News and Newsletter
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,
Simon
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.
