Collect whole blood in a purple top (EDTA) tube.
Refrigerate sample until shipment. Send the sample at room temperature with overnight delivery for receipt Monday through Friday within 24 hours of collection.
Whole blood can be refrigerated until shipment.
Heparinized specimens, severely hemolyzed specimens, frozen, clotted or possibly commingled specimens, blood in non-sterile or leaky containers, mislabeled or inappropriately labeled specimens.
Do not heat, freeze or centrifuge blood before shipment. Refrigerate sample until shipment.
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Noonan Spectrum disorders include Costello syndrome, LEOPARD syndrome, Cardiofaciocutaneous syndrome, Noonan syndrome, Noonan-like syndrome with loose anagen hair, and Legius syndrome. Heart defects, facial dysmorphism, skeletal and skin anomalies, growth retardation and developmental delay are some of the common clinical features of these disorders.
Noonan syndrome is characterized by variable developmental delay, short stature, pulmonic stenosis, and often chest malformations and a webbed neck. Patients with Noonan syndrome also present with distinct facial feature that become more prominent with age. These features include a low hairline, hypertelorism, ptosis, down slanted eyes, epicanthal folds, and low-set posteriorly rotated ears.
LEOPARD syndrome (lentigines, ECG abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, deafness) is an autosomal dominant disorder that demonstrates significant overlap with Noonan syndrome.
Costello syndrome shares features with Cardiofaciocutaneous syndrome and Noonan syndrome. The facial features of a patient with Costello syndrome are coarse and include a bulbous nose, thick eyebrows, full cheeks, a large mouth and tongue, a depressed nasal bridge, and strabismus. These patients also have macrocephaly with sparse, curly hair. Infants born with Costello syndrome are often above the 50th percentile for weight but then experience postnatal growth retardation. Other features of Costello syndrome include intellectual disability, congenital heart defects, redundant skin, and malignancies (including rhabdomyosarcoma and neuroblastoma). The most common heart conditions associated with Costello syndrome are pulmonic stenosis, septal defects, hypertrophic cardiomyopathy, and arrhythmias.
Cardiofaciocutaneous (CFC) syndrome is characterized by features including macrocephaly, a high forehead, bitemporal narrowing, ptosis, a depressed nasal bridge, and sparse, curly hair, similar to Costello syndrome patients. These patients also have sparse or absent eyelashes and eyebrows. Patients with CFC syndrome also present with intellectual disability, congenital heart defects, short stature, and skin abnormalities, including xerosis, eczema, and ichthyosis.
Noonan-like syndrome with loose anagen hair is similar to classic Noonan syndrome. The most distinct difference is thin, sparse, slow-growing hair that is easy to pluck. Other phenotypic differences include growth hormone deficiency, dark, pigmented skin with ichthyosis or eczema and hyperactive behavior.
Legius syndrome also known as neurofibromatosis type 1-like syndrome (NFLS)is an autosomal dominant disorder characterized by caf au lait spots, axillary and/or inguinal freckling, macrocephaly, cognitive problems and a Noonan-like dysmorphology. Although there is some phenotypic overlap with Neurofibromatosis (NF1), several key features such as cutaneous neurofibromas, Lisch nodules of the iris, skeletal abnormalities, and malignant peripheral nerve sheath tumors are absent. Molecular testing can resolve the diagnosis in most cases which can have a significant implication for prognosis, counseling and potentially prenatal diagnosis.
The genes involved in the Noonan Spectrum of disorders include PTPN11, SOS1, KRAS, NRAS, HRAS, RAF1, BRAF, SHOC2, MAP2K2, MAP2K1, CBL, and SPRED1. These genes are all part of the Ras-mitogen activated protein kinase (MAPK) signaling pathway which is involved in cell growth, differentiation, and apoptosis. A recurrent mutation in the SHOC2 gene (p.Ser2Gly) has been identified in the subgroup of patients with Noonan-like syndrome with loose anagen hair. Mutations in these disorders are all inherited in an autosomal dominant pattern, although many cases are de novo.
Analysis for mutations in the open reading frame of 12 genes (PTPN11, RAF1, SOS1, KRAS, NRAS, HRAS, BRAF, MAP2K2, MAP2K1, SHOC2, CBL, and SPRED1) involves hybridization-based enrichment of coding exons and splice sites using the SureSelect technology followed by massively parallel sequencing on the MiSeq. Sequences are aligned to human reference genome hg19 using Novoalign. Variants are then called using the GATK pipeline and annotated using ANNOVAR and SnpEff. Variants are then assessed for their likelihood to be pathogenic and classified into categories of pathogenic, likely pathogenic, benign or variations of unknown clinical significance.
Sanger sequencing is performed to confirm clinically significant variants and to fill in regions with insufficient coverage (bases with less than 30X coverage). Variants that are classified as benign or likely benign will not be confirmed.
Sensitivity: This assay has greater than 99.7% sensitivity for detecting substitution variants and <5 bp indels. Indel mutations are not common in the Noonan spectrum of disorders.
Reference Range: This test will not detect mosaicism, deletions, duplications, rearrangements or variants in the non-coding regions (apart from splice site variants) that could affect gene expression.
Sanger sequencing for individual Noonan Spectrum genes is also available.
Pathogenic mutations are identified in ~65-75% of individuals with a clinical diagnosis of Noonan syndrome, 90% of individuals with LEOPARD syndrome, 85% of cases with Costello syndrome and 90% of mutations in Cardiofaciocutaneous syndrome. The detection rate for Noonan-like syndrome with loose anagen hair is still unknown. Nonsense, frameshift, missense and large deletions have been identified in approximately 6-10% of patients with a NF-1 like phenotype in SPRED1.
Sanger sequencing for individual genes is also available.
Test results with interpretation will be mailed and/or faxed to the referring physician or send out lab following completion of the test. Additional reports will be provided as requested.
The clinical utility of the assay is to support a clinical diagnosis of the disease, facilitate genetic counseling, and assess the risk to other first degree relatives and to facilitate testing of at - risk family members.
Whole blood in EDTA purple top tubes is the preferred sample. High molecular weight genomic DNA, cheek epithelial cells, or other samples containing DNA may be acceptable. Contact the laboratory for specific instructions regarding such samples before sending the sample.
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