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Noonan Syndrome
PTPN11 (Protein-Tyrosine Phosphatase, Nonreceptor-Type, 11)
RAF1 (V-RAF-1 Murine Leukemia Viral Oncogene Homolog 1)
SOS1 (Son of Sevenless Homolog 1)
KRAS (V-Ki-Ras2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog)
Approximately 65%-78% of individuals with a clinical diagnosis of Noonan syndrome (NS) are expected to have a mutation in 1 of 4 genes encoding proteins of the RAS-ERK signaling pathway, PTPN11, RAF1, SOS1 and KRAS. Germline mutations in PTPN11 have been found in approximately 50% of individuals with a clinical diagnosis of Noonan syndrome (NS), with a higher rate (59%) in familial vs. sporadic (37%) cases. Germline mutations in the SOS1 gene are responsible for NS in about 10% of all NS patients, and 20% of those who do not have a mutation in PTPN11. Germline RAF1 mutations occur in approximately 3.5%-17% of NS patients, and 8.4%-30% of those without a mutation in PTPN11, SOS1 or KRAS. Finally, germline mutations in KRAS account for approximately 1-2% of all NS cases. Genotype-phenotype correlations suggest that PTPN11 mutations are often associated with pulmonic stenosis (70%), while association with hypertrophic cardiomyopathy is rare (6%). In contrast, about 76% - 80% of NS patients with a mutation in the RAF1 gene can be expected to develop hypertrophic cardiomyopathy. Certain RAF1 mutations that cluster in two mutational hotspots in exons 7 (encoding the CR2 domain) and exon 17 almost invariably appear to result in HCM.
Testing in Noonan syndrome is offered as
sequential tiered testing
(cost-effective) or a
comprehensive Noonan syndrome panel
(time effective). Alternatively, any of these tests can be ordered separately. Once a mutation in the proband is identified, mutation-specific testing in relatives and prenatal testing is available.
I. Sequential tiered testing (cost-effective and high test sensitivity
% of Mutations found/Gene
Test sensitivity in NS patients
Tier 1 Testing
PTPN11
(exons 3, 8, 9, 13)
~76% PTPN11
~38%
Tier 2 Testing
PTPN11 (rest of gene-11 exons)
&
RAF1 (exons 7, 14, 17)
~24% PTPN11
>99% RAF1
~12%
~3.5-17%
Tier 3 Testing
SOS1
(exons 7, 11, 17)
>80% SOS1
~8%
Tier 4 Testing
KRAS (exons 2-6)
>99% KRAS
~2%
Tier 5 Testing
SOS1
(rest of gene-20 exons)
~20% SOS1
~2%
Sequential analysis of levels 1 through 3 is expected to identify ~96% of disease-causing mutations in PTPN11, RAF1, & KRAS, and SOS1; the remainder of mutation (if one exists) will be detected in Tiers 4 and 5. Sequential testing in 5 tiers offers significant cost saving for the majority of patients without any significant loss in sensitivity (see the Information Sheet).
II. Comprehensive Noonan syndrome panel (simultaneous, time-saving testing)
Test sensitivity in NS patients
PTPN11 complete gene analysis (all 15 coding exons)
~50%
RAF1 selected analysis of exons 7,14, and 17 (where all mutations have been found to date)
~3.5-17%
SOS1 complete gene analysis (all 23 coding exons)
~10%
KRAS complete gene analysis (all 5 coding exons)
~2%
Comprehensive, simultaneous analysis of all 4 Noonan syndrome genes with a significantly shorter turn-around-time is expected to detect almost any existing mutation in these 4 genes (see the Information Sheet).
Information Sheet, including prices and CPT codes
Consent Document
Genetic Test Sample Submission Form (Test Requisition Form) including Payment Options
Cystic, Hygroma, Nuchal, Lucency, Cardiac, Heart, Ultrasound, Sonography, Prenatal, Pre-natal, Noonan, PTPN11, SOS1, KRAS
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