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Condition report · Cardiovascular

Noonan Syndrome

Whole genome sequencing identifies the specific RASopathy gene variant, enabling cardiac surveillance and growth management tailored to your genetic subtype.

A condition report looks for rare variants known to cause the conditions it covers.

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About this condition

Noonan Syndrome (NS) is characterized by short stature, typical facial dysmorphism and congenital heart defects.

Noonan syndrome is an autosomal dominant RASopathy affecting approximately 1 in 1,000 to 1 in 2,500 individuals. It is characterized by distinctive facial features (hypertelorism, ptosis, micrognathia, short stature), cardinal cardiac abnormalities, developmental delay, and significantly increased cancer predisposition. Pulmonary stenosis is the most common cardiac manifestation (~60% of NS patients), though hypertrophic cardiomyopathy (HCM) occurs in 10-30%. The disorder sits within a spectrum of genetically related RASopathies that include Costello syndrome, cardiofaciocutaneous syndrome, and neurofibromatosis type 1, all linked by disrupted RAS/MAPK signaling.

At least 16 RASopathy genes have been identified; PTPN11 (protein tyrosine phosphatase non-receptor type 11) accounts for approximately 50% of Noonan syndrome cases. RAF1 (a MAP kinase kinase) accounts for approximately 10% and is associated with HCM in approximately 75% of RAF1-positive families, making it far more predictive of cardiac involvement than pulmonary stenosis. SOS1 accounts for approximately 10% and is associated with increased perioral freckling and ectodermal features. Approximately 25% of clinically diagnosed Noonan patients remain genetically unresolved, indicating genetic heterogeneity is substantial and new genes continue to be discovered.

Genotype-phenotype correlation directly informs cardiac surveillance and family counseling. PTPN11-positive families should expect pulmonary stenosis as the primary cardiac manifestation; RAF1-positive families should prepare for intensive HCM surveillance and management. SOS1-positive families typically show more favorable disease courses with reduced penetrance in some kindreds. Early developmental support, periodic cardiac echocardiography, and coordinated growth management are standard. Cascade genetic screening identifies first-degree relatives; approximately 50% carry the familial variant. As MEK inhibitor trials progress, genetically confirmed RASopathy patients may qualify for experimental therapies that halt disease progression.

Noonan syndrome genotype strongly predicts cardiac phenotype: PTPN11 predicts pulmonary stenosis, RAF1 predicts hypertrophic cardiomyopathy, and SOS1 predicts milder disease with better outcomes.

The 3 conditions we analyse

Noonan Syndrome and Noonan-Related Syndromes

A group of RAS pathway conditions, including Noonan, Costello, cardiofaciocutaneous and Legius syndromes, with variable heart defects, short stature and distinctive facial features.

What a diagnosis changes

Knowing about it supports heart, growth and developmental assessment.

Genes analysed

Specific forms also covered

Includes 29 related subtypes ↓
  • cardiofaciocutaneous syndrome
  • cardiofaciocutaneous syndrome 1
  • cardiofaciocutaneous syndrome 2
  • cardiofaciocutaneous syndrome 3
  • cardiofaciocutaneous syndrome 4
  • Costello syndrome
  • Legius syndrome
  • LEOPARD syndrome 1
  • LEOPARD syndrome 2
  • LEOPARD syndrome 3
  • Noonan syndrome
  • Noonan syndrome 1
  • Noonan syndrome 10
  • Noonan syndrome 11
  • noonan syndrome 12
  • Noonan syndrome 13
  • Noonan syndrome 14
  • Noonan syndrome 2
  • Noonan syndrome 3
  • Noonan syndrome 4
  • Noonan syndrome 5
  • Noonan syndrome 6
  • Noonan syndrome 7
  • Noonan syndrome 8
  • Noonan syndrome 9
  • Noonan syndrome with multiple lentigines
  • Noonan syndrome-like disorder with loose anagen hair
  • Noonan syndrome-like disorder with loose anagen hair 1
  • Noonan syndrome-like disorder with loose anagen hair 2
MONDO:0020297Orphanet 98733MedGen 1826127

CBL-Related Disorder

Autosomal dominant

A Noonan-like condition caused by changes in CBL, which also carries a risk of juvenile myelomonocytic leukaemia in early childhood.

What a diagnosis changes

Knowing about it supports blood count monitoring in early childhood.

Genes analysed

Also known as

Cbl syndrome; Noonan syndrome-like disorder with JMML; Noonan syndrome-like disorder with juvenile myelomonocytic leukaemia; Noonan syndrome-like disorder with juvenile myelomonocytic leukemia; Noonan syndrome-like disorder with or without juvenile myelomonocytic leukaemia; Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia; Noonan-like syndrome; NSLL

MONDO:0013308OMIM 613563Orphanet 363972MedGen 462153

Why whole genome sequencing

Standard Noonan panels test the major genes but miss 25% of patients. Genetic heterogeneity is high and new genes continue to emerge.

The RASopathy gene causing Noonan syndrome may not be on your panel

Standard Noonan syndrome panels typically include PTPN11, RAF1, and SOS1, capturing the most common mutations. However, at least 16 RASopathy genes have been identified, and approximately 25% of clinically diagnosed Noonan patients receive no molecular diagnosis despite comprehensive testing. Genetic heterogeneity is substantial and continuously evolving. New genes continue to be discovered, making panels outdated rapidly. Whole genome sequencing captures all known RASopathy genes simultaneously and provides complete sequence interrogation, improving diagnostic yield for genetically unresolved cases.

Knowing your RASopathy gene predicts your cardiac and growth trajectory

Genotype-phenotype correlation is meaningful in Noonan syndrome. A PTPN11 variant predicts higher likelihood of pulmonary stenosis, enabling targeted echocardiographic surveillance and early surgical intervention if needed. A RAF1 variant predicts significantly elevated HCM risk (75% of RAF1-positive patients); these individuals require intensive cardiac follow-up and aggressive HCM management protocols. SOS1 variants point toward milder disease and better neurodevelopmental outcomes. Understanding your genetic subtype informs surveillance intensity, treatment planning, and family cascade screening.

Other cardiovascular conditions

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