HRAS gene testing
HRAS gene testing is a genetic examination that focuses on the HRAS gene, which plays a critical role in regulating cell division. This gene is categorized as a proto-oncogene, meaning that mutations in HRAS can lead to uncontrolled cell growth and are linked to various tumors, including bladder, thyroid, and skin cancers. Additionally, specific mutations in the HRAS gene are associated with Costello syndrome, a rare genetic disorder affecting development and physical traits. Costello syndrome is characterized by developmental delays, feeding issues, heart problems, and distinctive physical features such as loose skin and a unique facial appearance. The most common mutation linked to this syndrome occurs at the G12S position, but several mutations have been identified. HRAS mutations can also lead to benign skin growths called papillomata. The identification of HRAS mutations has significant implications for diagnosis and treatment, helping to differentiate Costello syndrome from other disorders with similar symptoms. Overall, HRAS gene testing provides valuable insights for understanding and managing associated health concerns.
Subject Terms
HRAS gene testing
SIGNIFICANCE: The HRAS gene controls production of a protein that regulates cell division. It is a member of a gene class called proto-oncogenes, and mutations in this gene can cause unusual, sometimes cancerous, growths, particularly in the bladder. Mutations in HRAS are also linked to a rare syndrome called Costello syndrome. Testing for this mutation can help distinguish between this disease and other syndromes.
Costello Syndrome
Mutations to the HRAS gene have been linked to a rare disease called Costello syndrome or faciocutaneoskeletal (FCS) syndrome, which affected between 100 to 1,500 people worldwide in 2023. In 80 percent of these cases, the mutation is at G12S (serine replaces glycine at position 12), but up to eight gene mutations of the HRAS gene have been discovered in those with Costello syndrome.
This syndrome is characterized by developmental delay, mental disability, reflux and other feeding problems (often leading to growth problems), and heart issues, including an extremely rapid heartbeat. Outwardly visible physical characteristics include reduced height as a result of delayed bone growth; extra, loose, stretchy skin; unusually flexible joints, curly or sparse hair; skin markings; tight Achilles tendons; a hoarse voice; premature aging; and a distinctive facial appearance including broad mouth, thick lips, droopy upper eyelids, low-set ears with large earlobes, and wide nostrils.
Following an autosomal dominant pattern (one copy of the altered gene in each body cell causes the syndrome), this syndrome arises from new gene mutations, as it is almost always found in cases where there is no family history of this syndrome. (There have only been two cases where siblings had Costello syndrome.) The rare nature of this disease could be attributable to underdiagnosis or to misdiagnosis as another disease such as cardiofaciocutaneous (CFC) syndrome or Noonan syndrome. It affects males and females equally with no known link to ethnic background.
Tumor Growth
The HRAS gene belongs to the Ras family of proto-oncogenes (the other members of this family are the KRAS and NRAS genes). Because the HRAS gene is involved in regulating cell division, mutations in this gene can interfere with signals that tell cells when to stop dividing, leading to uncontrolled growth. Often, those with HRAS gene mutations have small skin growths similar to warts, called papillomata, particularly around the mouth, nose, and anus. This uncontrolled cell growth can also lead to cancerous growths, and HRAS mutations have been particularly linked to thyroid cancer, kidney cancer, muscle tissue cancer (rhabdomyosarcoma), nerve cell cancer (neuroblastoma), and bladder cancer (transitional cell carcinoma). Bladder cancer, in particular, has been linked to the G12V mutation (valine replaces glycine at position 12). This may be a somatic (acquired during a person’s lifetime, not inherited) gene mutation.
Impact
Costello syndrome was first described in New Zealand in 1977 by Dr. J. Costello. It was linked to mutation of the HRAS gene in 2005. Discovery of this genetic mutation was instrumental in changing the way that some genetic researchers thought about and classified genetic disorders. Prior to the discovery that an HRAS mutation caused Costello syndrome, researchers assumed that genetic disorders that had similar symptoms would be on genetic material near a mutation that caused the similar disorder. The discovery of the mutation causing Costello syndrome on a gene far away from the gene containing the mutation causing Noonan syndrome led to new ways of classifying genetic disorders, such as by function or by body systems that were affected, rather than by where they were located on the gene.
Discovery of this mutation has been helpful in identifying and distinguishing those with Costello syndrome from those with Noonan or CFC syndrome earlier in the affected person’s life. Because these syndromes share some traits but also have different life-threatening possibilities, knowing which syndrome one has may alert medical providers to watch for those differing problems, particularly bladder cancer.
Key terms
- autosomal dominant pattern of inheritanceone copy of the altered gene in each body cell
- proto-oncogenea gene in which a mutation can cause cancer
- somatic gene mutationa gene mutation that happens during a person’s lifetime rather than being inherited from parents
Bibliography
Aoki, Y., et al. “Germline Mutations in HRAS Proto-oncogene Cause Costello Syndrome.” Nature Genetics 37.10 (2005): 1038–40. Print.
"Costello Syndrome." Medline Plus, 5 Sept. 2023, medlineplus.gov/genetics/condition/costello-syndrome/. Accessed 5 Sept. 2024.
Gripp, Karen W., and K. Nicole Weaver. “HRAS-Related Costello Syndrome.” GeneReviews. 21 Dec. 2023, www.ncbi.nlm.nih.gov/books/NBK1507/. Accessed 5 Sept. 2024.
Gripp, Karen W. “Tumor Predisposition in Costello Syndrome.” American Journal of Medical Genetics Part C: Seminars in Medical Genetics 137C (2005): 72–77. Print.
“HRAS gene.” Medline Plus, 1 Aug. 2016, medlineplus.gov/genetics/gene/hras/. Accessed 5 Sept. 2024.
Lin, A. E., K. W. Gripp, and B. K. Kerr. “Costello Syndrome.” Management of Genetic Syndromes. Ed. S. B. Cassidy and J. E. Allanson. 3rd ed. Hoboken: Wiley, 2010. Print.
Przybojewska, B., A. Jagiello, and P. Jalmuzna. “H-RAS, K-RAS, and N-RAS Gene Activation in Human Bladder Cancers.” Cancer Genetics and Cytogenetics 121.1 (2000): 73–77. Print.