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FeedbackMassively Parallel Sequencing
Massively Parallel Sequencing
Confirm a diagnosis of an NSD in a pregnancy with clinically suggestive findings, such as increased nuchal translucency, cystic hygroma, and cardiac defects. For a fetus with ultrasonographic abnormalities, genomic microarray should be ordered prior to the NSD panel.
If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.
Noonan spectrum disorders (NSDs) 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
- Approximately 99% for cardiofaciocutaneous syndrome (CFCS)
- Approximately 80-90% for Costello syndrome (CS) , , ,
- Approximately 70-80% for NS -
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 | Analytic Sensitivity (PPA) Estimatea (%) | Analytic 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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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.
Confirm a suspected clinical diagnosis of:
Given the genotypic and phenotypic overlap among NSDs, the NSD panel is the recommended first-line test for determining a genetic etiology.
Contraindications: This panel should not be ordered in individuals with primary juvenile myelomonocytic leukemia (JMML) as the assay may not detect mosaicism for somatic variants associated with malignancy.