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Human Genetics
14.06.2017

New Route to Diagnosis

Scientists have presented a new approach finding genes responsible for rare genetic disorders. To this end, a team at Helmholtz Zentrum München and the Technical University of Munich (TUM) doesn’t only look at DNA, but also at RNA. The new method significantly increases the chances of a successful search, as the researchers report in ‘Nature Communications’.

Gene sequence

Scientists have presented a new approach finding genes responsible for rare genetic disorders. Source: Fotolia/Catalin

Taken in the aggregate, so-called rare illnesses are anything but rare. They affect about eight percent of the global population. The majority of these conditions have genetic causes. To develop treatments, it is important to determine which genes trigger an illness. For some years, researchers have been able to sequence the entire genome. This also contains the information on the mutations causing the illness. The difficulty is to find it.

Difficult initial conditions

"Imagine a list with three million base pairs. That's an enormous amount of data in itself," explains Dr. Holger Prokisch, who heads a research group at the Institute for Human Genetics at Helmholtz Zentrum München and at the TUM. The mere presence of mutated genes in the list is by no means proof that the cause of the illness has been found: Every person carries genetic variants. In most cases they are harmless. Therefore, scientists have to compare different data sets to be able to make statements about changes in the genome at all. Without software, the search for the mutations that trigger diseases would be completely hopeless. And even with software, it is possible only with clever tricks. To limit the volume of data, for example, the search is often restricted to the "coding" regions of the genome. As a result, the analysis excludes segments of genes that do not contain specific instructions to build a molecule. But even with this approach, the success rate is just 50 percent.

New approach via RNA sequencing

"Our approach was to sequence not only the DNA but also the RNA from cells," says Laura Kremer, a first author of the study.* "A particular advantage of this method is that sequencing RNA reveals where the errors in executing the code from the DNA are. Even when there is no variation in the blueprint for a given molecule, variations in non-coding parts of the genome may influence how the blueprint is realized," adds Daniel Bader, who is also a first author. Looking only at the coding parts of the genome, these variations would not register. Sequencing the whole DNA, in turn, makes it possible to see all variations but does not tell researchers whether they have any effects at all.

In their study, the team investigated skin cell cultures taken from 48 patients with mitochondrial hereditary conditions. These conditions affect the metabolism of individual cells. Using new algorithms, they were able to make a definite identification of the triggering gene in 10 percent of the samples. In the remaining 90 percent, they were able to narrow down the number of candidates to just a few genes.

Holger Prokisch says that the procedure can be adapted to analyze other genetic conditions besides the mitochondrial diseases. "What's more, we use skin cells for our cultures, which can be removed almost pain-free. Especially with sick children, this is important."

Julien Gagneur, a professor of computational biology at TUM, is convinced that RNA sequencing will become a routine method for doctors in the future, alongside genomic analysis: "To find the causes of rare genetic conditions, it is essential to investigate the non-coding part of the genome as well. That's exactly what our method can do."

Further Information

* RNA – ribonucleic acid – is the name for a group of molecules in the cell whose function includes executing the blueprints coded in the DNA. Based on the composition and number of RNA molecules, the team was able to draw conclusion about specific problems in the DNA.

Parallel to the work of Prokisch, Gagneur and their team, a group at the Broad Institute in the USA was working on a similar approach. However, their cell cultures used muscle tissue, which can be sampled only through a relatively invasive procedure.

Original Publication:
Kremer, LS. Et al. (2017): Genetic diagnosis of Mendelian disorders via RNA sequencing. Nature Communications, DOI: 10.1038/ncomms15824



As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,300 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. 

The Institute of Human Genetics (IHG) at the Helmholtz Zentrum München and the Technical University of Munich: The Institute is concerned with identifying genes associated with disease and characterizing their functions. The main aim of the research projects is to develop disease-related genetic variation in humans and mice as well as to develop chromosome analysis techniques and new methods for dealing with specific issues in the sphere of pre- and post-natal diagnostics and tumor cytogenetics. 

Technical University of Munich (TUM) is one of Europe’s leading research universities, with more than 500 professors, around 10,000 academic and non-academic staff, and 40,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, com-bined with economic and social sciences. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf Mößbauer have done research at TUM. In 2006 and 2012 it won recognition as a German "Excellence University." In international rankings, TUM regularly places among the best universities in Germany.