Next-Generation Sequencing of HRAS Only for Costello Syndrome (CST-NG)
Information for Ordering
Acceptable Specimen Types
- Fresh blood sample: 3–6 mL EDTA; no time limitations associated with receipt
- Saliva: OGD-575 DNA Genotek collection kit; kits are provided upon request
- DNA extracted from lymphocyte cells: minimum volume of 25 µL containing 3 µg of DNA; A260/A280 ratio ≥1.8; must be extracted in a CLIA-certified or equivalent laboratory
Turnaround Time
Average turnaround time: 30 working days
Price, CPT Code, and Z Code
- Institutional/self-pay price: $700 USD
- CPT code: 81404
- Z code: ZB67V
Candidates for Testing
Patients with key features of Costello syndrome, including coarse facial features, severe feeding difficulties, mild to moderate intellectual disability, relative macrocephaly, short stature, cardiac abnormalities, and an increased risk of malignancy. Differentiation of Costello syndrome from other RASopathies, particularly cardio-facio-cutaneous syndrome, may be difficult early in life.
Specimen Shipping and Handling
Please refer to the specimen requirements listed above.
All submitted specimens must be shipped at room temperature. Do not ship specimens on ice.
Specimens must be packaged to prevent breakage. Absorbent material must be included to contain liquids if breakage occurs. Specimens must also be shipped in double watertight containers, such as a specimen pouch placed inside the shipping company’s diagnostic envelope.
To request a collection kit, please complete the Collection Kit Request Form .
Before shipping a specimen, please contact the UAB Medical Genomics Laboratory by email at medgenomics@uabmc.edu or by phone at 205-934-5562. Please provide the shipment date and package tracking number so the laboratory can help ensure proper and timely receipt.
Required Forms
About
Disorder Background
The RASopathies are a genetically heterogeneous group of disorders caused by variants in genes involved in the RAS/MAPK pathway. As a group, the RASopathies are among the largest groups of malformation syndromes known, affecting approximately 1 in 1,000 individuals. They include neurofibromatosis type 1, Legius syndrome, Noonan syndrome, cardio-facio-cutaneous syndrome, Noonan syndrome with multiple lentigines, and Costello syndrome.
Variants in NF1 and SPRED1 are typically loss-of-function variants and may include nonsense, missense, splice, frameshift, insertion-deletion, and copy-number changes. Variants in other RASopathy genes are more commonly missense variants or in-frame deletions or insertions involving one or more amino acids.
Dysregulation of the RAS/MAPK pathway can have profound effects on development because of its key role in differentiation, growth, senescence, and cellular signaling. Clinical features of the RASopathies may include short stature, cardiovascular defects, cutaneous and pigmentary findings, characteristic facial features, skeletal abnormalities, neurocognitive delays, and a predisposition to benign and malignant neoplasia.
The RASopathies are generally inherited in an autosomal dominant manner. A parent who carries a disease-associated variant has a 50% chance of passing it to each child, regardless of sex. These disorders demonstrate variable expressivity, meaning individuals with the same disorder may show different features and symptom severity, even within the same family. Some variants are not fully penetrant, and an individual may carry a variant while showing few or no signs of the syndrome. Clinical features may also change or progress with age.
An individual may carry a variant because:
- The variant was inherited from a parent who may be clinically affected or nonpenetrant; or
- The variant arose de novo in the egg or sperm from which the individual developed.
In some individuals, the variant occurs postzygotically during development. In these cases, the variant may not be present in every cell of the body and may result in a milder phenotype due to mosaicism.
Costello syndrome is caused by activating variants in HRAS. Key features may include coarse facial features, severe feeding difficulties, mild to moderate intellectual disability, relative macrocephaly, short stature, cardiac abnormalities, and an increased risk of malignancy. Differentiation of Costello syndrome from other RASopathies, particularly cardio-facio-cutaneous syndrome, may be difficult early in life.
Some individuals with a clinical diagnosis of a RASopathy have been found to carry a variant in a gene not traditionally associated with their clinical diagnosis. Examples include BRAF variants in individuals with a clinical diagnosis of Noonan syndrome, a SOS1 variant in an individual with cardio-facio-cutaneous syndrome, PTPN11 variants in individuals with paraspinal neurofibromas, and an NF1 missense variant in patients with Noonan-like features and no neurofibromas.
Some genes are associated with more than one syndrome, including PTPN11, KRAS, BRAF, RAF1, and NF1. In patients with overlapping or nonspecific clinical findings, a broader RASopathy panel may be more appropriate than single-gene testing.
Test Description
The HRAS-only NGS test involves sequencing of the entire coding region of HRAS.
Average coverage is approximately 1,100×, with 100% of the coding region covered at ≥350×.
Variant calls are made using a specialized bioinformatics pipeline that detects single-nucleotide substitutions, insertions, deletions, and frameshifts caused by deletions or duplications up to 112 bp.
View references for this testing .
Other Related Test Options
- Non-NF1 RASopathy Panel by Next-Generation Sequencing and Deletion/Duplication Analysis of LZTR1 and SPRED1 (NNP-NG)
- Expanded NF1 RASopathy Panel by Next-Generation Sequencing and Deletion/Duplication Analysis (RAS-NG)
For more information, test requisition forms, or collection kits, please contact the UAB Medical Genomics Laboratory at 205-934-5562 or medgenomics@uabmc.edu.