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Utility of Genetic Testing in Elite Volleyball Players with Aortic Root Dilation


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Medicine & Science in Sports & Exercise: July 2017 - Volume 49 - Issue 7 - p 1293-1296
doi: 10.1249/MSS.0000000000001236


The past two decades have brought important advances in the understanding of athlete’s heart. In addition to the changes in chamber size and ventricular wall thickness, the changes and differences in the aortas of elite athletes are now better known. Recent studies suggest that there are enough data on tall athletes to define their upper limit of normal aortic root size. Certain sports, including volleyball and basketball, select for individuals with a characteristic biophysical profile (exceptionally tall and thin, long arm span) such that when combined with cardiovascular abnormalities may be indicative of an underlying connective tissue disorder like Marfan syndrome (MFS) (10). Despite the lack of overt clinical features, these individuals may be at increased risk for having an aortopathy due to an underlying connective tissue disorder.

Several recent studies have suggested that an aortic root dimension >4.0 cm in men and >3.4 cm in women is abnormal, independent of height (4,6,7,9,10). A recent cross-sectional analysis revealed that the prevalence of aortic root dilation was as high as 8% in volleyball players compared with only 1% in elite athletes from all sports (1,3,7,9,10). Most recently, a study on 526 professional basketball players from the National Basketball Association helped to establish new normative values for this group of athletes, in which their average height is 6 ft 7 inches (5). In this study, the largest aortic root diameter was 4.2 cm, suggesting that an aortic root dimension exceeding 4.2 cm is likely indicative of an aortopathy.

Over the last 5 yr, the United States National Volleyball team has implemented a cardiac screening program that has included 90 male and female athletes. All members undergo a baseline history, physical, and echocardiogram, with serial follow-up indicated based on the initial findings. We recently reported our findings on the first 70 athletes that underwent screenings. In that study, three male athletes had an aortic sinus diameter ≥4 cm, (4, 4.2, and 4.3 cm).

One female athlete had an aortic sinus diameter >3.4 cm (3.6 cm). There were no other intracardiac or arterial abnormalities among these four athletes, and specifically, all had a trileaflet aortic valve. Twenty-four (34%) of the 70 athletes had at least one characteristic of MFS on physical examination based on Ghent criteria, but none had more than two characteristics. Sixteen (23%) athletes had an upper body/lower body ratio < 0.85 and 4 (6%) of 70 had armspan/height ratios ≥ 1.05, indicating the inherent selection for this body type in elite volleyball players. The clinical significance of these findings, and whether or not these individuals had an underlying aortopathy, was unclear.

Since that study, we have identified one additional male with a sinuses of Valsalva dimension >4.2 cm. Based on the recent study by Engel et al. (5), we performed genetic testing on two of the three men found to have a sinus of Valsalva measurement of at least 4.2 cm, and on the one woman with a measurement of >3.4 cm, that is, the individuals with the largest aortic root measurements among the 90 players that have undergone assessments. We report our findings and discuss their significance with respect to clinical implications and future screening approaches.


Informed consent was obtained from each of the subjects, and the institutional review board of the University of California San Diego approved the study as a community service project. Histories, physical examinations, and follow-up echocardiograms were performed on the three subjects with a dilated sinus of Valsalva, as we have described previously (7). Measurements of the sinuses of Valsalva were performed as described by Devereux et al. (10) (see document, Supplemental Digital Content 1, Supplemental Methods, A clinical genetics evaluation by a board-certified clinical geneticist, including generation of a revised Ghent systems score (7), as well as genetic testing, were performed on the three subjects. Genetic testing was performed by Ambry Genetics (Aliso Viejo, CA) using a 22-gene aortopathy panel (TAADNext panel: ACTA2, COL3A1, COL5A1, COL5A2, FBN1, FBN2, FLNA, MED12, MYH11, MYLK, NOTCH1, PLOD1, PRKG1, SKI, SLC2A10, SMAD3, SMAD4, TGFB2, TGFBR1/2, CBS, COL5A1, and TGFB3).


Three subjects (two men and one woman) who were found to have dilation of the sinuses of Valsalva underwent genetic evaluation. Their findings are listed in Table 1. One additional man had a sinus of Valsalva measurement of 4.3 cm, but declined having a genetic evaluation. He had no other clinical features of MFS.

Summary of cardiovascular profile and genetic findings of three subjects found on screening to have dilated sinuses of Valsalva.

Subject 1

Subject 1 is a 27-yr-old male member with a medical history of labral surgery and a stress fracture of L1 with epidural injection. There was no previous history of cardiac problems, ectopia lentis, or pneumothoraces. There was no known family history of connective tissue disorders, aortic aneurysms, or aortic dissections. Paternal height is 206 cm, and maternal height is 180 cm.

His initial echocardiogram demonstrated a sinuses of Valsalva dimension of 4.3 cm. There was no valve prolapse or regurgitation. His height is 205.7 cm; weight, 90.311 kg; and body mass index (BMI), 21.34 kg·m−2. Positive findings on physical examination included a mild pectus excavatum and striae atrophicae on his back. The remainder of the physical examination was normal, giving a revised Ghent criteria system score of 3 (8). A repeat echocardiogram a year after his initial study revealed a possible increase of 1 mm in his sinuses of Valsalva measurement. Genetic testing using the aortopathy panel (TAADNext*) was performed by Ambry Genetics, and was negative for all 22 genes in the panel.

Subject 2

Subject 2 is a 24-yr-old man with a medical history notable for myopia and an appendectomy. There was no previous history of cardiac problems, ectopia lentis, or pneumothoraces. There was no known family history for connective tissue disorders, aortic aneurysms, or aortic dissections. Paternal height is 188 cm, and maternal height is 170 cm.

An initial screening echocardiogram demonstrated a sinuses of Valsalva dimension of 4.5 cm. His height is 204.5 cm; weight, 89.5 kg; and BMI, 21.4 kg·m−2. His physical findings are notable only for striae. The remainder of the physical examination was normal, giving a revised Ghent system score of 1 (8). Repeat echocardiograms performed over the next 2 yr demonstrated a 1- to 2-mm increase in his sinuses of Valsalva dimension (Fig. 1), respectively. There was no valve prolapse or regurgitation.

Facial and upper extremity images of subject 2 (above). Echocardiographic parasternal long axis view (below), demonstrating marked dilation of the aortic root.

Genetic testing using the aortopathy panel revealed a sequence variant in the fibrillin-1 (FBN1) gene (c.1846G > C; Chr15: 48797336; p.Glu616Gln), which substitutes a highly conserved residue in an epidermal growth factor-like (EGF-like) domain. His parents were tested and did not carry the variant, indicating a likely de novo disease-causing mutation.

Subject 3

Subject 3 is a 27-yr-old woman with a history of mild scoliosis, stress fracture at L5-S1, osteoarthritis, and tendonitis of the left knee with arthroscopic repair in 2009. There was no history of cardiac problems, ectopia lentis, or pneumothoraces. There was no known family history for connective tissue disorders, aortic aneurysms, or aortic dissections. Paternal height is 182.8 cm, and maternal height is 170.18 cm.

A screening echocardiogram demonstrated a sinuses of Valsalva measurement of 3.6 cm without any significant valve prolapse or regurgitation. Her height was 189.4 cm; weight, 78.9 kg; and BMI, 21.7 kg·m−2. Her physical findings were notable for a positive wrist and negative thumb sign, positive striae, pes planus, an upper to lower segment ratio of 0.83, and mild thoracocolumbar scoliosis. The remainder of the physical examination was normal, giving a revised Ghent system score of 4.0 (one point for wrist sign, one point pes planus, one point for scoliosis, and one point for skin striae) (8). Repeat echocardiograms over the ensuing 4 yr demonstrated a possible 1 mm increase in her sinuses of Valsalva dimension.

Genetic testing revealed a heterozygous sequence variant in the TGFB3 gene (p.S55N), a known polymorphism occurring in at least 1% to 2% of the African population. Her biological parents were tested and both were also found to be heterozygous carriers of the same sequence variant. Screening echocardiograms were then performed on her parents. Her mother and father had a normal echocardiogram, including normal aortic root dimensions.


In this study, we identified 4 of 90 subjects with a dilated sinus of Valsalva, based on previously published normative data for tall athletes (6,7,9,10) and most recently for NBA players (5). In our cohort, three males had a sinuses of Valsalva measurement exceeding 4.2 cm, and two of them underwent a complete genetics evaluation. In both cases, serial echocardiograms over a 2-yr period demonstrated possible slight progression. Subject 1 was found to have several mild features of MFS (Ghent score of 3), whereas subject 2 had minimal stigmata of MFS (Ghent score 1), yet targeted gene sequencing revealed a likely de novo disease-causing mutation in the FBN1 gene. Based on the revised Ghent criteria, he meets the diagnostic criteria for having MFS. Current recommendations from the American Heart Association and the American College of Cardiology (task force 7) state that patients with aortic disease or who have a condition associated with development of aortic disease should only participate in “low-intensity, noncompetitive exercise” (2). In line with these recommendations and the results of our assessments, subjects 1 and 2 have retired from competitive volleyball and are under close medical care. Subject 1 is being followed up medically and with serial echocardiograms. Subject 2 has been started on Losartan and is contemplating having elective aortic root replacement surgery in the near future. Subject 3 had several extracardiac features of MFS (Ghent score = 4.0). Her initial sinuses of Valsalva measurement is 3.6 cm, just at the upper limit of normal, with a possible 1 mm increase over the ensuing 4 yr (9). Based on her current echocardiographic findings and negative gene test results, she is continuing to participate in competitive volleyball but with elimination of high-resistance weightlifting, with close medical monitoring including serial echocardiograms.

Our findings underscore the importance of determining which clinical parameters should be assessed in tall athletes and what should be considered abnormal. Most importantly, we identified one athlete (subject 2) with significant aortic root dilation in the absence of other significant findings of MFS that nonetheless very likely has an aortopathy caused by a de novo FBN1 gene mutation. Based on this study and previously published studies, elite tall adult athletes, independent of other physical findings of a connective tissue disorder, should be considered for undergoing a comprehensive cardiac evaluation including a history, physical, and a screening echocardiogram. Furthermore, genetic testing should be considered for men with sinuses of Valsalva dimensions >4.2 cm, and women >3.4 cm, which can help confirm the diagnosis of an aortopathy even in the absence of other noncardiac findings of a connective tissue disorder. However, a negative aortopathy gene panel does not rule out the possibility of a genetic etiology, because not all genetic causes have been identified, and such athletes require close medical follow-up.

In conclusion, our results suggest that clinical screening combined with genetic testing in elite volleyball players can lead to the identification of individuals with previously undiagnosed aortopathies who are at risk for life-threatening aortic dissections, as in the tragic case of Flo Hyman who was a top member of the US Olympic volleyball team that died from an acute aortic dissection during international competition and was diagnosed with MFS post-mortem (11).

In the future, longer serial follow-up times and more comprehensive genetic testing should aid in the identification of tall athletes with an aortopathy, and help guide recommendations for screening.

The authors would like to thank all of the members of the US Men’s and Women’s National Volleyball teams, the medical staff including men’s head trainer Aaron Brock, women’s head trainer Jill Wosmek, head team physician Dr. Chris Koutures, men’s head coach John Speraw and women’s head coach Karch Kiraly. This work was supported in part by the National Marfan Foundation and Ambry Genetics (who provided complimentary genetic testing on the parents of subject 3). The results of this study do not constitute endorsement by ACSM.

Conflict of Interest: The authors have no conflicts of interest to declare.


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