Hi Hacker News, We’re Harley and Lukas from Probably Genetic (https://www.probablygenetic.com). We built an at-home physician-ordered DNA test that covers all genes and looks for pathogenic variants related to thousands of rare genetic conditions.

Why rare genetic conditions? It may seem like a niche problem but there are ~400 million people worldwide with a rare genetic condition, half of which are currently undiagnosed. To put this into perspective, it’s estimated that 1 in 10 Americans has a rare condition and while each of the individual ~10,000 conditions is rare, the population that suffers such conditions is larger than cancer and HIV combined. Furthermore, for the patients that have been diagnosed, it takes on average 8 years for doctors to identify their conditions. You’ve already heard of rare genetic conditions, you might just not be aware of it. Remember the Ice Bucket Challenge for ALS? Most of these diseases initially look like more common conditions, such as autism, chronic pain, ADHD, or even the flu, before patients get worse. This diagnostic odyssey can be extremely costly for patients and in our experience, some are spending more than $30,000 and seeing more than 10 doctors before they get access to the right specialists and testing.

We have seen this problem first-hand. Lukas is a rare-disease expert and worked on the world’s largest rare disease project (the 100,000 genomes project) as a PhD candidate at Oxford University in the UK. I am trained as a theoretical computational astrophysicist and during my PhD and fellowship at Cambridge University and Oxford University, I spent my spare time working with National Healthcare Service doctors developing and publishing medical diagnostics with machine learning. Our original idea was actually slightly different from what we have now. We spent a lot of effort on developing a symptom checker specifically for rare conditions with the idea to comb through existing medical records and flag patients with potential rare genetic conditions because, unsurprisingly, WebMD and others aren't really great for this purpose. As we were building this, we realized that for the patients we worked with, even if their symptoms were suggestive of a genetic condition, access to clinical-grade genetic testing was extremely difficult for many as it was either too expensive because insurance wouldn’t cover the cost, or they couldn’t find a doctor that would order it. Thus, we decided to use our expertise to both find these patients more efficiently and built up a service to drastically reduce the time and cost to access clinical-grade genetic testing.

About the test:

Just like most DNA tests, you can do this from home and it’s noninvasive, all we need is a little saliva. Unlike most DNA tests, ours is physician-ordered, sequenced in a CLIA-accredited and CAP-certified lab, the results are signed out by a licensed clinical lab director, all users have access to genetic counseling, and we try to incorporate as much phenotypic data as possible into the analysis. Our product is a whole-exome sequencing test with 100x coverage and covers all of the more than 20,000 genes, where 85% of known disease-causing variants occur.

People always ask, how are you different from 23andme? Looking for a rare genetic condition is kind of like trying to find a typo in a novel. Using a 23andme (or similar) test to look for such a condition is like trying to find a typo in the first Harry Potter novel and stopping after 75 words. Those tests are just not meant for this purpose. Most are based on genotyping arrays that look for very specific variants at predetermined locations in the genome. However, the variants that cause rare diseases can occur anywhere. For example, there are over 1,700 different mutations in the CFTR gene that can cause cystic fibrosis. Approximately 85% of the known pathogenic mutations occur in the protein-coding regions of DNA called the exome. Our test is a whole exome sequencing test rather than a genotyping array, which allows us to cover all of the genes in a person’s DNA. We often get the question, why not do whole genome rather than whole exome? Right now it simply comes down to accessibility. For most consumers, whole genome sequencing is still too expensive and the additional gain in terms of coverage of pathogenic mutations doesn’t necessarily warrant the significant price increase. That being said, if you are interested in clinical-grade whole genome sequencing, we can soon offer this as well.

Patient privacy is a huge concern for us and something we think about all the time. Quite simply, we will never share any of our users' data without explicit consent and we are more than happy to both delete our users' data and destroy their sample if requested.

Interestingly, we often have the opposite problem where we receive inbound requests of people trying to share their data with us to see if we can help them. Out of the more than 10,000 rare diseases, over 95% do not have an FDA-approved treatment, which is why the rare disease community is so motivated to leverage their personal insights. We have started a waitlist to provide such services and are actively seeking ways to help these people and integrate them into our community, even if they have not had sequencing through us.

Finally, how much does it cost? A single test right now costs $899 on our website, but we try to offer the test in trios where we sequence both the patient and two family members as this often gives a higher diagnostic yield. The latter option is $1,799. We expect that the test price will decrease significantly with time as the cost of sequencing drops and more of the analysis can be automated. We don’t currently accept insurance; however, in our experience, using more traditional channels to access this kind of testing can result in bills of >$10,000, not all of which may be covered. Many insurance providers don’t even cover this kind of testing, except for very specific purposes, despite more and more of the medical literature recommending exome sequencing as a first-tier diagnostic for specific indications. Ideally, we would make the product so affordable that it simply makes sense to use us rather than billing insurance for the test plus the numerous doctor and specialist visits needed before and after it’s ordered. We are currently offering the test at cost, as we aim not to profit off of the patients that need it most, and this is sustainable because, with the consent of the patients, we can leverage our data asset for drug discovery, clinical trial recruitment, and drug repurposing.

Consumer genetic testing is growing rapidly as an industry and nearly doubling every single year. What is missing from this market is accessible physician-ordered testing that can genuinely help those with complex symptoms and undiagnosed genetic conditions. This is what we hope to provide. If you have any questions or feedback, we would love to hear it and please check us out at https://www.probablygenetic.com.

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created:	September 3, 2018
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