Guidelines for diagnostic next-generation sequencing We present, on behalf of EuroGentest and the European Society of Human Genetics, guidelines for the evaluation and validation of next-generation sequencing NGS applications for the diagnosis of genetic disorders. The statements that were written during the elaboration of the guidelines are presented here. The background document and full guidelines are available as supplementary material. They include many examples to assist the laboratories in the implementation of NGS and accreditation of this service. The work and ideas presented by others in guidelines that have emerged elsewhere in the course of the past few years were also considered and are acknowledged in the full text.
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The investigators collected experiences of the practical challenges that researchers face. To exercise this right, they must be informed about the processing of their data in research repositories, but the way in which some repositories are set up can make it difficult for researchers to comply with the law.
The destruction of such data eliminates resources that may be useful in the future and therefore reduces research efficiency. The current difficulties stem from the fact that legal and ethical design are not always embedded into the planning of a system from the beginning. And while the GDPR needs to be interwoven into the everyday work of researchers, it is still a fairly new regulation. It is the same with the GDPR, that in essence is a good piece of law. What we are facing now with the repositories is that they are often based outside the EU or in in one EU member state as the UK model without taking into account all EU member state regulations," says Dr Mascalzoni.
They may be able to share data with reviewers and editors, and in some cases with other researchers who request the data for specific purposes, but not more widely. If a law prohibits a practice it is difficult to require individual scientists to either disobey or be excluded, so exceptions and waivers should apply.
If we are to operate in an open, efficient science environment, we need to build a safe place where researchers and patients can participate knowing human rights and research are taken seriously simultaneously", Dr Mascalzoni concludes. This study investigates how the new EU data protection regulations affect data sharing and what should be done to allow for this to be done in a safe and responsible manner. But measuring liver iron is difficult and until recently could only be done through an invasive biopsy.
These genes are the driving cause of high levels of iron in the liver in populations of European, especially Celtic, ancestry, and suggest that this is most likely a systemic and not organ-related problem. This finding can point the way to simple strategies for reducing the excess.
The research is presented at the annual conference of the European Society of Human Genetics today Monday. Dr Hanieh Yaghootkar and colleagues carried out genome-wide association studies on liver iron content, measured via magnetic resonance imaging MRI , in volunteers who had provided biological samples to the UK Biobank.
Genome-wide association studies work by scanning markers across the complete sets of DNA of large numbers of people in order to find genetic variants associated with a particular condition.
They found three independent genetic variants associated with higher liver iron and involved in t he production of hepcidin, a protein that regulates the entry of iron into the blood. The investigators used a genetic approach to explore the causal link between higher waist-to-hip ratio and elevated liver iron content.
This provided genetic evidence that higher central abdominal obesity was associated with increased liver iron levels.
The fact that the mechanisms causing elevated liver iron were generalised and not organ-specific means that high iron levels probably occur in other organs too, including the brain. The researchers found an association between excess iron and many other disorders, including neuropsychiatric conditions.
Because the clinical manifestations of elevated iron levels are so diverse, a multi-specialty approach will be needed to assess and evaluate new therapies, including treating patients with hepcidin to reduce iron accumulation. MRI is continuing for , individuals in the Biobank study. The genetic study presented at the ESHG today reveals a key role for genes regulating iron metabolism, and also revealed a link between certain types of obesity and iron overload.
In cases where the genetic mutation causing the disorder is not present in either parent it is assumed to be a one-off event with a very small chance of recurrence. Identifying such high-risk families and providing an accurate assessment of their chances of having a unaffected child is therefore a high priority for clinical geneticists.
Currently, most diagnostic genetic services utilise DNA extracted from somatic tissues, for example blood or saliva, where the genetic information is not transmitted to the next generation.
Analysis of these tissues alone hinders the obtaining of true recurrence risk estimates for individual families. The study stratifies each family into one of seven scenarios that account for the parental origin of the DNM and the developmental time at which the mutation is likely to have occurred.
Tissue samples from the mother, father and child are studied. While the researchers detected some mosaicism in these parents, in most cases the DNM was undetectable in their samples.
When the mutation has been shown to have originated from the father, this confirms that the risk of recurrence is very low. Parents who are themselves healthy, but have already had one or more children with a developmental disorder caused by a defined DNM and who wish to have another child, are invited by their local Clinical Genetics team to participate in the study.
Ethical approval to conduct this study in families throughout England has been given, so the investigators hope to recruit many more families. This can have important consequences for the couple and can result in instances of voluntary but unwarranted childlessness, poorly-justified use of expensive in vitro fertilisation or prenatal diagnostic procedures, and sometimes the avoidable birth of children with a recurrence of serious genetic disorders.
By studying DNA mutations in different samples from parents of a child with a developmental disorder, the researchers aim to provide information about the chance that next pregnancies could result in another affected child.
This study shows the importance of genetic studies not only to provide a diagnosis but also to provide relevant information for family planning. Currently, it can only be diagnosed in pregnancy by carrying out an invasive test that has a small risk of miscarriage and is therefore sometimes declined by parents. Although cell-free fetal DNA testing is already available for some disorders, technical difficulties have hampered the development of such a test for SCD, despite it being one of the most commonly requested prenatal tests in the UK.
Non-invasive prenatal diagnosis NIPD of conditions that are inherited in this way is difficult. The researchers analysed samples from 24 pregnant SCD carriers. Using unique molecular identifiers, a kind of molecular barcode, they were able to reduce errors, and by only analysing smaller fragments they were able to enhance the fetal contribution to the samples.
This led to successful diagnosis of the sickle cell status for 21 of the 24 pregnancies, in samples from as early as eight weeks gestation, with three samples giving inconclusive results.
Further development and validation of the findings is ongoing. Worldwide, there are over children born with SCD each year. It is the most common genetic haematological disorder, with millions of people currently affected across the globe.
Approximately couples at risk of passing on the disease per year are detected through the national antenatal screening programme, which offers carrier testing to pregnant women and if appropriate their partners. Prenatal diagnosis is available to these couples to test whether the fetus has SCD.
Previous research has shown that if the option of a non-invasive test were available, more women whose fetus is at risk of sickle cell disease would opt for prenatal testing2. These scientists have developed a novel state-of-the art genomics approach to do this for sickle cell disease in couples at risk. Their first results presented at the ESHG conference indicate that their test is very promising. Although they have a genetic cause, this is often difficult to detect through standard genetic analysis of the parents.
Analysis of these trios yielded more than 45, DNMs. They developed an improved method to test for the enrichment over-representation of damaging DNMs in individual genes. The prevalence increases with the age of the parents. The disorders usually become apparent during childhood and include such conditions as autism spectrum disorder, attention deficit hyperactivity disorder ADHD , intellectual disability, and Rett syndrome.
They may be mild, but in many cases they are severe, and those affected will need lifetime support. However, when they are unidentifiable making a decision on the best care for the affected child is difficult. Given the size of the dataset, the researchers were not surprised to have been able to identify new genes. However, the identification of 40 new genes already provides valuable information to clinicians and to drug developers.
By combining data on new mutations identified in the DNA of more than This study shows the power of large-scale international collaboration to advance our understanding of this disorder and improve diagnostics as well as patient management.
A study to be presented at the annual conference of the European Society of Human Genetics tomorrow Saturday has uncovered new potential genetic causes, and this discovery will help to develop better diagnostic tests for male infertility. Ms Manon Oud, from the Radboud University Medical Centre, Nijmegen, The Netherlands, will describe to the conference how she and her team carried out the first exome sequencing study to investigate the role of de novo mutations genetic changes that are not present in the DNA of the parents of an individual in male infertility.
The exome is the DNA sequence of genes that are translated into protein, where most of the currently-known disease-causing mutations are situated. But in some cases they have a strong effect on gene function and can lead to disease. Until now, their role in male infertility had not been studied. Comparison of the parental DNA with that of the offspring enabled the identification of the de novo mutations.
The researchers hope to screen more patients and their parents in order to search for patterns in the locations of the novel mutations, and to learn more about the function of the genes that are affected by them.
The results will help establish new diagnostic tests, which will be able to provide a patient with a detailed analysis of the reason for his infertility, and allow for personalised care. By establishing the molecular cause of infertility, the risk of transmitting infertility to another generation can be predicted. The de novo mutations leading to infertility can result from errors in DNA that occur during the production of sperm and egg cells of the parents, or during the early development of the embryo.
Although by their very nature these spontaneous mutations cannot be predicted, in other diseases patients with a highly similar presentation of a disease often have mutations in the same gene. People still tend to think that failure to conceive is more likely to be caused by a female factor. It makes therefore perfect sense to compare the DNA of infertile patients to that of their normally fertile parents, as was done in this study.
This new approach may hopefully provide more insight into the underlying causes and help to provide relevant information to couples affected. The protocol, an addition to the Convention on Human Rights and Biomedicine, lays down rules on the conduct of genetic tests, including direct-to-consumer testing.
It specifies the conditions under which tests may be carried out on persons not able to consent, with particular attention to children, and addresses privacy issues and the right to information obtained through genetic testing. It also covers counselling and screening. The protocol enters into force thanks to its ratification by five Council of Europe member states Norway, Montenegro, the Republic of Moldova, Slovenia and Portugal.
The major push for ratification came from the Czech Presidency of the Council of Europe, following extensive lobbying by the Czech Society of Medical Genetics and Genomics. The ESHG therefore welcomes the Council of Europe protocol and believes that it will be an important factor in ensuring that genetic progress continues to be applied in the most ethical way possible to the benefit of all concerned. The prize is awarded to an outstanding young researcher in the field of human genetics.
The prize honours the memory of Dr. Leena Peltonen, a world-renowned human geneticist from Finland who died in , and contributed greatly to the identification of disease genes for human diseases. Her research focus is onfunctional genetic variation in human populations.
She and her research group at NYGC study regulatory variation affecting the transcriptome, as well as cellular mechanisms underlying genetic associations to diseases. The work of her research group links computational and population genomics to experimental molecular biology.
She plays a major role in several consortium projects thatproduce essential resources for the human genetics and genomics research community, creating and integrating functional genomics data sets from hundreds or thousands of people.
In the UK there are approximately 90, admissions to neonatal intensive care units per year. Nearly all these patients receive antibiotic therapy during their hospital stay, but babies with a specific genetic change can suffer irreversible hearing loss as a result.
Now, in a collaboration between Manchester-based geneticists and a molecular diagnostics company, a rapid test for distinguishing those infants who will have this adverse reaction to the antibiotic gentamicin has been developed. We are thus able to avoid the antibiotic-related deafness that can occur in infants with this genetic mutation.
But, in new-borns, a particular mutation in mitochondrial DNA2that is present in one in every of the population, means that a single dose of gentamicin can cause profound and irreversible hearing loss. All children admitted to these centres will be tested for the genetic change and antibiotics tailored accordingly.
Identifying those patients within an hour can now allow doctors to prescribe alternative drugs in this group of patients, whereas the majority of patients can safely use the standard antibiotics. Development of a point of care pharmacogenetic test to avoid antibiotic related hearing loss in neonates Session C01 - Precision and Predictive Medicine, Saturday, June 15, - hrs 1 Sepsis, also referred to as blood poisoning or septicaemia, is a potentially life-threatening condition, triggered by an infection such as pneumonia or a urinary tract infection.
In neonates the symptoms of sepsis can include extreme tiredness, mottling of the skin and an abnormally fast breathing rate.
ESHG Flashletter 1/2013
Past ESHG Meetings