‘Untraceable’ genetic abnormalities detected by new diagnostics

It is widely applicable and increasingly produces molecular diagnoses

Demonstrate hidden genetic defects by applying an existing method differently to an existing dataset. Researchers at the Radboudumc have succeeded: they showed that the ‘Expansion Hunter’ method detects errors in the DNA that lead to repeat expansion diseases, such as the movement disorder ataxia. This result offers fellow researchers worldwide a guideline for the application of this method, because it increases the chance of finding genetic causes.

With the current diagnostic technique for hereditary disorders, it is possible to map all 20,000 genes in our DNA at once. Doctors are increasingly opting for this so-called exome technique: it is widely applicable and increasingly produces molecular diagnoses. The exome technique is particularly suitable for finding simple changes in the DNA.

Repetitions in the DNA
In a publication in Genetics in Medicine Radboud university medical center researchers have now shown that the technique can also be used to find a much more difficult type of change in DNA: so-called repeat expansions. This is a type of mutation in which the same number of, usually three, building blocks of the DNA (nucleotides) in the genome are repeated in sequence. Examples of abnormalities caused by repeat expansions are fragile X syndrome and Huntington’s disease. Erik-Jan Kamsteeg, laboratory specialist in the Department of Clinical Genetics: “Sometimes we knew there had to be an abnormality, but it did not show up in the exome test. Then this part of the dataset was ignored, as it were thrown away. But we knew there were gaps, that we didn’t see everything. ”

The researchers then investigated whether it is possible to apply the repeat expansion analysis to already available data from 2700 patients with a movement disorder. When reading their genes, no cause had previously emerged, while in this group of patients there was a very strong suspicion of a hereditary abnormality. With this new analysis, the cause of the abnormality was found in seven patients, without performing laboratory experiments.

Associate Professor of Genome Bioinformatics Christian Gilissen: “These numbers may seem small, but the impact for diagnostics is of great value. Because if every genetic center is going to do this, and we have now shown that it can be done easily, you can now still make a diagnosis for a lot of patients where the cause of their condition has remained unknown. And we know that a diagnosis in itself is already very important for the patient, because it offers certainty and an explanation, can provide a prognosis of the course of the disease, but also the opportunity to contact fellow sufferers. ” In addition, the patients do not stand alone, but finding the correct molecular diagnosis also affects the risk for the condition in children and other family members of patients.

Causes of movement disorder ataxia
In this case, the researchers looked in particular at the movement disorder ataxia, because it is known that repeat expansions are often a cause of this. Ataxia is mainly caused by disease or damage to the cerebellum (cerebellum). The main function of the cerebellum is to ensure a perfect adjustment in the cooperation between muscles, so that a smooth movement is created. When the cerebellum is affected, people have problems with their motor skills: walking, articulating and swallowing are more difficult, and they can suffer from trembling hands or double vision. The seven new molecular diagnoses that have now been found for ataxia consist of six relatively known causes, which had not been detected before, despite years of research.The researchers also found one exotic dominant ataxia (type 12) that has only been described three times worldwide. is.

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