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Identification of Genetic Defects Causing Thoracic Aortic Aneurysm by Whole Exome Sequencing: Experience in 211 Patients
Bulat A Ziganshin, Allison E Bailey, Adam Brownstein, Maryann Tranquilli, Allen E Bale, John A Elefteriades
Yale University School of Medicine, New Haven, CT

Objectives:
Multiple genes have been discovered which cause syndromic and non-syndromic thoracic aortic aneurysm and dissection (TAAD). This study reports our experience in genetic testing of 211 TAAD patients by whole exome sequencing (WES). We focus on the frequency distribution of genetic mutations/variants.
Methods:
WES was performed in 211 patients, mean age 56.5 14.2 (range 15-83), 73.0% males (n=154), 43.1% with positive family history of aneurysm disease (FHAD). The entire exome of these patients was scanned for genetic variants that might underlie TAAD, with concentrated focus on genes known to cause TAAD. Among patients found to carry suspicious mutations/variants, we plotted the frequency distribution of these genetic defects in all patients and in three sub-cohorts: 1) patients < 60 years, 2) patients with a positive FHAD, and 3) patients in whom rare and completely novel (previously unreported) variants were detected. The younger patients and those with a positive family history were expected to manifest stronger genetic influence.
Results:
Of 211 patients, 150 (71.1%) were found to carry no mutations in TAAD-related genes. Among the remaining 61 patients, 65 mutations/variants were identified as potentially causative of TAAD. 7 of these variants were deleterious (FBN1 (n=3), TGFBR2 (n=2), FLNA (n=1), MYLK (n=1)), while 58 were classified variants of uncertain significance (VUS). Among the VUS, 24 were found to be "common" (frequency > 1/10,000 (ExAC database)), while 11 were found to be rare (frequency <1/10,000), and 21 were completely novel (0 or 1 entry in the ExAC). Variants in FBN1, NOTCH1, and MYH11 genes were seen most commonly (17%, 15%, and 14%, respectively) accounting for half of all identified variants (Figure). ACTA2 variants were not seen with the expected high frequency. In patients < 60 years (n=30, 49.2%) FBN1 and NOTCH1 variants were most frequent (23% each), followed by MYH11 (10%), and COL5A1, FLNA, MYLK genes (7% each). Among patients with a positive FHAD (30, 49.2%) the following genes were most commonly affected: FBN1 (22%), NOTCH1 (15%), MYH11 and MYLK (12% each). In patients with rare/novel variants (39, 63.9%) the most common variants were identified in the FBN1 gene (21%), NOTCH1 (12%), COL5A2, FLNA, and MYH11 genes (7% each). Patients with a positive FHAD showed a stronger tendency for variants/mutations than non-familial cases (35.2% vs. 24.2 %, p=0.08), as well as more rare/novel variants (78.1% vs. 58.6%, p = 0.10).
Conclusions:
Genetic defects in TAAD-related genes are identified in a quarter of all tested patients. Contrary to previous reports, not the ACTA2, but MYH11 and NOTCH1 variants are most commonly found. Familial cases are more commonly "explained" by variants/mutations. Positive identification of variants/mutations permits personalized aneurysm and enables definitive screening of family members.


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