FeedbackMassively Parallel Sequencing
Massively Parallel Sequencing
Ordering Indications
Confirm a diagnosis of a NSD in a pregnancy with clinically suggestive findings, such as increased nuchal translucency, cystic hygroma, and cardiac defects.
Testing Strategy
For a fetus with ultrasonographic abnormalities, genomic microarray should be ordered prior to the NSD panel.
Massively Parallel Sequencing
- Testing for a known familial sequence variant by sequencing gene of interest. A copy of the family member’s test result documenting the familial gene variant is REQUIRED.
- To determine if the variant(s) of interest are detectable by this assay, contact an ARUP genetic counselor at 800-242-2787.
Noonan spectrum disorders (NSD) are a group of genetic syndromes caused by pathogenic germline variants in genes in the Ras/mitogen activated protein kinase (MAPK) pathway, which controls the cell cycle and cell differentiation. The vast majority of causative variants increase pathway signaling; thus, the resulting syndromes exhibit phenotypic overlap and share a predisposition for developing malignancies.
Disease Overview
Symptoms of Noonan Syndrome (NS)
- Characteristic facial features
- Short stature
- Broad webbed neck (fetal cystic hygroma/increased nuchal translucency)
- Congenital heart defect
- Developmental delay
- Undescended testes
- Coagulation defects
- Lymphatic dysplasias
Etiology of NSDs
Pathogenic sequence variants in Ras pathway genes
Prevalence
NS: 1/1,000-2,500
Inheritance
Autosomal dominant for all analyzed genes
Genotype-Phenotype Correlation
Variants in multiple genes cause overlapping phenotypes for NSD
Test Description
See Genes Tested table for genes included in this panel.
Clinical Sensitivity
Dependent on clinical phenotype
Limitations
- A negative result does not exclude a diagnosis of a MAPK pathway disorder.
- Diagnostic errors can occur due to rare sequence variations.
- Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
- The following will not be evaluated:
- Variants outside the coding regions and intron-exon boundaries of the targeted genes
- Regulatory region variants and deep intronic variants
- Large deletions/duplications
- Noncoding transcripts
- The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
- Low-level somatic variants
Analytic Sensitivity
For massively parallel sequencing:
| Variant Class | Analytical Sensitivity (PPA) Estimatea (%) | Analytical Sensitivity (PPA) 95% Credibility Regiona (%) |
|---|---|---|
|
SNVs |
99.2 |
96.9-99.4 |
|
Deletions 1-10 bp |
93.8 |
84.3-98.2 |
|
Deletions 11-44 bp |
100 |
87.8-100 |
|
Insertions 1-10 bp |
94.8 |
86.8-98.5 |
|
Insertions 11-23 bp |
100 |
62.1-100 |
|
bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants |
||
Genes Tested
| Gene | Alias Symbol(s) | MIM Number | Disorder |
|---|---|---|---|
|
BRAF |
BRAF1 |
164757 |
CFCS 1 NS 1 NS 7 LEOPARD syndrome 3 |
|
CBL |
CBL2, RNF55, c-Cbl |
165360 |
NS-like disorder with or without juvenile myelomonocytic |
|
HRAS |
HRAS1 |
190020 |
Melanocytic Nevus syndrome, congenital Schimmelpenning-Feuerstein-Mims syndrome CS |
|
KRAS |
KRAS2, KRAS1 |
190070 |
Schimmelpenning-Feuerstein-Mims syndrome NS 3 CFCS 2 |
|
LZTR1 |
LZTR-1, BTBD29 |
600574 |
NS 10 |
|
MAP2K1 |
PRKMK1, MEK1, MAPKK1 |
176872 |
NS 1 CFCS 3 |
|
MAP2K2 |
PRKMK2, MEK2 |
601263 |
CFCS 4 |
|
NRAS |
N-ras |
164790 |
Schimmelpenning-Feuerstein-Mims syndrome NS 6 |
|
PTPN11 |
NS1, BPTP3, SH-PTP2, SHP-2, PTP2C, SHP2 |
176876 |
LEOPARD syndrome 1 NS 1 |
|
RAF1 |
Raf-1, c-Raf, CRAF |
164760 |
NS 5 LEOPARD syndrome 2 |
|
RASA2 |
GAP1M |
601589 |
|
|
RIT1 |
RIT, RIBB, ROC1, MGC125864, MGC125865 |
609591 |
NS 8 |
|
SHOC2 |
KIAA0862, SOC2, SUR-8, SOC-2, SUR8 |
602775 |
NS-like disorder with loose anagen hair 1 |
|
SOS1 |
GINGF, HGF, GF1 |
182530 |
NS 4 |
|
SOS2 |
601247 |
NS 9 |
|
|
SPRED1 |
FLJ33903, PPP1R147 |
609291 |
Legius syndrome |
References
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23875798
Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355-369.
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Aoki Y, Niihori T, Kawame H, et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005;37(10):1038-1040.
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Estep AL, Tidyman WE, Teitell MA, et al. HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am J Med Genet A. 2006;140(1):8-16.
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Gripp KW, Lin AE, Stabley DL, et al. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A. 2006;140(1):1-7.
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Kerr B, Delrue MA, Sigaudy S, et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006;43(5):401-405.
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Tartaglia M, Kalidas K, Shaw A, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002;70(6):1555-1563.
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Roberts AE, Araki T, Swanson KD, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet. 2007;39(1):70-74.
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Tartaglia M, Pennacchio LA, Zhao C, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007;39(1):75-79.
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Aoki Y, Niihori T, Inoue Sichi, et al. Recent advances in RASopathies. J Hum Genet. 2016;61(1):33-39.
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Schubbert S, Zenker M, Rowe SL, et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006;38(3):331-336.
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Brasil ASalem, Pereira AC, Wanderley LTurolla, et al. PTPN11 and KRAS gene analysis in patients with Noonan and Noonan-like syndromes. Genet Test Mol Biomarkers. 2010;14(3):425-432.
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Sarkozy A, Carta C, Moretti S, et al. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat. 2009;30(4):695-702.
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Nava C, Hanna N, Michot C, et al. Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome. J Med Genet. 2007;44(12):763-771.
Ordering Indications
Confirm a suspected clinical diagnosis of:
Contraindications
This panel should not be ordered in individuals with primary JMML as the assay may not detect mosaicism for somatic variants associated with malignancy.
Testing Strategy
Given the genotypic and phenotypic overlap among Noonan spectrum disorders (NSDs), the NSD panel is the recommended first-line test for determining a genetic etiology.