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Researchers find exome sequencing is fast and cheap
Dutch researchers in a new study have discovered that exome sequencing offers good, fast and cheap diagnosis of heterogeneous disease. Presenting their results at the recent European Society of Human Genetics (ESHG) conference, the researchers genetically diagnosed around 20% of 100 cases of patients with intellectual disability and 50% of 25 cases of patients with blindness.
Researchers at the Radboud University Nijmegen Medical Centre in the Netherlands observed that the exome test surpasses the commonly used Sanger sequencing method, which uses the deoxyribonucleic acid (DNA) as a template to produce a set of fragments that differ in length from each other by a single base. These fragments are later separated by size, and the bases at the end are then identified, recreating the original sequence of the DNA. The main advantages of exome sequencing are that it is quick and low-cost.
Dr Marcel Nelen, chief of Radboud's Core Genome Analysis Laboratory of the Genetics Department, and colleagues evaluated exome sequences from 262 patients suffering from six different heterogeneous diseases: intellectual disability, blindness, deafness, movement disorders, cancer and oxidative phosphorylation (OXPHOS).
As part of their study, 500 exome sequences were analysed. The researchers evaluated exomes from the father, mother and child for the intellectual disability cases, and only the patient's exome data was filtered by all other diseases.
'The chances of finding a causal mutation in a single gene is small,' explained Dr Nelen. 'But in a package containing more than 100 genes it is high, as our results from the blindness patients show. This new strategy means that we can analyse up to 20,000 genes with a single generic test, and the high throughput and lower cost means that we can test more for less money. But before we implemented the test more widely in our laboratory we needed to be sure that it would give us reliable diagnostic results.'
Exons are short sequences of DNA, representing the regions in genes that are translated into proteins. The human genome contains around 180,000 exons, making up about 1% of the total genome. Experts believe the exon regions contain around 85% of all mutations that cause disease despite exome sequencing only being able to identify the conditions where protein function is affected.
Compared to the Sanger method, which focuses on some 500 base pairs per analysis, more innovative sequencing technologies examine millions of sequencing reactions per analysis.
Commenting on the work, Dr Nelen said: 'There were no best practice guidelines available for exome sequencing, and so we had to create diagnostic workflows, procedures and criteria. What criteria did we have to set before we could authorise the outcome? What type of informed consent was necessary? How could we organise confirmation of our results? All these questions had to be answered, and we undertook numerous discussions with clinical geneticists, researchers and ethicists before we could get started.'
The team validated their findings via the Sanger method. Besides their observations in the intellectual disability and blindness cases, they confirmed deafness disease-causing mutations in around 20% of cases, in movement disorders between 15% and 20%, and in OXPHOS diseases around 25% of cases.
'Although it is often not possible to treat their diseases, we should take into account that most of these patients will have had a long and worrying journey through different doctors and hospitals before they are diagnosed,' Dr Nelen pointed out. 'Exome sequencing can shorten that route, and it can also simplify the work of clinicians because they don't have to make a decision about which gene to test for - with 100 or more genes per disease, that can be a very difficult decision to make.
'Exome sequencing tests for all the causative gene mutations at the same time, and that means that fast and accurate diagnoses can be made. Even if there is no treatment available, such diagnoses can help parents, patients and clinicians to make well-informed decisions on treatment and care, as well as being able to plan for the future. Genetic diagnosis is becoming more and more important in the clinic and we believe that, as it develops, the exome technique will be one of the first tests to be considered by a doctor where a genetic disease is suspected.'
Contact person:For more information, please visit:
European Society of Human Genetics:
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Data Source Provider:European Society of Human Genetics; Radboud University Nijmegen Medical Centre
Document of reference:Based on information from the European Society of Human Genetics; Radboud University Nijmegen Medical Centre
Subject index:Biotechnology,Coordination, Cooperation,Life Sciences,Medicine, Health,Scientific Research
Programme Acronym: MS-NL C
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