(Other synonyms: Disorders related to the Ras/MAPK pathway, Noonan spectrum disorders, Noonan-like syndrome)
Variants affecting the function of genes in the RAS–MAPK signal transduction pathway have been identified as responsible for RASopathies (1). The most common and studied RASopathies, Noonan syndrome (NS) and cardiofaciocutaneous syndrome (CFC), are characterized by multiple congenital anomalies (MCA). More than 50 types of congenital anomalies have been described in both syndromes (2). The cutaneous manifestations may include transient lymphedema of the dorsum of the hands and feet in infancy and stationary or progressive lymphangectatic edema in adulthood (3).
Prevalence of NS is about 1 in 1000 and 1 in 2500 live births (4, 5), whereas the prevalence for CFC is unknown.
The literature describes variable lymphatic abnormalities associated with NS and CFC. For example, a cross-sectional cohort study of 35 NS patients found a 49% prevalence of lymphedema, which was chronic and intermittent in nature and occurred at the extremities (6).
To date, 17 genes have been identified as associated with RASopathies:
CFC is mainly caused by mutations in
RASopathies are inherited in autosomal dominant pattern.
Noonan syndrome 1 (NS1, OMIM disease 163950) -
Noonan syndrome 3 (NS3, OMIM disease 609942) -
Noonan syndrome 4 (NS4, OMIM disease 610733) -
Noonan syndrome 6 (NS6, OMIM disease 613224) -
Noonan syndrome 8 (NS8, OMIM disease 615355) -
Noonan-like syndrome with or without juvenile myelomonocytic leukemia (NSLL, OMIM disease 613563) -
Costello syndrome (CSTLO, OMIM disease 218040) -
Noonan-like syndrome with loose anagen hair (NSLH1, OMIM disease 607721) -
Cardiofaciocutaneous syndrome 1 (CFC1, OMIM disease 115150) -
Cardiofaciocutaneous syndrome 2 (CFC2, OMIM disease 615278) -
Cardiofaciocutaneous syndrome 3 (CFC3, OMIM disease 615279) -
Patients with RASopathies may show lymphatic anomalies due to the fact that RAS/MAPK pathway is strictly linked to other pathways associated with the onset of syndromes with the predominant involvement of the lymphatic system (12).
Pathogenic variants may include missense, nonsense, splicing, small insertions and deletions, small indels, gross deletions and insertions, and complex rearrangements.
To determine the gene defect responsible for the disease;
To confirm clinical diagnosis;
To assess the recurrence risk and perform genetic counselling for at-risk/affected individuals.
The test is listed in the Orphanet database and is offered by 35 accredited medical genetic laboratories in the EU, and in the GTR database, offered by 21 accredited medical genetic laboratories in the US.
Guidelines for clinical use of the test are described in Genetics Home Reference (
Clinically distinguishable syndromes can be analyzed by sequencing only those genes known to be associated with that specific disease using Sanger or Next Generation Sequencing (NGS); if the results are negative, or more generally if clinical signs are ambiguous for diagnosis, a multi-gene NGS panel is used to detect nucleotide variations in coding exons and flanking introns of the above genes. Potentially causative variants and regions with low coverage are Sanger-sequenced. Sanger sequencing is also used for family segregation studies.
To perform molecular diagnosis, a single sample of biological material is normally sufficient. This may be 1 ml peripheral blood in a sterile tube with 0.5 ml K3EDTA or 1 ml saliva in a sterile tube with 0.5 ml ethanol 95%. Sampling rarely has to be repeated. Gene-disease associations and the interpretation of genetic variants are rapidly developing fields. It is therefore possible that the genes mentioned in this note may change as new scientific data is acquired. It is also possible that genetic variants today defined as of “unknown or uncertain significance” may acquire clinical importance.
Identification of pathogenic variants in the above genes confirms the clinical diagnosis and is an indication for family studies.
A pathogenic variant is known to be causative for a given genetic disorder based on previous reports, or predicted to be causative based on loss of protein function or expected significant damage to proteins or protein/protein interactions. In this way it is possible to obtain a molecular diagnosis in new/other subjects, establish the risk of recurrence in family members and plan preventive and/or therapeutic measures.
Detection of a variant of unknown or uncertain significance (
The absence of variations in the genomic regions investigated does not exclude a clinical diagnosis but suggests the possibility of:
alterations that cannot be identified by sequencing, such as large rearrangements that cause loss (deletion) or gain (duplication) of extended gene fragments;
sequence variations in gene regions not investigated by this test, such as regulatory regions (5’ and 3’ UTR) and deep intronic regions;
variations in other genes not investigated by the present test.
Unexpected results may emerge from the test, for example information regarding consanguinity, absence of family correlation or other genetically based diseases.
In autosomal dominant transmission, the probability that an affected carrier transmit the variant to his/her children is 50% in any pregnancy, irrespective of the sex of the child conceived.
The test is limited by current scientific knowledge regarding the gene and disease.
NGS Analytical sensitivity >99.99%, with a minimum coverage of 10X; Analytical specificity 99.99%.
SANGER Analytical sensitivity >99.99%; Analytical specificity 99.99%.
Clinical sensitivity is estimated at about 80-85% (13).
Clinical specificity: data not available.
The genetic test is appropriate when:
the patient meets the diagnostic criteria for Noonan syndrome or a RASopathy;
the sensitivity of the test is greater than or equal to that of tests described in the literature.
Clinical management | Utility |
---|---|
Confirmation of clinical diagnosis | Yes |
Differential diagnosis | Yes |
Couple risk assessment | Yes |
Availability of clinical trials can be checked on-line at |