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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 tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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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.

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Primary panel (14 genes)

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

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

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.

  • 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. 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. 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
  3. Roberts, AE, et al. Noonan syndrome. Lancet. 2013; 381(9863):333-42. doi: 10.1016/S0140-6736(12)61023-X. PMID: 23312968
  4. 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
  5. Rauen, KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013; 14:355-69. doi: 10.1146/annurev-genom-091212-153523. PMID: 23875798
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. Yamamoto, GL, et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J. Med. Genet. 2015; :None. PMID: 25795793
  12. Cordeddu, V, et al. Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome. Hum. Mutat. 2015; :None. PMID: 26173643
  13. Aoki, Y, et al. Recent advances in RASopathies. J. Hum. Genet. 2016; 61(1):33-9. PMID: 26446362
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. Schubbert, S, et al. Germline KRAS mutations cause Noonan syndrome. Nat. Genet. 2006; 38(3):331-6. doi: 10.1038/ng1748. PMID: 16474405
  23. 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
  24. 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
  25. 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
  26. 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
  27. 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

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 in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

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