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Finnish Startup with Stanford Technology Offers NGS-based Testing for Inherited Disorders


Blueprint Genetics, a Finnish startup with ties to Stanford University, has launched its first diagnostic gene panels for inherited diseases, starting with cardiovascular disorders.

The company, based in Helsinki, was founded in late 2011 by Tero-Pekka Alastalo, Juha Koskenvuo, and Samuel Myllykangas, three Finnish researchers – two of them also clinicians – who had been postdocs at Stanford and the University of California, San Francisco, respectively.

While a postdoc at the Stanford Genome Technology Center, Myllykangas, now the firm's chief technology officer, invented a targeted sequencing method called oligonucleotide-selective sequencing, or OS-seq (IS 10/25/2011), that the company employs in its assays, which run on the Illumina MiSeq.

The firm is currently funded by angel investors from Finland and has 11 employees.
While it has "pretty ambitious plans to grow" and is constantly looking for funding, it is not conducting a financing round at the moment, according to CEO Tommi Lehtonen.

Blueprint just launched its first 10 gene panels, which focus on cardiovascular disorders, the area of expertise of Alastalo, a pediatric cardiologist. The firm plans to offer its test globally, aiming to compete with other laboratories by providing more comprehensive tests at lower cost and with faster turnaround times.

The panels range in size from 5 genes to about 100 genes and cover cardiomyopathies, aortic dilatation, arrhythmia disorders, Brugada syndrome, long and short QT syndrome, Noonan syndrome, and other disorders. List prices range from €1,000 to €1,600 ($1,300 to $2,100) per panel, and the turnaround time will be 21 days starting in July. There is no reimbursement policy in place at the moment, though health insurance may cover the test on a case-by-case-basis, Lehtonen said.

Next in line will be panels for retinal and neuromuscular diseases, a nephrology panel, as well as single-gene tests, where the analysis will be restricted to one gene out of a multi-gene panel. Those tests will be particularly efficient for large genes, such as dystrophin or ryanodine receptor 2, which are expensive to analyze by Sanger sequencing, Lehtonen said.

Ordering physicians receive a report – an example of which is posted on the company's website – that explains the results and the implications for patients and includes all pathogenic mutations as well as "gene variants considered clinically relevant," with key references from the literature. The question of how to report de novo variants, also known as variants of uncertain significance, is "a tough one," according to Alastalo, who is one of the company's medical directors, but generally speaking, "it is more beneficial for the patient to have no genetic diagnosis than an unsure one," he said.

The tests employ the OS-seq method to capture the target genes, which was described in a paper in Nature Biotechnology two years ago, and which Blueprint licenses from Stanford. OS-seq uses the Illumina flow cells both as a capture device and to sequence the DNA, which the researchers say shortens sample prep times compared to other hybridization-based capture systems.

According to Lehtonen, the company has optimized the technique for the MiSeq and uses an in-house-developed algorithm to design the required oligonucleotides. "The uniformity of the capture is really solid and it is extremely easy to evaluate the performance of individual oligos and redesign new oligos for regions with poor coverage, which allows for a really flexible design and update of new and existing panels," he said in an e-mail.

The company has also developed a bioinformatics pipeline to align reads, call and annotate variants, and to help with their clinical interpretation. All variants are confirmed by Sanger sequencing prior to reporting.

So far, the firm has only run a small number of samples for clinical diagnostic purposes. It also provides services for clinical research — studies that will help validate its tests and develop them further. As throughput increases, the lab might consider switching from the MiSeq to the HiSeq, according to Myllykangas.

Blueprint is initially marketing its diagnostic services in Europe, and it has permission from regulating authorities to provide human clinical diagnostic testing in the European Union, Lehtonen said. Its laboratory already complies with ISO 15189 standards, and it is in the process of being certified by the European Molecular Biology Quality Network quality assessment program and being accredited by the Finnish Accreditation Service.

Longer term, the firm plans to sell its services in the US as well and is working toward CLIA certification, Lehtonen said. "We feel that both the US and Europe provide us with a huge opportunity."

He said he has no concerns about shipping samples between the US and Finland, other than shipment adding to the turnaround time, but the company is also "seriously considering" opening a laboratory in the US in the future.

Lehtonen said the competitive landscape in Europe is "quite fragmented," with many laboratories providing genetic testing services to their local institutions. While some diagnostic labs also provide international services, many are only starting to invest in next-gen sequencing technology now. "We do see that there is a lot of room for competition at the moment."

In the US, Blueprint will encounter a number of competitors that offer NGS-based panels for inherited cardiovascular disease and other conditions, among them GeneDx and the Laboratory for Molecular Medicine of the Partners Healthcare Center for Personalized Genetic Medicine.

Another company, Aviir, which was founded by researchers and cardiologists at Stanford, also just launched NGS-based panels for more than a dozen inherited cardiovascular disorders (CSN 4/10/2013).

Tiina Heliö, a cardiologist at the University Hospital of Helsinki who specializes in hereditary cardiovascular diseases, has just started working with Blueprint and recently sent the company more than 200 cardiomyopathy patient samples for a clinical research study. "We have an obvious clinical interest in genotyping patients but it has so far been difficult because the cost has been high, and there has not been any laboratory in Finland which provides clinical services for patients," she told CSN. "We hope this system could be applied soon for clinical purposes as well."

Right now, she is sending patient samples to laboratories "all over the world" for analysis, mainly in Europe and the US, and getting results back typically takes several months. "Surely, it would be a great advantage to have a good laboratory in the vicinity," she said. "Also, the communication would be a lot easier."