RASopathies [26 genes]

Noonan, LEOPARD, Costello

RAS genes play an important role in the mitogen-activated protein kinase-dependent signaling pathway (MAPK), a metabolic pathway that regulates cell proliferation, differentiation, survival and death or apoptosis. Germinal mutations described in some of these genes cause developmental anomalies in the subject (depending on the affected gene), which often overlap clinically, with an autosomal dominant inheritance pattern. Therefore, all patients share a variable degree of intellectual disability, cardiac anomalies, facial dysmorphism, skin anomalies, and predisposition to develop cancer (RASopathies).

  • The most widely known pathology in this group is Noonan syndrome, with an estimated incidence between 1/1,000 and 1/2,500 live births.

  • Subjects under suspicion or clinical diagnosis of Noonan, LEOPARD, Costello, Legius or cardiofaciocutaneous syndrome. There is frequent clinical overlapping among these syndromes (these patients share a variable degree of intellectual disability, cardiac anomalies, facial dysmorphism, skin anomalies, and predisposition to develop cancer); therefore the genetic study would facilitate differential diagnosis. All these syndromes share an autosomal dominant pattern of inheritance.
  • Familial study: A search for the mutation previously identified in a proband (relatives of patients with Noonan, LEOPARD, Costello, Legius or cardiofaciocutaneous syndrome, in which a mutation has been previously identified).

The probability of identifying a causal mutation when a patient has been diagnosed with one of these syndromes is high, over 70% in all cases. It can range from 70%-80% for one mutation or relevant variant in case of Noonan syndrome to 88%-98% in the case of Legius syndrome.

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RASopathies

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Turnaround time (TAT): 5 weeks

Ref. S-201906395

RASopathies: View panel

  • This panel is indicated when there is a suspicion of any RASopathy in the patient, having been specifically designed for this group of symptoms. It includes priority genes, which have been clearly associated with these diseases, and secondary genes, which have been sporadically associated with them.

  • BRAF
  • HRAS
  • KRAS
  • LZTR1
  • NF1
  • PTPN11
  • RAF1
  • RIT1
  • SOS1
  • SOS2
  • A2ML1
  • ALPK3
  • CBL
  • MAP2K1
  • MAP2K2
  • NRAS
  • PPP1CB
  • RASA2
  • RRAS
  • SHOC2
  • SPRED1
  • KAT6B*
  • MAP3K8*
  • RASA1*
  • SPRY1*
  • SYNGAP1*

Priority Genes : Genes where there is sufficient evidence (clinical and functional) to consider them associated with the disease; they are included in the clinical practice guidelines.
Secondary Genes: Genes related to the disease, but with a lower level of evidence or that constitute sporadic cases.
* Candidate Genes: Not enough evidence in humans, but potentially associated with the disease.

Related panels
Hypertrophic Cardiomyopathy – Basic Panel [18 genes]

Panel that include RASopathies cardiomyopathy genes

Hypertrophic Cardiomyopathy – Extended Panel [118 genes]

Panel that include RASopathies cardiomyopathy genes

Cardiovascular Diseases General Panel [405 genes]

Panel that include RASopathies cardiomyopathy genes

References

  • Noonan Syndrome: Judith E Allanson and Amy E Roberts. 2011 August 4. GeneReviews.
  • Noonan Syndrome: Van der Burgt I. Orphanet J Rare Dis. 2008 June.
  • Noonan Syndrome with Multiple Lentigines (Leopard Syndrome): Bruce D Gelb and Marco Tartaglia. 2015 May 14. GeneReviews.
  • Costello Syndrome: Karen W Gripp and Angela E Lin. 2012 January 12. GeneReviews.
  • Legius Syndrome (Neurofibromatosis Type 1-Like Syndrome): David Stevenson, David Viskochil and Rong Mao. 2015 January 15.
  • Cardiofaciocutaneous Syndrome: Katherine A Rauen. 2012 September 6. GeneReviews.