Invitae Noonan Syndrome Panel


Test description

The Invitae Noonan Syndrome Panel analyzes up to 13 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.

Noonan syndrome is a multisystemic disorder whose expression is highly variable. Proper management by specialists across a variety of disciplines is critical because Noonan syndrome must be correctly identified and comprehensively managed. Distinguishing Noonan syndrome from other phenotypically similar syndromes, such as cardio-facio-cutaneous (CFC) syndrome or Costello syndrome, is important for proper medical management. Additionally, the risk of a patient with PTPN11-associated Noonan syndrome developing specific symptoms such as hypertrophic cardiomyopathy and growth hormone abnormalities differs from that of a patient with RAF1-associated Noonan syndrome, so identifying the genetic etiology is helpful in guiding management.

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Primary panel (12 genes)


Add-on Baraitser-Winter syndrome gene (1 gene)

Some clinical features of Noonan syndrome overlap with Baraitser-Winter syndrome (BRWS), a rare autosomal dominant developmental disorder characterized by multiple congenital anomalies and intellectual disability. Patients with classic BRWS present with lissencephaly and distinctive facial features including ptosis, hypertelorism and ocular colobomata; however, clinical expression is variable. Characteristic features of Noonan syndrome such as short stature, developmental delay, downslanting palpebral fissures and webbed neck have also been observed in BRWS. If ACTB analysis has not been performed previously, adding the ACTB gene to this analysis may be considered. This gene can be included at no additional charge.


Alternative tests to consider

The RASopathies are multisystemic disorders whose clinical expressions are highly variable, even among family members. Many of the clinical features that can differentiate RASopathy conditions 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.

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%
SHOC2 <1%
SOS1 10%-15%

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: 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. 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
  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. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. Rauen, KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013; 14:355-69. doi: 10.1146/annurev-genom-091212-153523. PMID: 23875798
  11. 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
  12. 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
  13. Roberts, AE, et al. Noonan syndrome. Lancet. 2013; 381(9863):333-42. doi: 10.1016/S0140-6736(12)61023-X. PMID: 23312968
  14. 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
  15. Schubbert, S, et al. Germline KRAS mutations cause Noonan syndrome. Nat. Genet. 2006; 38(3):331-6. doi: 10.1038/ng1748. PMID: 16474405
  16. 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
  17. 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
  18. 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

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
ACTB NM_001101.3
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
SHOC2 NM_007373.3
SOS1 NM_005633.3