Dr. Nika Schuermans

 Identifying genetic causes of unexplained rare neurological disorders 

(promotor Prof. Bart Dermaut) 

Rare brain and nerve disorders that appear in adults are often hard to figure out because they can show up in many different ways and have complex genetic causes. These diseases are serious and can lead to major health problems or even death. As people live longer, the number of these brain-related disorders is growing. 
Getting a clear genetic diagnosis is important. It not only helps people understand their condition, but it can also guide treatment choices. Plus, it gives patients more control over their family planning, allowing them to consider genetic testing for future pregnancies. 

A technology called next-generation sequencing (NGS), especially whole-exome sequencing (WES), has really improved how doctors diagnose these rare disorders. It looks at all the important genes at once, which has helped discover new disease-causing genes. Despite this, about half of all people suspected of having a rare genetic disease still don't get a diagnosis. 

This research paper had two main goals: 

1. To see how well WES works in diagnosing unexplained rare neurological disorders in adults and to find out its limitations. We also wanted to see if re-examining the genetic data later on helps.
2. To find new genes that cause diseases and understand how these diseases work, using advanced genetic methods.

Here's what Nika found: 
Part 1: How well WES works 

• WES successfully diagnosed about 10% of adult patients with neurological conditions.
• It worked best for people with problems like ataxia (coordination issues) or spastic paraplegia (muscle stiffness), diagnosing 19% of them.
• It was less effective for conditions like leukoencephalopathies (white matter brain diseases, 8%) and movement disorders (6%).
• A special program called UD-PrOZA, which involves different medical experts, advanced genetic tools, and international teamwork, helped diagnose an additional 18% of patients at Ghent University Hospital. This shows how crucial a team-driven approach is.
• Re-analyzing the genetic data later on helped solve another 10% of cases that were previously undiagnosed. This means that if you get a negative or unclear WES result, it's a good idea to have it re-checked periodically.
• They also found that using special computer tools to look for bigger changes in the DNA (called structural variants) within WES data added significant diagnostic value.

Part 2: Discovering new diseases and understanding them 

• This part of the research identified two new diseases.
• They found that a problem with the PLAAT3 gene causes a condition involving fat tissue disorders and neurological symptoms. This is due to issues with how fat cells develop.
• They also discovered a new genetic change in the TARDBP gene that causes a muscle disease, which is different from the well-known ALS/FTD diseases also linked to this gene. This specific change seems to reduce harmful effects in nerve cells and cause problems in muscle cells.

In summary: 

This research gives a good overview of how well current genetic tests work, and tells us their limitations, for diagnosing rare, especially neurological, diseases. It shows that: 

• Re-examining genetic data, international collaboration, and advanced computer analysis are vital to get the most out of genetic sequencing.
• Combining different research methods (like studying cells in the lab and observing live organisms) is important for truly understanding how genetic changes lead to disease.
• New technologies like "long-read WGS" and "optical genome mapping" hold great promise for finding missing genetic causes and further improving diagnosis, ultimately leading to better treatments for rare diseases.