Costello Syndrome: HRAS Gene Sequencing
Test Code: 8429
Turnaround time: 5 weeks
Costello syndrome is characterized by developmental delay, intellectual disability, diffuse hypotonia, failure to thrive in infancy (due to severe postnatal feeding difficulties), short stature, coarse facial features (full lips, large mouth); curly or sparse, fine hair; loose, soft skin, and tight Achilles tendons. Cardiac features includes cardiac hypertrophy, congenital heart defect , and arrhythmias. Individuals with Costello syndrome have an approximately 15% lifetime risk for malignant tumors. The solid tumors rhabdomyosarcoma and neuroblastoma occur most frequently in young children. Adolescents and young adults are at risk for transitional cell carcinoma of the bladder.
The HRAS gene is the only gene (11p15.5) currently known to be associated with Costello syndrome. In patients with a clinical diagnosis of Costello syndrome, 80-90% of mutations in the HRAS gene can be identified. Mutations in the HRAS gene are inherited in an autosomal dominant manner; however most individuals with Costello syndrome has a de novo mutation. Please note that the HRAS gene is part of the Ras/MAKP pathway and other syndromes should be considered as alternative diagnoses if an HRAS mutation is not identified.
For patients with suspected Costello syndrome, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.
• OMIM #218040: Costello syndrome
• OMIM #190020: HRAS gene
This test is indicated for:
- Confirmation of a clinical diagnosis of Costello syndrome.
- Carrier testing in adults with a family history of Costello syndrome.
PCR amplification of 4 exons contained in the HRAS gene is performed on the patient’s genomic DNA. Direct sequencing of amplification products is performed in both forward and reverse directions, using automated fluorescence dideoxy sequencing methods. The patient’s gene sequences are then compared to a normal reference sequence. Sequence variations are classified as mutations, benign variants unrelated to disease, or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions, or other regulatory elements, and does not detect large deletions.
Clinical Sensitivity: 80-90%. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient’s clinical and/or biochemical phenotype.
Analytical Sensitivity: ~99%
Submit only 1 of the following specimen types
* Preferred specimen type: Whole Blood
Type: Whole Blood
In EDTA (purple top) or ACD (yellow top) tube: Infants (2 years): 3-5 ml
Older Children & Adults: 5-10 ml
Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.
OrageneTM Saliva Collection kit (available through CEN4GEN) used according to manufacturer instructions.
Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.
- Deletion/duplication analysis of the HRAS gene by CGH array is available for those individuals in whom sequence analysis is negative.
- Please note that the HRAS gene is part of the Ras/MAKP pathway and other syndromes should be considered as alternative diagnoses if an HRAS mutation is not identified.
- Custom diagnostic mutation analysis (test code: 6875) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.