 
Noonan Syndrome
NOONAN SYNDROME
Genes: PTPN11 at 12q24.1
KRAS at 12p12.1
Methodology: Bi-directional DNA sequencing of 15 exons and splice
sites for
PTPN11 and 5 exons and splice sites
for KRAS
Specificity: 99.9%
Sensitivity: Approximately 30-50% in patients with a
clinical diagnosis of Noonan Syndrome
and up to 2% have a mutation
in KRAS
Turn-Around-Time:
- PTPN11 Gene Test: 5 weeks
- If negative, reflex to KRAS: 7 weeks (total)
- KRAS Gene Test: 3 weeks
Sample Requirements: 7cc's blood in an K3EDTA (purple top) tube
Costs:
- PTPN11 full gene sequencing: $950.00
- PTPN11 reflex to KRAS: $1400.00 (total)
- KRAS full gene sequencing: $450.00
- Known mutation test: $250.00
How to order test | Brochure PDF | Resources | Clinical Services
Background:
Noonan syndrome (NS) is an autosomal
dominant, clinically heterogeneous disorder occurring in about 1
in 1000-2500 live births (Schollen et al, 2003). It is characterized
by short stature, distinct facial features, congenital heart disease,
motor delay, learning difficulties or mild mental retardation, hearing
loss, chest deformity, scoliosis, undescended testes, pubertal delay
and varied coagulation defects and lymphatic dysplasias
(www.GeneTests.org/Gene
Reviews). Although these are common manifestations of the condition,
this syndrome exhibits both inter- and intra familial variations.
According to studies by Tartaglia et al (2001, 2002), mutations in PTPN11
have been detected in about 30 - 50% of clinically diagnosed NS patients.
All mutations reported thus far are missense exonic changes that have been
found in exons 2,3,4,7,8, and 13, with the majority clustering in exons 3
and 8 (80%). The prevalence of such mutations is higher in familial cases
(50 %) than in sporadic cases (30%). Mutations co-segregate with NS within
families, however, variable expressivity has been observed. Germline
mutations in KRAS have also been identified in 3/124 and 1/50 individuals
with Noonan syndrome and no PTPN11 mutations. PTPN11 encodes SHP-2, a
phosphatase in the same signal transduction pathway as RAS, which is a
downstream effector.
Genotype-phenotype correlation studies demonstrate a statistically
significant association between pulmonic stenosis and NS patients
with PTPN11 mutations, whereas a lower incidence of mutations in
this gene has been found in NS patients with hypertrophic cardiomyopathy
(Tartaglia et al., 2002).
Synonyms:
Noonan syndrome (Online Mendelian
Inheritance in Man #163950)
| Gene |
Protein |
OMIM# |
Locus |
| PTPN11 |
Protein tyrosine phosphatase non-receptor type 11 |
176876 |
7q34 |
| KRAS |
V-KI-RAS2 Kirsten Rat Sarcoma 2 Viral
Oncogene Homolog |
190070 |
12p12.1 |
Other diseases caused by mutations in PTPN11: LEOPARD syndrome (OMIM #151100).
Other diseases caused by mutations in KRAS: Cardio-Facio-Cutaneous (CFC) syndrome
(OMIM #115150)
Epidemiology:1/1000-2,500
- Both males and females are affected in equal frequency.
- There is no known association with ethnic origin.
Clinical Features: *Features in bold are the most common manifestations of Noonan syndrome
Growth
Facial Dysmorphology
- Epicanthal folds
- Ptosis of eyelids
- Hypertelorism
- Low nasal bridge
- Downward eye slant
Hearing
Eye
Neck
Heart
- Pulmonary valve stenosis
- Left ventricular hypertrophy
- Septal defects
- Patent ductus arteriosis
Cognitive development
- Learning disability
- Mental retardation
Bleeding diathesis
- Von Willebrand disease
- Thrombocytopenia
- Factor deficiencies (VII, XI, XII)
Other manifestations may include lymphatic dysplasia, skin findings,
chest deformity, scoliosis, undescended testes, and
pubertal delay. The clinical features of this condition are variable
within the same family.
Inheritance Pattern: Autosomal dominant
- The presence of one pathogenic mutation in one copy of PTPN11 or one copy of KRAS is causative of Noonan syndrome.
- Each child of an affected individual has a 50% (or 1 in 2) chance of inheriting the mutation.
- Many cases of Noonan syndrome involving a PTPN11 mutation are sporadic and likely due to a new mutation, although germline mosaicism in a parent is possible.
- All KRAS mutations to date have been de novo.
Test Indications
- Patients who have clinical features associated with Noonan syndrome.
- Parents of a fetus or child diagnosed with Noonan syndrome and an
identified PTPN11 or KRAS mutation.
- Prenatal testing when a parent, or first-degree relative is diagnosed
with Noonan syndrome and has an identified PTPN11 or KRAS mutation.
- Prenatal diagnosis for a fetus with cystic hygroma and negative chromosome analysis.
- KRAS testing is indicated for individuals with the clinical features of
Noonan syndrome and a negative PTPN11 test result.
Test Outcome:
- The detection of a pathogenic mutation in either one copy of PTPN11 or KRAS
is considered a positive test result.
- A negative test result does not rule out Noonan Syndrome. According to
studies by Tartaglia et al (2001, 2002), mutations in the PTPN11 gene have
been detected in about 30 - 50% of clinically diagnosed NS patients. Up to
2% of individuals with a negative PTPN11 test result may have a KRAS mutation.
Additional genes that have not yet been identified may also be associated with
Noonan syndrome.
Turn-Around-Times:
- PTPN11 Gene Test: 5 weeks
- If negative, reflex to KRAS: 7 weeks (total)
- KRAS Gene Test: 3 weeks
Methodology:
Bi-directional sequence analysis of 15 exons and splice sites in PTPN11,
and/or of 5 exons and splice sites of KRAS. This test does not detect
large deletions or mutations in noncoding regions that could affect
expression of the gene.
Analytical and Clinical Sensitivity:
This assay is greater than 99.9% accurate in detecting mutations in the
sequence analyzed. According to published data, PTPN11 mutations have
been detected in 59% of patients with a family history of Noonan syndrome
whereas 37% of mutations have been detected in sporadic cases (Tartaglia,
2002). The overall PTPN11 mutation rate for Noonan syndrome, including
familial and sporadic cases, approaches 30-50%. Mutations in KRAS have
been observed in 3/124 and 1/50 individuals with Noonan syndrome (Schubbert, 2006).
Cost and CPT codes:
PTPN11 Full Gene Sequencing Test
- Cost: $950
- CPT codes: 83891(1), 83894(1), 83898(15), 83904(15), 83912(1)
If PTPN11 negative, reflex to KRAS Gene Sequencing Test
- Cost: $1400 (total)
- CPT codes: 83891(1), 83894(1), 83898(5), 83904(5), 83912(1)
KRAS Gene Sequencing Test only
- Cost: $450
- CPT codes: 83891(1), 83894(1), 83898(5), 83904(5), 83912(1)
Testing for known familial mutation
- Cost: $250
- CPT codes: 83891(1), 83894(1), 83898(1), 83904(1), 83912(1)
References:
Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H,
van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA,
Kucherlapati RS, Gelb BD (2001) Mutations in PTPN11, encoding the protein
tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. Dec;29(4):465-8.
Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner
HG, Bertola DR, Crosby A, Ion A, Kucherlapati RS, Jeffery S, Patton MA, Gelb
BD (2002) PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype
correlation, and phenotypic heterogeneity. Am J Hum Genet. Jun;70(6):1555-63.
Schollen E, Matthijs G, Gewillig M, Fryns JP, Legius E (2003) PTPN11 mutation
in a large family with Noonan syndrome and dizygous twinning. Eur J Hum Genet.
Jan;11(1):85-8.
Schubbert S, Zenker M, Rowe SL, Boll S, Klein C, Bollag G, van der Burgt I,
Musante L, Kalscheuer V, Wehner LE, Nguyen H, West B, Zhang KY, Sistermans E,
Rauch A, Niemeyer CM, Shannon K, Kratz CP (2006) Germline KRAS mutations cause
Noonan syndrome. Nat Genet. Mar;38(3):331-6.
If you have any questions, please call the Laboratory
for Molecular Medicine at 617-768-8500 or email us at LMM@partners.org
|
