About This Project

Ask the Scientists

What is the context of this research?

New sequencing technologies revolutionized the way we do diagnostics in patients with genetic disorders today: We sequence their whole exome that is the protein coding part of their genome, which comprises about 30 million bases. There is a 70% probability that the disease causing mutation can be found in such a data set and this makes exome sequencing to one of the most effective diagnostic tests ever.

The challenge is not anymore to generate the data but to filter and interpret the sequence variants. In any individual there are thousands of rare variants that are of unknown significance and to identify the single disease-causing mutation in the exome of a patient is like finding the needle in the haystack.

We started an online platform called GeneTalk that allows geneticists to filter such data sets. So far the platform is a big success and already helped to solve dozens of cases suffering from rare genetic disorders.
Over the recent months we gained considerable experience and identified the two most urgent needs:

1. Better classifications for variants of unknown significance.
2. Establishing contacts between geneticists with similar patient.
3. Exchange of knowledge on scientific and clinical level.

What is the significance of this project?

For many genetic disorders the genes involved in the disease are still unknown. Exome sequencing is a promising new approach to identify the disease causing mutations. For the patients this matters because making the molecular diagnosis is the first step in the long journey to a treatment for their disease.

Currently thousands of exomes have been sequenced, many cases have been solved, but for even more patients the diagnosis hasn’t been made yet, because there are just too many variants of unknown significance.
The problem is thus twofold:

1. We are missing rare variants that are classified as medically insignificant.
2. We are missing a broker for rare variants that are possibly disease causing because they were detected in a patient.

What are the goals of the project?

The goal of the project is to start a collaboratively edited knowledge
base for genetic sequence variants and an independent exchange platform.

We know that crowdsourced approaches can work and that there are plenty of successful examples.
The question is now how to achieve the critical mass of expert contributors?
- Lets face it: most of the large sequencing centers won’t share their data.
Science is competitive and they might fear that sharing data is rather a disadvantage in their field. However who are the ones for which sharing their knowledge makes complete sense?

- It’s all the geneticists working in small research labs and clinics. Each of them consults hundreds of patients with genetic disorders but as these disorders are so rare it hardly happens that they will see more than just one patient with the same rare disease in their life time. The best way to improve the odds of solving such cases is to share their data.
Thus there is an incentive especially for these experts to use GeneTalk.

For the first trial of the Personal Exome Project we recruited study participants with the following profile: professional genetic counselor capable of analyzing exome data and that work with patients suffering from rare genetic disorders. These geneticitsts were faced with the issue to analyze their own exome. The participants were asked to filter their data on GeneTalk and to classify all their personal sequence variants in the categories medical relevance and scientific evidence. For an expert this requires at least 10 hours of work in GeneTalk. All participants consent that their annotations are made publicly available in GeneTalk so that anyone can use the knowledge that they contributed for filtering patient exomes. Furthermore they are asked to serve as contact person for rare variants in their personal exomes that are of unknown significance. By this means they gain experience with the functionality in GeneTalk that brings together individuals with knowledge about a specific rare sequence variant.

So what is the worst case and best case scenario for the research money that you donate on the personal exome project?

- Either we don’t succeed in achieving the critical mass.
Well, at least you got several experts to spend their time and knowledge on rare sequence variants that is in the public domain and that can be used by the whole research community.
- However, your nickel might also be the ignition spark that is needed to create a successful expert knowledge platform that will serve thousands of patients to get their diagnosis.