Worldwide, 1 to 3 percent of the world's population has an intellectual disability. In severe (syndromal) form, it is frequently caused by an abnormality in their DNA. Patients with intellectual disabilities often undergo years of diagnostic testing to arrive at the correct genetic diagnosis and thus the cause of their disease. This diagnosis is crucial for them and their families because it allows for planning further family advancement, knowing the disease prognosis, thinking out targeted treatment, and so on. Unfortunately, in 40% of patients we still cannot identify the genetic cause. 

                    A possible explanation for this can be found in the current diagnostic tests being used. Indeed, these fail to cover the whole area of genetic variability. For example, current techniques are very good at picking up variants of 1 or a few base pairs and also very large variants of 50 kilobases or larger. However, they are not so good at recognizing so-called structural rearrangements located in between. These are variations in DNA in which large parts of the genome are reorganized. Most of these rearrangements belong to the normal variation in the human genome, but because of their size, their impact on the phenotype is also often pernicious and they are a major cause of diseases (e.g., cri-cu-chat syndrome, velocardiofacial syndrome, several types of cancer).  

                    Several years ago, a new technique called nanopore long-read sequencing was developed, which does manage to accurately pick up structural rearrangements. This technique involves pulling DNA through a miniscule hole - the nanopore - in a membrane that is energized. Each time a different DNA base passes through the hole, the current inside the pore changes slightly. A chip inside the pore records these current changes and, using computational algorithms, these changes can then be translated back into the original base-pair sequence. Unlike classical DNA reading techniques, with nanopore long-read sequencing there is no limit on the length of the genomic sequence you read. This allows you to go up to sequences as long as four megabases, thus covering structural rearrangements in their entirety. 

                    We are going to apply the above techniques to a cohort of patients with intellectual disabilities and their parents - so-called trios. In doing so, we will look for newly formed, or de novo, structural rearrangements in the patient. These are variants that are newly formed and thus were not inherited from the parents. Such de novo rearrangements are very rare, and it is assumed that if they occur that they are most likely causal to the patient's clinical picture. 
                    Blood is taken from each member of the trio from which DNA is extracted. We read out this DNA via the above nanopore long-read sequencing and through a combination of a variety of bioinformatics techniques we identify the ~22000 structural rearrangements present in both the patient and their parents. By then meticulously comparing these variants between the patient on the one hand and their parents on the other, we are able to pick up de novo variants. Once we have identified these, we continue our search for the causal link between the abnormalities found and the patient's clinical picture.

                    Through this research, we hope to reduce the number of missed genetic diagnoses in patients with intellectual disability, and provide our patients with a concrete genetic diagnosis.