Rare genetic disorders: New approach uses RNA in search for genetic triggers

June 13, 2017
This is a computer graphic of an RNA molecule. Credit: Richard Feldmann/Wikipedia

In about half of all patients with rare hereditary disorders, it is still unclear what exact position of the genome is responsible for their condition. One reason for this is the enormous quantity of information encoded in human genes. Scientists from the fields of informatics and medicine have now joined forces to find a solution: A team at the Technical University of Munich (TUM) and Helmholtz Zentrum München has developed a method that significantly increases the chances of a successful search. The new approach looks not only at DNA, but also at RNA.

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 . In other words, they can use a tissue sample from a patient to create a list containing all of the genetic information from a patient's genetic material. The sequenced genome 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 TUM Institute for Humane Genetics and at the Helmholtz Zentrum München. 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.

In order to tell, which parts of the genome are altered, scientists have to compare different data sets. 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.

An international team from the fields of medicine and informatics headed by Prof. Prokisch and Julien Gagneur, a professor of computational biology at TUM, has developed a new approach that complements previous methods.

A new approach produces new results

"Our approach was to sequence not only the DNA but also the RNA from cells," says Laura Kremer, a first author of the study. 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.

"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," says 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 ten percent of the samples. In the remaining 90 percent, they were able to narrow down the number of candidates to just a few genes.

A new standard?

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." 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 used muscle tissue, which can be sampled only through a relatively invasive procedure.

Julien Gagneur 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."

Explore further: Disease-associated genes routinely missed in some genetic studies

More information: Laura S. Kremer et al, Genetic diagnosis of Mendelian disorders via RNA sequencing, Nature Communications (2017). DOI: 10.1038/ncomms15824

Related Stories

Disease-associated genes routinely missed in some genetic studies

April 21, 2017
Whole-exome DNA sequencing—a technology that saves time and money by sequencing only protein-coding regions and not the entire genome—may routinely miss detecting some genetic variations associated with disease, according ...

Using RNA sequencing to diagnose patients with rare muscle conditions

April 20, 2017
(Medical Xpress)—An international team of researchers has developed a way to use RNA sequencing to help in diagnosing patients with rare genetic muscle conditions. In their paper published in the journal Science Translational ...

Defect in non-coding DNA might trigger brain disorders such as severe language impairment

March 14, 2017
Genetic variation in the non-coding DNA could give rise to language impairments in children and other neurodevelopmental disorders including schizophrenia, autism, and bipolar disorder, scientists from the Max Planck Institute ...

Cause of acute liver failure in young children discovered

July 2, 2015
Acute liver failure is a rare yet life-threatening disease for young children. It often occurs extremely rapidly, for example, when a child has a fever. Yet in around 50 percent of cases it is unclear as to why this happens. ...

Largest study of its kind finds rare genetic variations linked to schizophrenia

November 22, 2016
Many of the genetic variations that increase risk for schizophrenia are rare, making it difficult to study their role in the disease. To overcome this, the Psychiatric Genomics Consortium, an international team led by Jonathan ...

Disease-causing regions of the genome that affect gene expression levels are mapped with a new method

January 6, 2016
A new technique for pinpointing the exact DNA regions that impact gene regulation lays the groundwork for identifying new drug targets and for developing diagnostics to predict disease risk, A*STAR scientists report.

Recommended for you

Gene variants identified that may influence sexual orientation in men and boys

December 8, 2017
(Medical Xpress)—A large team of researchers from several institutions in the U.S. and one each from Australia and the U.K. has found two gene variants that appear to be more prevalent in gay men than straight men, adding ...

Disease caused by reduction of most abundant cellular protein identified

December 8, 2017
An international team of scientists and doctors has identified a new disease that results in low levels of a common protein found inside our cells.

Study finds genetic mutation causes 'vicious cycle' in most common form of amyotrophic lateral sclerosis

December 8, 2017
University of Michigan-led research brings scientists one step closer to understanding the development of neurodegenerative disorders such as ALS.

Mutations in neurons accumulate as we age: The process may explain normal cognitive decline and neurodegeneration

December 7, 2017
Scientists have wondered whether somatic (non-inherited) mutations play a role in aging and brain degeneration, but until recently there was no good technology to test this idea. A study published online today in Science, ...

Researchers find genes may 'snowball' obesity

December 7, 2017
There are nine genes that make you gain more weight if you already have a high body mass index, McMaster University researchers have found.

Gene therapy shows promise against blood-clotting disease

December 7, 2017
Gene therapy has freed 10 men from nearly all symptoms of hemophilia for a year so far, in a study that fuels hopes that a one-time treatment can give long-lasting help and perhaps even cure the blood disease.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.