Cracking the genetic code in MND

Cracking the genetic code in MND

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Hi, I’m Heather, a PhD student from King’s College London, and a Communications Ambassador for the 34th International Symposium on ALS/MND which was held in Basel last December. Over 1,300 attendees from around the world gathered to connect with researchers and people affected by MND and engage with the latest research presented in the platform presentation and poster sessions. In this blog post, I will be sharing several of my personal highlights of the symposium, which cover how differences in our genetic code can be explored to understand their effects on MND risk and progression.

What is genomics and why is it used in MND research?

Genomics is the study of the complete genetic code, or genome, of an individual. This code, which contains all of the instructions for our cells to work, is stored in a structure called DNA. DNA is housed in structures called chromosomes in the nucleus or ‘hub’ of each cell. We inherit 23 pairs of these chromosomes from our parents. DNA is organised into sections called genes, which contain both coding and non-coding parts. The coding parts, which are sections of the genetic code that contain the building blocks of DNA, carry specific instructions for making proteins, which are vital for performing all tasks in every cell of our bodies.

Exploring genomics is crucial to MND research because MND is a complex disease. This means that instead of a single gene causing the disease, there could be a mixture of gene interactions and variations that can increase the risk of MND. Researchers use information about our genes to figure out the complex genetic factors that contribute to the risk and progression of the disease. This helps us to understand why some people may be more prone to developing MND and how the disease develops over time. Scientists use fast and efficient approaches, such as next generation sequencing (NGS) and bioinformatics, to study genetic information on a large scale. NGS helps to read the genetic sequences, and bioinformatics involves using computational tools to gather, organise and analyse genetic information generated with NGS.

Applications of genomics in MND research include:

  • Genetic testing and counselling: This helps people to understand if they have a genetic link to MND, and also provides support and guidance to people with MND and their families based on genetic insights
  • Personalised medicine: By understanding the genetic makeup of individuals with MND, researchers can customise medical approaches towards more effective treatments.
  • Targeted therapies: Genomics helps to identify specific genetic factors involved in MND. This knowledge can pave the way for developing treatments that address the root causes of disease.

Using large-scale genetic information for insights into the complex genetics of MND

The power of massive data sets are really important for understanding the complex genetic factors of MND as you can more easily analyse them to reveal large-scale patterns and trends. Project MinE is one large international effort which aims to sequence the DNA of over 25,000 people with MND and controls. This data has been used in many studies, helping us understand the genetic factors of MND risk and progression. Project MinE is crucial for finding genes that could provide more personalised diagnoses for people with MND.

Dr. Alfredo Iacoangeli from King’s College London conducted a study using Project MinE’s extensive sequencing data, focusing on a crucial aspect of MND genetics called oligogenicity. Oligogenicity refers to individuals that carry DNA variants in more than one MND-associated gene. Individually, these genetic variations may have small effects on the risk of developing MND, but when inherited together, they contribute more significantly to the overall risk of MND. In his research on 24 MND-related genes, Dr. Iacoangeli found that more than 25% of people with MND had one variant, while 6% were oligogenic, meaning they carried more than one variant.

This study also found that individuals with multiple variants had an increased risk of MND. While there was no difference in the onset of MND, those with oligogenic variants had shorter survival and faster disease progression, especially if one variant was the C9orf72 mutation, which is one of the most common gene mutations in MND. This study emphasises the importance of looking at the genetics as a whole, rather than just focusing on individual genes. This will help provide a more comprehensive understanding of the disease’s complexity and could lead to more accurate prognosis for people with MND.

Creating Clear Guidelines for Genetic Testing and Counselling

Dr Jennifer Roggenbuck from Ohio State University Wexner Medical Center highlighted the need for clear genetic testing and counselling guidelines for people with MND. She worked with experts in neurology, genetics, and patient advocacy to develop these guidelines, with the aim of providing consistent and effective care for people with MND and their families.

These guidelines are ready-to-use for multiple health care professionals in the USA, which includes neurologists in private practices and nurse and general practitioners when neurologists or genetic counsellors are not available. The guidelines can also be used in academic settings to inform future research studies worldwide.

These guidelines are available as a 35-item recommendation checklist, and cover five main areas:

  1. Everyone with MND should have access to thorough genetic testing, which covers specific genes strongly linked to MND and those associated with FDA-approved therapies
  2. Laboratories should use consistent methods for reporting results of genetic testing. This ensures accuracy and reliability in the interpretation of genetic information.
  3. Patients should be informed about which genes were tested and be provided with clear explanations of what the results mean. Individuals will be empowered with the knowledge of genes tested and the implications of their results, which promotes informed decision making.
  4. Individuals and their families should have access to information and support throughout the genetic testing process, including before and after testing, which will ease the emotional and practical challenges associated with genetic testing.
  5. Individuals receiving positive results should be provided with support to understand their genetic risks, access available therapies, and be guided on participating in clinical trials

Work is still needed to see how many healthcare providers and academic researchers are following and correctly using these recommended guidelines, and make sure they can be successfully used worldwide. Nevertheless, these clear guidelines will hopefully enhance the overall care and support for individuals with MND, contributing to a more informed, coordinated and patient-centered approach to genetic testing and counselling.

Blood samples in tubes with a genetic testing label

Blog | 10 August 2023 | Research Dev Team
Developing a patient decision aid for genetic testing in MND

Non-Coding DNA – more than just junk?

In the Genetics and Genomics session, Yan Wang, a PhD student from UMC Utrecht,  introduced SpliPath, a computational tool that looks at DNA and RNA sequences to find non-coding events which may affect the genetic risk of MND. Around 98% of our DNA is non-coding, which means that they do not provide instructions for making proteins. For this reason, we often call it ‘junk DNA’. However, this non-coding DNA actually contains important elements which control when genes are turned on and off, maintaining the overall function of our genetic code.

Wang’s research is focused on specific regions of non-coding DNA called introns, which are found within genes. She is particularly interested in how editing processes that remove introns from genes before creating instructions for building proteins, are altered in MND. She emphasised that SpliPath is an important tool because it helps to identify unusual editing processes that may produce proteins that do not function properly. Examples of these events include skipping parts or creating hidden sections of the genetic code or making sections shorter or longer.

These editing processes are tricky to spot by looking at only RNA or DNA. Wang used SpliPath to analyse DNA and RNA from brain samples from 293 people with MND and 76 controls (people without MND). SpliPath checks the RNA to find new parts of the genetic code where editing might happen.  It also finds changes in DNA that are predicted to strongly alter editing events. Both of these results are then combined and analysed. SpliPath found over 7,000 potential editing sites with DNA changes in both people with MND and the general population. Wang then narrowed down the results to 794 sites that were more common in people with MND.

By doing this, she was able to:

  • Concentrate on 17 genes known to cause MND. New disease-causing editing sites were found in genes that have DNA changes and are known to disrupt normal function in cells, such as KIF5A and NEK1
  • Detect DNA changes affecting editing processes in less-studied genes which control gene activity and stability, such as ELP3 and NEK6. When gene activity and stability is disrupted anywhere in the genetic code, it can lead to errors in processing of genetic information, which affects the production of vital proteins and causes cells to function abnormally.
  • Reveal hidden sections of the genetic code linked to TDP-43, which is the protein that behaves abnormally in the brain and is a key player in the disease.

SpliPath helps to understand how changes in DNA affect editing processes in people with MND. This could be crucial for identifying new targets for gene therapies to treat MND and could open new avenues for personalised treatment options for individuals with MND.  


To sum up, the symposium was a wonderful experience, and it was truly encouraging to see just how enthusiastic everybody was in trying to advance our understanding of MND. Genomics is a really exciting and cutting-edge field and the research presented here has massive potential to advance our understanding of how genetics can influence the prognosis of MND, improve genetic testing and counselling, and identify new target for gene therapies to treat MND. The future of MND research looks very bright indeed!

We would like to thank Heather for taking the time to write this blog and also for being a Symposium Communications Ambassador. You can follow Heather on Twitter/X here.

The MND Association’s vision is a world free from MND. Realising this vision means investing more in research, further developing partnerships with the research community, funding bodies and industry, while ensuring that advances in understanding and treating MND are communicated as quickly and effectively as possible. Our Research Development team, composed of 11 members, work hard to achieve this. Principally, the Research Information team within this are involved in communication activities including this MND Research blog.