News and Newsletter

September 20, 2012
A couple of really important pieces of progress have occurred in the last two months.

The National Institutes of Health has funded the research I mentioned in the November 2011 newsletter! This is a really significant step on three counts.

1. It recognizes the contribution that 1,200 of you have made in donating DNA and your support of the research. It's a reflection on all of you that this work got funded.

2. It recognizes the approximately 3,000,000 Americans with BAV and the public health importance of this disease.

3. It funds the investigation of the genetic causes of BAV to a level that has not been done before and allows us to start the real science we envisioned three years ago.

The second important piece of progress is that we have formed a larger international consortium of centers with interest in BAV. In my last newsletter I talked about the six GenTAC centers who were joining us. That group has blossomed to 16 centers in the US and Canada, as well as centers in Italy, Germany, Austria, UK and Spain. Each of these centers and their Investigators brings expertise and additional patients to the Consortium that will allow us to do better research. Representatives from each of the sites met in Chicago last month to lay out a broad plan for the next five years. We are meeting again in LA in November to go over the nitty-gritty details of doing good research.

Office notes: Sarah is in Nursing School. Makes me proud to say so. Chelsea has taken her place and is doing a tremendous job. Its been especially busy for her as she has been organizing the details of the International Consortium.

All my best,


November 28, 2011
Update of Progress in 2011

I'm sorry for not having updated the news for a year. It's been a busy year, but that's no excuse.

I'm very grateful to everyone who has enrolled in the study. To date we have 1045 patients enrolled and 920 DNA samples in hand. You have all been very generous.

Here is the progress so far.

We joined colleagues in the GenTAC consortium, based in Texas, in publishing a paper identifying a genetic association of the gene fibrillin-1 with thoracic aortic aneurysm. You can see the paper here. The interesting part is that this is the same gene for Marfan's syndrome which also has thoracic aortic aneurysm as one of its problems. Please note that I'm not saying they are the same diseases; the genetic variations identified for Marfan's are different from the ones identified for thoracic aortic aneurysm. But it tells us that the protein made by the fibrillin-1 gene must be important in the normal structure of the thoracic aorta.

We completed the exome sequencing described for the Catalyst grant mentioned below. The results did not give us a "smoking gun" for bicuspid aortic valve disease. But it did give us a couple of candidates that we are exploring. Just a small step, not a giant leap.

We have applied to the NIH for funding of a study looking at the causes of aortic stenosis in biscuspid valves. Earlier this year, the NIH published a request for applications in the field of aortic stenosis. Along with six other institutions and the GenTAC consortium, we requested funding to identify the causes of aortic stenosis in bicuspid aortic valve disease. The research involves using your samples to identify genetic causes of BAV and aortic stenosis and then "proving" the genetic findings by changing the activity of the identified genes in Zebrafish. Zebrafish are great models of human cardiac development as they are transparent so you can see the heart develop and look for changes that occur in heart development by turning on and off a gene. Cross fingers for the NIH Funding!

Many of you have corresponded with Adrienne Kicza over the last two years. Adrienne was accepted into Medical School this last summer. Her position has been taken by Sarah Ronayne who will be off to Nursing School in August 2012. I like hiring young enthusiastic people for this position as it brings a breath of fresh air into the office.

All my best,


Please see Supporting BAV Genetics for more information about how you can help.

21st June, 2010
Thank you. Over 300 people have enrolled in the study.

Letters sent: 1,086
Postcards returned: 539
Consents returned: 331
DNA samples in hand: 238

10th June, 2010
Good news. We have been awarded a Harvard Catalyst Pilot Grant.

The Harvard Catalyst Program awards one year grants for pilot funding of studies that will lead to sustainable, innovative, and collaborative projects that will impact human health. We were fortunate to receive one of the sixty grants from the pool of over 600 applicants.

We will use the award to whole exome-sequence twenty individuals with BAV. Whole-exome sequencing is a new technique that allows cost-efficient identification of every genetic variant in every protein made by the body from the DNA that has been provided by our participants. The rationale for using this technique is that it is likely that BAV is caused by one or more variants in one or more proteins. The difficulty is knowing which one. By performing whole-exome sequencing in twenty individuals, we hope to narrow the list of culprit proteins to a manageable number, most likely less than ten proteins. We can then sequence these proteins in many more individuals to help identify even fewer higher-likelihood candidates.

For those who are interested, the study design is:

Experiment 1: Exome sequence patients with a family history of BAV and R-L cusp fusion.
For this experiment we hypothesize that coding variants are responsible for BAV. We therefore anticipate that several coding variants will be identified by whole exome sequencing that occur at high frequency in the BAV cohort but rarely occur in reference genomes of non-BAV patients. Genes that over-express variants identified by whole-exome sequencing in BAV patients will be sequenced in Experiment 2.

Experiment 2: Sequence genes that over-express variants identified by whole-exome sequencing in 46 BAV patients.
Newly identified BAV target genes will then be resequenced in a larger BAV cohort of 46 patients (92 chromosomes) to define the spectrum of mutations using target capture high throughput DNA sequencing procedures developed in the Seidman laboratory.

Experiment 3. Genotyping variants associated with BAV in the sequencing effort.
Subsequently, all potentially pathogenic variants identified by the initial sequencing effort (10 BAV patients) and the subsequent targeted resequencing effort (46 patients) will be genotyped in an additional ~550 BAV patients and comparable ethnically- and gender-matched controls.

BAV Genetics


Simon C. Body, MD, MPH
Brigham and Women's Hospital
Department of Anesthesiology, Perioperative and Pain Medicine
75 Francis Street
Boston, MA 02115

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