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.
Mon - Fri 9:00am to 4:00pm
81404 x 2, 81405 x 2, 81406 x 6, 81479
Noonan Spectrum disorders include Costello syndrome, LEOPARD syndrome, Cardiofaciocutaneous syndrome, Noonan syndrome, and Noonan-like syndrome with loose anagen hair. 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.
The genes involved in the Noonan Spectrum of disorders include PTPN11, SOS1, KRAS, NRAS, HRAS, RAF1, BRAF, SHOC2, MAP2K2, MAP2K1, and CBL. 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 11 genes (PTPN11, RAF1, SOS1, KRAS, NRAS, HRAS, BRAF, MAP2K2, MAP2K1, SHOC2, and CBL) involves PCR amplification of the coding region by Raindance technology followed by massively parallel sequencing on the MiSeq. Sequences are first aligned to the reference genome using the Burrows-Wheeler Alignment tool followed by SAMtools analysis. Targets not meeting sufficient depth of coverage criteria are sequenced by the Sanger sequencing. Subsequent analysis and annotation of variants was performed using customized bioinformatics pipeline. The presence of any potentially disease causing variant is confirmed by Sanger sequencing. Sequences are analyzed on an automated DNA sequencer (Life Technologies) and compared with control sequences. Sequence variations are classified into categories of disease causing mutations, benign variants, or variations of unknown clinical significance. Variants of unknown clinical significance may require additional studies.
Sensitivity: This assay has greater than 99.7% sensitivity for detecting substitution variants and 1- 4 bp indels. Indels are typically not identified in the Noonan spectrum of disorders.
Reference Range: Mutations within the promoter regions, deep intronic regions or regulatory elements would also not be detected by this assay.
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.
Sanger sequencing for individual genes is also available.
Noonan-like dysmorphology has been reported in Legius syndrome patients with mutations in the SPRED1 gene. Testing for SPRED1 gene is offered in MGL.
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.