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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
-
23875798
Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355-369.
-
16170316
Aoki Y, Niihori T, Kawame H, et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005;37(10):1038-1040.
-
16372351
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.
-
16329078
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.
-
16443854
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.
-
11992261
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.
-
17143285
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.
-
17143282
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.
-
26446362
Aoki Y, Niihori T, Inoue Sichi, et al. Recent advances in RASopathies. J Hum Genet. 2016;61(1):33-39.
-
16474405
Schubbert S, Zenker M, Rowe SL, et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006;38(3):331-336.
-
20578946
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.
-
19206169
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.
-
17704260
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.