Genetic testing useful for patients with thoracic aortic aneurysm and dissection

By Will Boggs MD

NEW YORK (Reuters Health) - Routine genetic testing can provide useful information for patients with thoracic aortic aneurysm and dissection (TAAD) and their relatives, according to a whole exome sequencing (WES) study.

"Identification of a mutation can lead to personalized care (especially, early surgery before severe aortic dilatation for the highest-risk mutations)," said Dr. John A. Elefteriades from Yale University School of Medicine in New Haven, Connecticut.

"Also, identification of a mutation can lead to conclusive clearing of unaffected family members ('like it never happened') and close monitoring of affected family members," he told Reuters Health by email.

There is a strong genetic component to TAAD, and specific genetic defects are associated with aortic dissection even at small aortic sizes. This suggests that genetic testing of TAAD patients could foster a personalized treatment strategy for each patient, Dr. Elefteriades and colleagues note in Annals of Thoracic Surgery, online July 15.

The team initiated a program of routine genetic testing of TAAD patients by comprehensive WES.

Based on initial findings in 102 patients, 72.5% had no medically important mutations. Meanwhile, mutations in known TAAD genes were found in 23 patients, suspicious novel variants in two, and various incidental findings in four.

The likelihood of finding a medically important genetic alteration did not differ between patients who were 50 years or younger and those who were older.

Subsequent to identification of specific variants in four patients, 13 family members were tested. This testing identified a deleterious mutation in two adolescents without clinical signs of thoracic aortic disease and confirmed the absence of a variant of unknown significance in a teenage son of one patient.

"Even those patients without identifiable mutations will derive some benefit," Dr. Elefteriades said. "Specifically, they will know conclusively that they do not have Marfan's disease, Ehlers-Danlos syndrome, Loeys-Dietz syndrome, or other very severe aortopathies. In the future they will likely benefit from the general advancement of aortic science. They probably do harbor mutations, especially those patients with familial patterns - just not mutations that medical science has thus far identified."

"As more and more novel genes responsible for TAAD are being discovered, we anticipate that a 'dictionary' of these genes and variants will grow rapidly, another benefit of routine WES in the clinical setting," the researchers say.

Dr. Alan C. Braverman, director of Washington University School of Medicine's Marfan Syndrome Clinic in St. Louis, Missouri, told Reuters Health by email, "Approximately 20% of individuals with TAA or dissection will have another first-degree relative with aortic disease. Thus, screening of first-degree relatives of the patient with TAA or aortic dissection for aortic disease is recommended. In the past, this was done primarily with echocardiogram or CT/MRI surveillance. Mutation analysis is now being done by many centers in this setting."

"Genetic testing for mutations in panels of genes associated with TAA and dissection are offered by multiple reputable labs at a reasonable cost," Dr. Braverman said. "At our aortic center, we have recently been utilizing a 22-gene exome slice process to evaluate for mutations in genes associated with these disorders. This type of genetic testing is becoming less expensive and can target genes known to be associated with aneurysm disease."

"It is also important to recognize that the number of patients with pathogenic mutations in new aneurysm syndrome-related genes is relatively small," Dr. Braverman said. "In many of these disorders, there are already widespread variations in phenotypic expression and age of onset. This makes it difficult to predict aortic outcomes in many cases. Collaboration amongst aortic and genetic centers will be very important to understand specific genotype-phenotype correlation regarding aortic outcomes and involvement of extra-aortic vascular territories."

SOURCE: http://bit.ly/1OC48OB

Ann Thorac Surg 2015.

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