, although many cases are the result of a spontaneous de novo mutation in a proband. Males and females are affected equally.

Noonan syndrome is a highly penetrant condition whose clinical expression is widely variable. The exact penetrance is unclear as more genes are being implicated in the genetic etiology.

Prevalence is reported as 1 in 1000 to 1 in 2500 individuals, but Noonan syndrome may be underdiagnosed because mild phenotypes can escape detection.

Testing for Noonan syndrome is indicated in any individual with a family history of Noonan syndrome or suspected diagnosis in a proband due to clinical features consistent with Noonan syndrome (see the clinical features list above).

Noonan syndrome testing is also indicated in cases in which the clinical phenotype is consistent with cardio-facio-cutaneous syndrome or Costello syndrome, but previous molecular testing for these conditions is negative.

  1. Niemeyer, CM, et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat. Genet. 2010; 42(9):794-800. doi: 10.1038/ng.641. PMID: 20694012
  2. Roberts, AE, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat. Genet. 2007; 39(1):70-4. doi: 10.1038/ng1926. PMID: 17143285
  3. Verloes, A, et al. Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. Eur. J. Hum. Genet. 2015; 23(3):292-301. PMID: 25052316
  4. Tartaglia, M, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat. Genet. 2001; 29(4):465-8. doi: 10.1038/ng772. PMID: 11704759
  5. Cordeddu, V, et al. Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome. Hum. Mutat. 2015; :None. PMID: 26173643
  6. Yamamoto, GL, et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J. Med. Genet. 2015; :None. PMID: 25795793
  7. Aoki, Y, et al. Recent advances in RASopathies. J. Hum. Genet. 2016; 61(1):33-9. PMID: 26446362
  8. 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
  9. Romano, AA, et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010; 126(4):746-59. doi: 10.1542/peds.2009-3207. PMID: 20876176
  10. Vissers, LE, et al. Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome. Eur. J. Hum. Genet. 2015; 23(3):317-24. doi: 10.1038/ejhg.2014.115. PMID: 24939586
  11. Aoki, Y, et al. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am. J. Hum. Genet. 2013; 93(1):173-80. doi: 10.1016/j.ajhg.2013.05.021. PMID: 23791108
  12. Schubbert, S, et al. Germline KRAS mutations cause Noonan syndrome. Nat. Genet. 2006; 38(3):331-6. doi: 10.1038/ng1748. PMID: 16474405
  13. 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
  14. Di, Donato, N, et al. Severe forms of Baraitser-Winter syndrome are caused by ACTB mutations rather than ACTG1 mutations. Eur. J. Hum. Genet. 2014; 22(2):179-83. PMID: 23756437
  15. Rivière, JB, et al. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat. Genet. 2012; 44(4):440-4, S1-2. PMID: 22366783
  16. Mégarbané, A, et al. Ptosis, down-slanting palpebral fissures, hypertelorism, seizures and mental retardation: a possible new MCA/MR syndrome. Clin. Dysmorphol. 1997; 6(3):239-44. PMID: 9220194
  17. Verloes, A. Iris coloboma, ptosis, hypertelorism, and mental retardation: Baraitser-Winter syndrome or Noonan syndrome?. J. Med. Genet. 1993; 30(5):425-6. PMID: 8320709
  18. Roberts, AE, et al. Noonan syndrome. Lancet. 2013; 381(9863):333-42. doi: 10.1016/S0140-6736(12)61023-X. PMID: 23312968
  19. Tartaglia, M, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat. Genet. 2007; 39(1):75-9. doi: 10.1038/ng1939. PMID: 17143282
  20. Bertola, DR, et al. Further evidence of the importance of RIT1 in Noonan syndrome. Am. J. Med. Genet. A. 2014; 164A(11):2952-7. doi: 10.1002/ajmg.a.36722. PMID: 25124994
  21. Cordeddu, V, et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat. Genet. 2009; 41(9):1022-6. doi: 10.1038/ng.425. PMID: 19684605
  22. Bezniakow, N, et al. The RASopathies as an example of RAS/MAPK pathway disturbances - clinical presentation and molecular pathogenesis of selected syndromes. Dev Period Med. 2014; 18(3):285-96. PMID: 25182392
  23. Cirstea, IC, et al. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat. Genet. 2010; 42(1):27-9. doi: 10.1038/ng.497. PMID: 19966803
  24. Rauen, KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013; 14:355-69. doi: 10.1146/annurev-genom-091212-153523. PMID: 23875798
  25. Pandit, B, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat. Genet. 2007; 39(8):1007-12. doi: 10.1038/ng2073. PMID: 17603483
  26. Martinelli, S, et al. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am. J. Hum. Genet. 2010; 87(2):250-7. doi: 10.1016/j.ajhg.2010.06.015. PMID: 20619386
  27. Razzaque, MA, et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat. Genet. 2007; 39(8):1013-7. doi: 10.1038/ng2078. PMID: 17603482

For management guidelines please refer to:

American Management Guidelines
Romano, AA, et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010; 126(4):746-59.

European Management Guidelines
Noonan Syndrome Guideline Development Group. Management of Noonan syndrome – a clinical guideline (pdf). University of Manchester: DYSCERNE. Accessed July 2015.

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
ACTB NM_001101.3
ACTG1 NM_001614.3
BRAF NM_004333.4
CBL NM_005188.3
KRAS NM_004985.4
MAP2K1 NM_002755.3
MAP2K2 NM_030662.3
NRAS NM_002524.4
PTPN11 NM_002834.3
RAF1 NM_002880.3
RIT1 NM_006912.5
RRAS NM_006270.4
SHOC2 NM_007373.3
SOS1 NM_005633.3
SOS2 NM_006939.2

Clinical resources
Invitae brochure Pediatric genetics gene list
Patient resources
Patient guide: Genetic testing simplified
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. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am. J. Hum. Genet. 2013; 93(1):173-80. doi: 10.1016/j.ajhg.2013.05.021. PMID: 23791108
  3. Aoki, Y, et al. Recent advances in RASopathies. J. Hum. Genet. 2016; 61(1):33-9. PMID: 26446362
  4. Bertola, DR, et al. Further evidence of the importance of RIT1 in Noonan syndrome. Am. J. Med. Genet. A. 2014; 164A(11):2952-7. doi: 10.1002/ajmg.a.36722. PMID: 25124994
  5. Bezniakow, N, et al. The RASopathies as an example of RAS/MAPK pathway disturbances - clinical presentation and molecular pathogenesis of selected syndromes. Dev Period Med. 2014; 18(3):285-96. PMID: 25182392
  6. Cirstea, IC, et al. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat. Genet. 2010; 42(1):27-9. doi: 10.1038/ng.497. PMID: 19966803
  7. Cordeddu, V, et al. Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome. Hum. Mutat. 2015; :None. PMID: 26173643
  8. Cordeddu, V, et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat. Genet. 2009; 41(9):1022-6. doi: 10.1038/ng.425. PMID: 19684605
  9. Di, Donato, N, et al. Severe forms of Baraitser-Winter syndrome are caused by ACTB mutations rather than ACTG1 mutations. Eur. J. Hum. Genet. 2014; 22(2):179-83. PMID: 23756437
  10. 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
  11. Martinelli, S, et al. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am. J. Hum. Genet. 2010; 87(2):250-7. doi: 10.1016/j.ajhg.2010.06.015. PMID: 20619386
  12. Mégarbané, A, et al. Ptosis, down-slanting palpebral fissures, hypertelorism, seizures and mental retardation: a possible new MCA/MR syndrome. Clin. Dysmorphol. 1997; 6(3):239-44. PMID: 9220194
  13. Niemeyer, CM, et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat. Genet. 2010; 42(9):794-800. doi: 10.1038/ng.641. PMID: 20694012
  14. Pandit, B, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat. Genet. 2007; 39(8):1007-12. doi: 10.1038/ng2073. PMID: 17603483
  15. Rauen, KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013; 14:355-69. doi: 10.1146/annurev-genom-091212-153523. PMID: 23875798
  16. Razzaque, MA, et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat. Genet. 2007; 39(8):1013-7. doi: 10.1038/ng2078. PMID: 17603482
  17. Rivière, JB, et al. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat. Genet. 2012; 44(4):440-4, S1-2. PMID: 22366783
  18. Roberts, AE, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat. Genet. 2007; 39(1):70-4. doi: 10.1038/ng1926. PMID: 17143285
  19. Roberts, AE, et al. Noonan syndrome. Lancet. 2013; 381(9863):333-42. doi: 10.1016/S0140-6736(12)61023-X. PMID: 23312968
  20. Romano, AA, et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010; 126(4):746-59. doi: 10.1542/peds.2009-3207. PMID: 20876176
  21. Schubbert, S, et al. Germline KRAS mutations cause Noonan syndrome. Nat. Genet. 2006; 38(3):331-6. doi: 10.1038/ng1748. PMID: 16474405
  22. Tartaglia, M, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat. Genet. 2007; 39(1):75-9. doi: 10.1038/ng1939. PMID: 17143282
  23. Tartaglia, M, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat. Genet. 2001; 29(4):465-8. doi: 10.1038/ng772. PMID: 11704759
  24. Verloes, A, et al. Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. Eur. J. Hum. Genet. 2015; 23(3):292-301. PMID: 25052316
  25. Verloes, A. Iris coloboma, ptosis, hypertelorism, and mental retardation: Baraitser-Winter syndrome or Noonan syndrome?. J. Med. Genet. 1993; 30(5):425-6. PMID: 8320709
  26. Vissers, LE, et al. Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome. Eur. J. Hum. Genet. 2015; 23(3):317-24. doi: 10.1038/ejhg.2014.115. PMID: 24939586
  27. 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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