Some private fertility clinics have begun to sell polygenic risk scores¹ (PRSs) analyses on embryos to prospective parents.   This practice raises many concerns, says the European Society of Human Genetics in a paper published today (Friday 17 December) in the European Journal of Human Genetics*, since there is no evidence that PRSs can predict the likelihood of as-yet unborn children being liable to a specific disease in the future.

While it is quite normal for parents to consider any genetic risks they may pass to their children, this would usually be done by performing genetic testing for typical genetic conditions, such as Down syndrome or cystic fibrosis. In these cases, the disease has a single genetic cause and therefore the ability of the test to predict its development in any offspring is high.

“PRSs are a completely different matter. Many conditions are caused by a combination of genetics and environment, and PRSs are only able to capture parts of any of the relevant genetic component, which is itself likely to be highly complex and difficult to analyse.  In addition, while PRS may identify individuals at risk of a given disease in the general population (where the genetic variability is very wide) there is no evidence that they can be useful for a couple in determining the choice of one embryo over another, as the genetic variability within an individual family is limited,” says Dr Francesca Forzano, chair of the ESHG Public and Professional Policy Committee.

In addition, research on PRSs has been performed and is ongoing on liveborn, mostly adult, individuals, with the aim of deciphering the pathological mechanisms underlying complex multifactorial diseases.  No information on the value of PRSs to predict disease development in postnatal life is available for embryos. In fact such studies would be wellnigh impossible to perform in embryos, given that one might have to wait decades for the predicted disorder to appear - or not.

At present, performing a PRS test for embryo selection would be premature at best, say the authors Adequate, unbiased information on the risks and limitations of this practice should be provided to prospective parents and the public, and a societal debate must take place before any potential application of the technique in embryo selection.  Such a debate should be focused particularly on what would be considered acceptable regarding the selection of individual traits. Without proper public engagement and oversight, the practice of implementing PRS tests for embryo selection could easily lead to discrimination and the stigmatisation of certain conditions.

“It is also vital to provide prospective parents with a clear understanding of the difference between counselling and marketing,” says Professor Maurizio Genuardi, ESHG President. “And at a time when healthcare resources are under strain, it is important that the limited money available should be spent on tests that are known to be effective. Currently, research resources would be better spent on improving knowledge about how PRSs interact with the environment in which we live, rather on the premature application to our future children of an inadequately assessed test with potentially misleading results.”

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*https://www.nature.com/articles/s41431-021-01000-x

¹A polygenic risk score reflects an individual’s estimated genetic predisposition to a given disorder and can be used in predicting the likelihood of that individual developing the disorder

August 28-31, 2021, Virtual Meeting

Epilepsy is one of the most common chronic neurological diseases, affecting more than 50 million people worldwide. Although it is believed that a large proportion of childhood-onset epilepsies are caused by genetic changes, it remains unknown precisely how many of these patients suffer from a genetic disorder and how often the treatment can be targeted to their specific genetic alteration. Now, results from research to be presented at the annual conference of the European Society of Human Genetics today [Tuesday] have shown a genetic cause for their condition among half of those studied. This will not only aid in the prescription of appropriate, tailored, treatments, but also preclude the use of unnecessary diagnostic procedures, say the investigators.

Dr Allan Bayat, MD, a consultant in paediatric neurology at the Danish Epilepsy Centre, Dianalund, Denmark, and colleagues studied 290 children with a diagnosis of epilepsy or who presented with seizures accompanied by a high temperature that were either long, or in which consciousness was not regained between events (prolonged and clustering febrile seizures).  The children were born between 2006-2011 and followed at the centre in 2015.  After obtaining informed consent, the children underwent genetic testing. “We found a genetic cause in half of those tested and also that half of those again could receive a tailored treatment. We hope that drug companies and the scientific community will be able to produce new drugs or repurpose existing ones that may be being used to treat entirely unrelated conditions to improve precision treatment possibilities for those for whom this is currently not available,” says Dr Bayat.

In recent years, the number of genes known to be associated with epilepsies has risen to over 500, and gene panel testing and exome sequencing* are now routine analyses in many countries. Such testing is most important in children whose seizures commence when they are under three years of age, or with a family history of seizures, brain malformations, or cognitive comorbidities. However, in many parts of the world genetic testing is not systematically offered to such people, and there is often a long delay between the onset of symptoms and the test. Our results show that genetic testing is crucial in such patients in order that they may receive appropriate counselling and treatment,” Dr Bayat says.

An additional advantage of being able to identify a genetic cause is the avoidance of potentially harmful treatments. Genetic sequencing has shown that the majority of monogenic epilepsies, in which a single genetic change is involved, are caused by changes in ion channels, membrane proteins that are abundant in the central nervous system. While some genetic changes reduce the function of ion channels, others increase them. Most anti-epileptic drugs currently available target and block these ion channels, so treatment with them in patients with symptoms cased by genetic changes that have already suppressed ion channel function would most likely do more harm than good.

The researchers intend to continue their work with further study of those individuals where they were unable to find a genetic explanation for their epilepsy. “We will re-evaluate the dataset obtained from exome sequencing at regular intervals and perform additional genetic testing with a method that can detect genetic changes that may be missed by exome sequencing. And we hope to explore whether these patients have an accumulation of risk variants in genes or pathways associated with epilepsy when compared to those where a genetic cause has been uncovered, and to controls.

“Getting a genetic diagnosis is of great importance for the children and the families. It provides an explanation and certainty, and it enables a more targeted genetic counseling, including knowledge about the prognosis and recurrence risk. Furthermore, it allows the subject and families to enter gene specific networks of families with the same genetic condition,” Dr Bayat concludes.

Chair of the ESHG conference, Professor Alexandre Reymond, Director of the Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, said: “The field has made great progress in identifying causative mutations following the introduction of high-throughput sequencing in epilepsy patients. Despite the high occurrence of the disease and its high genetic heterogeneity with hundreds of associated genes, my colleagues can now suggest a tailor treatment to a quarter of their patients and counsel half of the families, a remarkable step forward for precision health.”

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*Exome sequencing is a technique for sequencing all of the protein-coding regions of genes in a genome. It is a quicker and cheaper alternative to while genome sequencing.  

Abstract no: C25.6 Genetic testing and its impact on therapeutic decision making in childhood-onset epilepsies - a study in a tertiary referral centre

De novo variants (DNVs), genetic mutations that were not previously identifiable in the family history of one of two prospective parents, may cause disease in any children they have. Where a disease-causing DNV is present in one parent, the risk of passing it to a child can be as high as 50% and being able to identify healthy embryos for transfer to avoid an affected pregnancy is clearly a high priority. To achieve this goal, identification of the group of genes inherited from one parent (the haplotype) that is linked with the mutation is necessary to transfer only healthy embryos. Until now this has been a difficult process and can often involve multiple embryo biopsies, which in themselves carry a risk.  But a group of Belgian researchers have developed a new, one-stop method using DNA from the parents of the affected prospective parent (the embryo’s/child’s grandparents). They will present their findings to the annual conference of the European Society of Human Genetics today (Tuesday).

Dr Eftychia Dimitriadou, Head of the Reproductive Genetics Unit at the Centre for Human Genetics, Leuven University Hospital, Leuven, Belgium, and colleagues recruited 22 couples where one of the partners carried a DNV mutation causing a Mendelian disorder. A Mendelian disorder is normally, but not always, caused by alterations in a single gene. Current practice for pre-implantation genetic testing (PGT) embryo selection for such couples is complicated, says Dr Dimitriadou. “It involves targeting a specific gene, and therefore important genome-wide information is missing.”

The researchers decided to try to streamline the process by using long read sequencing (LRS), a technique that can read the sequence of very long fragments of DNA. A major advantage of LRS is that it is much more accurate in detecting copy number variants (CNVs), that is deletions or duplications of DNA fragments, and single nucleotide variants (SNVs), i.e., alterations in the sequence of a single DNA molecule, especially in regions where the same sections of DNA are repeated. Determining the existence of such variants has important implications for the diagnosis or prediction of genetic disease. Specifically, LRS enables the separate sequencing of the two copies of a DNA region or fragment (in the prospective parent carrying the de novo mutation), one inherited from each parent (the ‘grandparents’ of the embryo).

“This allows us to determine whether the disease-causing mutation is located on the maternal or paternal copy of the affected chromosome in patients with DNVs,” says Dr Dimitriadou. “Subsequently, we can perform a comprehensive analysis of embryos in a single test and transfer those that are unaffected - and all this in a single workflow. However, this is the best-case scenario. On the rare occasions when the two grandparents have the same SNP profiles, interpretation is even more challenging.”

In addition to detecting dominantly inherited disease, where a single copy of the disease-associated mutation is sufficient to cause disease, the test is also able to detect embryos with a genome-wide abnormal number of chromosomes (aneuploidies). However, a comprehensive test does not mean that it is possible to detect every single genetic abnormality.

The new test only came into clinical application recently, but of the 23 IVF/PGT cycles that have already taken place, 15 embryos were mutation-free, free of detectable genome-wide genetic abnormalities, and of adequate quality for transfer. Six pregnancies resulted, and three babies have been born.

“Because children born with a genetic disorder often have severe physical manifestation, it is understandable that their parents are frequently concerned by the risk of a child being affected with inherited disease, for example, neurofibromatosis¹ or Alport syndrome². For the parents, the discovery that one of them has the disease has already imposed a huge emotional burden, and so we are proud to have been able to bring new hope to affected families. Our work is a good example of what can be achieved by a patient-oriented, multidisciplinary academic team,” says Dr Dimitriadou.

“However, there is a cloud on the horizon. New, innovative, tests such as ours, ‘home-grown’ in our hospital, may be outlawed by the EU’s In Vitro Device Regulation (IVDR) due to come into force in May 2022. The IVDR threatens the development and use of in-house, laboratory-developed tests by banning their use if there is a commercially produced ‘equivalent’ on the market. But often the test deemed to be equivalent is not sufficiently precise. Prohibiting the usage of tests for rare diseases, or those that are performed infrequently and hence of little importance to the commercial sector, threatens the facility of laboratories to develop the new, specialised diagnostic tests that are required if we are to continue to best serve the interests of patients,” she will conclude.

Chair of the ESHG conference, Professor Alexandre Reymond, Director of the Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, said: “Reproductive medicine started out with the goal of allowing infertile couples to have children. Progress has been rapid in the 43 years since the birth of the first IVF baby, leading to many advances, including in prenatal diagnosis. Now, through long-read sequencing, it can take yet another step forward and help “genetically at risk” families in their desire to have unaffected offspring.”

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¹Neurofibromatosis is a genetic disorder affecting the formation and growth of nerve cells, that causes tumours to grow on nerves.

²Alport syndrome is a genetic condition involving kidney disease, hearing loss, and eye abnormalities. Affected patients lose kidney function progressively.

Abstract no: C26.2 Comprehensive PGT for patients with de novo pathogenic variants following single-molecule long read amplicon sequencing based haplotyping

How strictly patients follow a prescribed drug treatment (drug adherence) is clearly important if the therapy is to have maximum effect. A number of things can affect adherence, including behavioural and socioeconomic factors, but to date there have been few investigations into the role played by genetics. Now, research to be presented at the annual conference of the European Society of Human Genetics today has thrown new light on the potential biological mechanisms that can affect adherence to treatment.

Mattia Cordioli, MSc, a PhD student at FIMM, the Institute for Molecular Medicine Finland, Helsinki, Finland, and colleagues examined data from the FinnGen¹ study, from Finnish nationwide health registries, and the national drug purchase registry to try to uncover determinants of adherence across different medication groups. Using information on the date that the individual purchase was made, and the quantity purchased, they were able to define adherence by dividing the initial quantity by the number of days, with reference to the prescribed daily dose.

The researchers then carried out a genome-wide association study (GWAS)² to see if genetic variants might help explain variation in adherence. “We used these results to see whether we could find a correlation between adherence and other traits that are controlled by multiple genes, rather than just one (polygenic traits). We found that a positive genetic correlation between adherence and other traits, for example, educational achievement, meant that individuals with a genetic predisposition for higher educational achievement tended to be more adherent. On the other hand, those with a genetic predisposition for risk-taking were less adherent to the medication schedule,’ says Mr Cordioli.

The researchers also found that, while a genetic predisposition for higher systolic blood pressure was correlated with increased adherence to blood pressure medication, there was no such association in patients with such a predisposition for higher LDL (bad) cholesterol and statin adherence. “This is interesting and may reflect the need for better feedback on the action and efficacy of a particular medication in order to improve adherence,” says Mr Cordioli. Drug adherence was also positively correlated in patients with a genetic predisposition for type 2 diabetes and higher body mass index, suggesting that patients in higher risk categories tend to be more adherent.

Demographic and socioeconomic factors remain important, though they are probably rather more related to access to treatment than compliance with a drug regime. But studying individual genetics can unveil possible biological mechanisms affecting adherence. Their sample size to date has not been large enough for them to look at medications that are less commonly prescribed to see whether specific biological factors are involved in adherence there, too, but the researchers suggest that it would be worthwhile to do so.

“Our research has shown that adherence pertains more to an individual’s predisposition to a particular behaviour rather than to underlying biological factors such as the adverse effects of a particular drug. We are hopeful that the identification of those patients who are less likely to adhere to drug therapy may encourage and facilitate the design of effective information campaigns directed at them,” Mr Cordioli says. 

“Along with the advances in genetic testing that can show how an individual responds to drugs and therefore allow the prescription of tailored treatment, we believe that further biological investigations into individual adherence may make a valuable contribution to the design of new standard clinical practice in the future”, he will conclude.

Chair of the ESHG conference, Professor Alexandre Reymond, Director of the Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, said: “Adherence to a prescribed treatment has not previously been looked at from a genetic point of view and finding that this is potentially more linked to behavior than to adverse effects gives us clues on where the health system should put its efforts to gets the best results.”

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¹The FinnGen project was launched in 2017 with the aim of producing a data resource with genome data of 500,000 biobank sample donors in Finland (about 10% of the population) over six years with the aim of improving health through genetic research.

²GWAS are observational studies of a genome-wide set of genetics variants in individuals to see if any variant is associated with a trait. Such studies compare the DNA of participants with varying phenotypes (observable characteristics) for a particular trait or disease.

Abstract no: C17.5 Genetic and environmental determinants of drug adherence and drug purchasing behaviour.

The EU’s General Data Protection Regulation (GDPR) has created a great deal of uncertainty about how key requirements should be interpreted. This means that collaborators in international genetic research projects do not always agree on fundamental issues such as whether they are processing personal data, consent requirements under the GDPR and on what basis genetic data can be transferred outside the EU/EEA, if at all.  These results from a study carried out by Colin Mitchell, Senior Policy Analyst in Law, Regulation and Digital Health, and colleagues from the PHG Foundation, University of Cambridge, UK will be presented to the annual conference of the European Society of Human Genetics today (Monday).

The investigators carried out legal research, interviews, and held an expert meeting to investigate the subject. They were supported by the UK Information Commissioner’s Office, responsible for national data protection. “This topic is of great concern to scientists and people working in genetic medicine because of the way that the GDPR made significant changes to the way that personal data from patients or research participants may be used,” says Dr Mitchell. “These changes are not specific to genetic data, but because such data are highly sensitive, their impact on the genetics field is considerable.”

Their analysis demonstrates that a range of legal interpretations are possible, and that other parts of the regulation, like those setting out ‘data subject rights’, are also potentially ambiguous in the genetic context. For example, interpreting the ‘right to access’ data in the genomic context will be complicated because multiple individuals or family members might be able to claim the data as their own.

Another problem is how to characterise ‘personal data’ (those data that can be used to identify an individual), as opposed to data that cannot be used in this way. The GDPR requires that a risk assessment be undertaken to see what sources of information could lead to identification. In the genomic context, finding agreement on this can be particularly challenging. And now, recent developments such as the growth of ancestry websites can complicate things further.

In the UK, Brexit is another new difficulty. The UK is a leader in genomic healthcare and research, and it is vital that collaboration with individuals and institutions in the EU/EEA should continue, say the researchers. “The UK is now a ‘third country’ and therefore subject to strict rules about receiving data from the EU. Now, the UK’s rules are almost identical to the GDPR. But should they diverge in the future due to changes on either side, this will pose a major problem,” says Dr. Mitchell.

Having identified the challenges associated with the GDPR and its impacts, the researchers looked into measures that could reduce these. “We believe that it will be possible to pursue a more genetics-sensitive approach with the regulators,” Dr Mitchell says. “And the GDPR also contains some mechanisms that could allow the genomics community to develop best practice for compliance with the regulation and set this out incodes of conduct or certification schemes to demonstrate compliance with the law. Developing such a system will not be easy, but it is crucial if confusion about data protection law is not to act as an unwarranted barrier to data sharing and scientific progress in genetics.”

Because of the high potential sensitivity and identifiability of genomic data, it is crucial that the correct balance between individual privacy and genomic science and medicine is struck. Getting this right is essential to avoid a breakdown in trust between the public and professionals that could lead to considerable, long-lasting harm to healthcare and scientific research.

The GDPR may have brought this issue into sharper focus, but it is not a new problem. “We were surprised to find that some of the major challenges and uncertainties related to legal standards that already existed in previous EU law. What has changed, though, is how these may need to be interpreted and how that interpretation now should be uniform across the whole EU/EEA. True coordination of the interpretation of the GDPR for genetic data across all the Member States will take time, and may be very difficult in practice”, says Dr Mitchell. “Though to some this may appear to be a somewhat technical and esoteric issue, it is absolutely essential to get it right if we are to continue to exploit the enormous potential of genetic medicine to the best of our ability.”

Chair of the ESHG conference, Professor Alexandre Reymond, Director of the Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, said: “Choosing between an individual’s privacy and the responsibility of a nation regarding the health of its citizens that can only progress with the exchange of increasing amounts of data has become more and more difficult. Legal standards are not adapted to the fast pace of technological change in genetics. Society as a whole will need to decide where the balance should be.”

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The research was funded by the UK Information Commissioner’s Office as part of their innovation grant scheme.

Abstract no: PL2.6 The impact of the GDPR on genomic medicine and research

Although epilepsy is a relatively common condition, affecting approximately 1% of individuals worldwide, it is often difficult to diagnose in clinical practice, and it is estimated that up to a quarter of all cases may be misdiagnosed initially. Epilepsy is often inherited, and recent research has shown that sufferers have elevated polygenic risk scores¹ (PRSs) for the condition. Now, investigators from Finland have proposed that PRSs could be used as a tool to help diagnose epilepsy in those individuals who have had a single seizure and distinguish them from those where the seizure has another cause. The results will be presented at the annual conference of the European Society of Human Genetics today [Sunday].

Together with other colleagues at the Institute for Molecular Medicine (FIMM), Helsinki, Finland, Henrike Heyne, MD (now working at the Hasso Plattner Institute, Potsdam, Germany) extracted data on 9660 individuals with epilepsy-related diagnoses from the over 269K people included in the FinnGen² project and looked at their polygenic risk scores as compared to those of health controls. As expected, the individuals with epilepsy had a higher polygenic risk for the condition.

“In FinnGen we could also investigate the health records of participants who had suffered convulsions where the cause was unclear. Although some of them had later received a specific diagnosis of epilepsy, the majority had not. And we found that the genetic risk for epilepsy was significantly higher in individuals who received a specific epilepsy diagnosis than in those with only one seizure where the case was unclear,” says Dr Heyne.

Participants in the study ranged in age from a few months to over 90. In those under 40, the researchers found that the influence of the genetic factors was larger than in older individuals. This genetic influence was particularly high in those with adolescent myoclonic epilepsy, the type that made up the largest proportion of cases in the international epilepsy consortium used to identify which genetic variants convey highest risk to epilepsy. Although the sample size was relatively small, the results clearly showed the potential for the use of PRSs in the diagnosis of epilepsy, and the researchers hope to see them replicated in further studies with the larger sample sizes that are more usual in other common diseases such as high blood pressure or diabetes.

“Genetic risk could serve in future as a biomarker for epilepsy,” says Dr Heyne. “This could prove to be a very useful addition to existing methods, such as electroencephalograms. PRSs have been shown to be useful in many other diseases and it is likely that in the future their use may become standard practice, meaning that genetic data could help to make an epilepsy diagnosis immediately after a seizure.

Chair of the ESHG conference, Professor Alexandre Reymond, Director of the Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, said: “Genetic information often tells us whether a person is at increased risk to develop a disorder or not. In this study, the authors have pioneered the use of a genetic risk score to identify people at risk for epilepsy. Combining genetic data with other more traditional methods such as electroencephalograms could help identification of epileptic individuals, potentially allowing early treatment. Of note is that about 25% of epilepsy patients are under an effective regimen.”

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¹A polygenic risk score reflects an individual’s estimated genetic predisposition to a given trait or disorder and can be used as a predictive tool.

²The FinnGen project was launched in 2017 with the aim of collecting biological samples from 500,000 participants in Finland (about 10% of the population) over six years with the aim of improving health through genetic research.

Abstract no: PL2.6 Epilepsy polygenic risk scores in > 269k individuals with and without epilepsy

The underlying cause of sudden cardiac death (SCD) in a young person is often difficult to identify. A genetic analysis could provide more information in many cases, but blood samples are not collected routinely at the time of death, and DNA extracted from the tissues collected at autopsy is damaged because of the way they are fixed in formalin and paraffin-embedded. But finding the cause is vital if relatives who may carry the same genetic variant as the victim are to be screened. Now, for the first time, researchers in Sweden have been able to carry out molecular autopsies for SCD nationwide, using dried blood spots (DBS) collected up to 40 years ago as part of the routine screening of newborn babies. Their findings will be presented at the annual conference of the European Society of Human Genetics today (Saturday).

Dr Angelica Delgado-Vega, MD, a specialist in Clinical Genetics at Uppsala University Hospital, Uppsala, Sweden, and colleagues from Uppsala and Gothemburg, identified all 22 Swedish cases of SCD between 2000 and 2010 in people aged under 35 with a post-mortem diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), an inherited disease of the heart muscle that affects approximately 1 in 1000 to 1 in 5000 individuals. Using whole exome sequencing¹, they extracted DNA from DBS, post-mortem formalin-fixed paraffin-embedded (FFPE) heart tissue, and frozen blood samples of victims, where they existed.

Although the researchers found a lower yield of DNA from DBS compared with FFPE, all of the DBS samples passed quality control, compared to 62.5% of the FFPE samples. The quality of the results from DBS were similar to those from the frozen blood samples, and analysis showed clinically relevant genetic variants in 12 out of 19 families. “Four were located in ARVC genes and six in another gene known for causing an arrhythmic syndrome,” says Dr Delgado-Vega. “Additionally, we identified one case with hemochromatosis, an iron overload disorder, and one with myotonic dystrophy, a disorder of muscle function. Not only did this show us that molecular autopsy of DBS gave a reliable result in ARVC, but also allowed us to identify relatives who might be at risk of other disorders. We were pleased to find that the quality of the sequence data from such small amounts of DNA was better than we expected.”

The researchers now intend to offer carrier testing to these relatives and follow them clinically. They will also apply the DBS molecular autopsy technique in a larger group of 903 SCD victims from SUDDY, the Swedish Sudden Cardiac Death of the Young cohort. Even though their first results are impressive, this has not been a simple task, they say.

“It has been difficult to obtain the samples from the biobanks even though we have ethical permissions and consent from the relatives, due to logistic and internal regulations specific to each of them. The Swedish Board of Forensic Medicine, for example, has not provided any sample due to legal regulations,” says Dr Delgado-Vega. “Even though the results from FFPE samples had lower quality than those from DBS it still works in them. The acquisition of FFPE samples is also important because DBS are only available from 1976, when newborn screening started in Sweden.”

The sudden and often unexplained death of a young person is a devastating event for their families.

Through the identification of disease-causing variants, health systems can offer them an explanation. “And the identification of relatives who are carriers and thus at risk of sudden cardiac death means that we can offer them treatment and other preventive measures, because this is a preventable outcome. Tragically, however, many of our families have already lost several members to SCD,” Dr Delgado-Vega says.

“As this is a postmortem study, we cannot be totally sure whether the arrhythmogenic syndromes identified were a contributing cause of death or an alternative diagnosis or an overlapping phenotype. However, our findings provide valuable new knowledge about the biology of cardiomyopathies, where overlapping genes and phenotypes are common. We are evaluating each family individually. In several cases there are relatives diagnosed with the arrhythmogenic syndrome identified without evidence of ARVC. We hope that our findings will enable better risk assessment and care in these cases,” she will conclude.

Chair of the ESHG conference, Professor Alexandre Reymond, Director of the Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, said: “Arrhythmogenic syndromes are “sneaky killers” and it would seem to be common sense to try to identify individuals at risk as early as possible.  This is a typical example where an established practice, i.e. routine screening of newborn babies via dried blood spots, could and should be modernised in the years to come to assess more genes for the greater good.”

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The research was funded by grants from Marcus Borgström, the Swedish Society of Medicine, Uppsala University Hospital, and Uppsala University Hospital, and Uppsala University, Sweden.

¹Exome sequencing is a technique for sequencing all of the protein-coding regions of genes in a genome. It is a quicker and cheaper alternative to whole genome sequencing

Abstract no: C02.1 Sudden cardiac death due to ARVC in the young: molecular autopsy by whole exome sequencing of DNA from dried blood spots (DBS) collected at birth.

June 6-9, 2020, Virtual Meeting

The winner of this year’s Leena Peltonen prize, to be awarded at the ESHG annual meeting being held entirely on line, is Dr Gosia Trynka, from the Wellcome Sanger Institute, Hinxton, Cambridge, UK. The prize is awarded to an outstanding young researcher in the field of human genetics, and honours the memory of Dr. Leena Peltonen, a world-renowned human geneticist from Finland who died in 2010 and who contributed greatly to the identification of disease genes for human diseases.

After an MSc in Biotechnology from Jagiellonian University, Krakow, Poland, Gosia Trynka obtained a PhD cum laude from the University of Groningen, The Netherlands. In 2012 she moved to the US to take up a Postdoctoral fellowship at Brigham and Women's Hospital, Harvard Medical School and the Broad Institute. She has led the Immune Genomics Group at the Wellcome Sanger Institute since 2014 and this year she took on an additional responsibility as the Experimental Science Director at Open Targets, a public/private partnership that uses genomics data to improve drug target identification and prioritisation.

Her group at the Sanger Institute combines immunology and genomic assays with statistical approaches to study how human genetic variation impacts the immune system and predisposes to the development of autoimmune diseases. "As a head of Human Genetics at the Sanger Institute, Leena Peltonen recruited a cadre of young faculty. She was seen as a champion and an inspiration to the younger generation of scientists. As a junior faculty whose independent research career was enabled by the Sanger environment that Leena has championed I feel honoured to be recognised with this prize," she says.

Professor Nicole Soranzo, Senior Group Leader of the Human Complex Traits Group at the Wellcome Sanger Institute, and a member of the award’s nominating committee, said: “I am delighted that Dr Gosia Trynka has been bestowed this important recognition for her contribution to the understanding of the genetic and molecular causes of devastating human immune diseases. Gosia is a hugely talented, original and courageous scientist, who continues to break new ground through her highly innovative statistical, experimental and translational approaches. A passionate educator and mentor, she has already established herself as a role model and champion for the next generation of human genetics scientists.”

The clinical presentation of Covid-19 varies from patient to patient and understanding individual genetic susceptibility to the disease is therefore vital to prognosis, prevention, and the development of new treatments. For the first time, Italian scientists have been able to identify the genetic and molecular basis of this susceptibility to infection as well as to the possibility of contracting a more severe form of the disease. The research will be presented to the 53rd annual conference of the European Society of Human Genetics, being held entirely on-line due to the Covid-19 pandemic, today [Saturday].

Professor Alessandra Renieri, Director of the Medical Genetics Unit at the University Hospital of Siena, Italy, will describe her team’s GEN-COVID project to collect genomic samples from Covid patients across the whole of Italy in order to try to identify the genetic bases of the high level of clinical variability they showed. Using whole exome sequencing (WES)1 to study the first data from 130 Covid patients from Siena and other Tuscan institutions, they were able to uncover a number of common susceptibility genes that were linked to a favourable or unfavourable outcome of infection. “We believe that variations in these genes may determine disease progression,” says Prof Renieri. “To our knowledge, this is the first report on the results of WES in Covid-19.”

Searching for common genes in affected patients against a control group did not give statistically significant results with the exception of a few genes. So the researchers decided to treat each patient as an independent case, following the example of autism spectrum disorder. “In this way we were able to identify for each patient an average of three pathogenic (disease-causing) mutations involved in susceptibility to Covid infection,” says Prof Renieri. “This result was not unexpected, since we already knew from studies of twins that Covid-19 has a strong genetic basis.”

Although presentation of Covid is different in each individual, this does not rule out the possibility of the same treatment being effective in many cases. “The model we are proposing includes common genes and our results point to some of them. For example, ACE2 remains one of the major targets. All our Covid patients have an intact ACE2 protein, and the biological pathway involving this gene remains a major focus for drug development,” says Prof Renieri. ACE2 is an enzyme attached to the outer surface of several organs, including the lungs, that lowers blood pressure. It serves as an entry point for some coronaviruses, including Covid-19.

These results will have significant implications for health and healthcare policy. Understanding the genetic profile of patients may allow the repurposing of existing medicines for specific therapeutic approaches against Covid-19 as well as speeding the development of new antiviral drugs. Being able to identify patients susceptible to severe pneumonia and their responsiveness to specific drugs will allow rapid public health treatment interventions. And future research will be aided, too, by the development of a Covid Biobank accessible to academic and industry partners.

The researchers will now analyze a further 2000 samples from other Italian regions, specifically from 35 Italian Hospitals belonging to the GEN-COVID project.2 . “Our data, although preliminary, are promising, and now we plan to validate them in a wider population,” says Prof Renieri. “Going beyond our specific results, the outcome of our study underlines the need for a new method to fully assess the basis of one of the more complex genetic traits, with an environmental causation (the virus), but a high rate of heritability. We need to develop new mathematical models using artificial intelligence in order to be able to understand the complexity of this trait, which is derived from a combination of common and rare genetic factors.

“We have developed this approach in collaboration with the Siena Artificial Intelligence Lab, and now intend to compare it with classical genome-wide association studies3 in the context of the Covid-19 Host Genetics Initiative, which brings together the human genetics community to generate, share, and analyse data to learn the genetic determinants of COVID-19 susceptibility, severity, and outcomes. As a research community, we need to do everything we can to help public health interventions move forward at this time.”

Chair of the ESHG conference, Professor Joris Veltman, Dean of the Biosciences Institute at Newcastle University, Newcastle upon Tyne, UK, said: “We are very excited to have this work on the genetics of COVID19 susceptibility presented as one of our late-breaking abstract talks at the ESHG. Our Italian colleagues present the first insight into the role of genetic susceptibility influencing the severity of the response to a COVID19 infection. It needs to be expanded to encompass much larger populations, but it is impressive to see the speed at which research on this virus has proceeded in just a few months’ time.”

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1.Whole exome sequencing involves sequencing all the protein-coding regions of genes in a genome. It can identify genetic variants that alter protein sequences at a much lower cost than whole genome sequencing.
2. sites.google.com/dbm.unisi.it/gen-covid
3. A genome-wide association study is an observational study of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait.

Abstract no: C25.6 WES profiling of COVID-19

The increasing popularity of direct to consumer (DTC) genetic testing is having an impact on clinical genetics services, according to Australian researchers who will present their work to the 53rd annual conference of the European Society of Human Genetics, being held entirely on-line due to the Covid-19 pandemic, today [Saturday]. Many consumers are unsure about what to do with the results they receive, and many general practitioners are ill-equipped to advise them, meaning that they turn to clinical genetics services for help.

Ms Jane Tiller, Ethical, Legal and Social Adviser in Public Health Genomics, Monash University , Victoria, Australia, and colleagues analysed how often clinical genetics services were receiving referrals related to DTC testing, and what actions were taken by the clinic after receiving the referral. Until now, this subject has received little attention. «We knew that clinical genetics services had limited resources and long waiting lists. We wanted to explore the impact of DTC-related referrals in order to be able to forecast effects on the delivery of clinical genetics services and inform policymakers so that they could adjust resource needs accordingly,» she says.

The researchers surveyed eleven publicly-funded Australian clinical genetics services, asking questions related to the DTC-generated referrals they had received over the past ten years. They found that 83% of such referrals were made by general practitioners, in order to aid interpretation of results, and that over 30% of referrals were related to imputed disease risk estimates, where an online tool interprets raw genetic data to obtain a health risk profile. The services reported that DTCGT results were often unreliable; fewer than 10% of the results tested were validated.

Currently the national regulator, the Therapeutic Goods Administration (TGA) is considering the issue of DTC genetic testing. Because the sale of health-related DTC testing is prohibited in Australia, some Australians obtain this testing through overseas companies or use data from ancestry sites to obtain imputed health data.

"If the TGA relaxes these restrictions on DTC genetic testing, this could increase yet further the need for clinical genetics services by consumers of DTC tests,» says Ms Tiller. «Our study raises many issues. There are tensions between the desire to allow consumers access to their genetic information and subsequently managing and funding the healthcare follow-up that they need, either to interpret their results, or to determine an individual risk management plan. Commercial companies who gain from selling these tests often neither consider nor contribute to the cost in downstream health management."

In addition to the need for sufficient resources and funding for public genetics services, measures that could be taken to improve the situation include increasing the genomic knowledge of general practitioners. «GP knowledge ranges from the extremely genomically literate to the extremely genomically illiterate. There is no way of guaranteeing that all GPs have a sufficient degree of genomic literacy to interpret potentially inaccurate DTC results. Improving genomic literacy across GPs would certainly assist with this aim, and is critical as genomic testing becomes more common,» she says.

Another problem that needs addressing is the lack of a consistent policy for referral management across Australia. Some services provide an appointment to all DTC-related referrals, some provide none, and some assess referrals on a case-by-case basis, leading to considerable inequalities in access. «A uniform national policy regarding the treatment of DTCGT-related referrals should be developed to reduce inequality and ensure consistent decision-making by publicly-funded genetics services in this area.

"Now we need to look in further detail at year on year rates of referral, rates of validation and specific disease risk. As DTC genetic testing continues to grow, we expect its impact on health services will increase. Although our study was carried out in Australia, our findings are relevant for other countries with publicly-funded or single-payer clinical genetics. Policymakers need to take note and act now in order to facilitate efficient operation of clinical genetics and to provide the maximum benefit to the population," Ms Tiller will conclude.

Chair of the ESHG conference, Professor Joris Veltman, Dean of the Biosciences Institute at Newcastle University, Newcastle upon Tyne, UK, said: “Direct to consumer (DTC) genetics tests are becoming more widely available in society and this study asks the question whether this increases the workload for clinical genetics services in Australia. Overall, my impression is that the number of referrals related to these DTC tests is rather low, but it does make clear that most GPs do not know what to do with these and that shows a need for more education in this area.”

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Abstract no: C07.3 Measuring the burden of direct-to-consumer genetic testing on clinical genetics services

Genome-wide association studies (GWAS) analyse a genome-wide set of genetic variants in different individuals to see if any are associated with a trait or disease. Such studies are getting larger and larger and, in some cases, millions of participants are involved. This means that researchers can see smaller and smaller effects increasing the number of genes they can link to a disease or trait.

"It is good for us, because it allows us to understand much more about genetics influences our make-up, behaviour, and disease status, " says Dr Andrea Ganna, from the Institute for Molecular Medicine Finland, Helsinki, Finland, who will present his team’s research to the 53rd annual conference of the European Society of Human Genetics, being held entirely on-line due to the Covid-19 pandemic, today [Monday]. " But this good news comes with a downside. These large numbers mean that biases can creep in and affect our results. The most difficult of these to control is participation bias – when people who participate in a study are not from a random set but have something in common that is linked to their participation."

"To give an extreme example, if we were to use the participants in a professional basketball team to understand how tall or fit people are, the results would not be at all representative of the general population. But even low- level participation bias can skew results,» says Dr Ganna.

Recent studies looking at people who have participated more than once in a genetic study have shown a correlation with their level of educational attainment, for example. The researchers set out to characterise better what the consequences of this type of bias were. To do so, they needed a trait that they were certain was not determined genetically on the non-sexual chromosomes and about which they could be sure in advance that no association with those genes existed.

"The only area where we felt certain that genetics outside the sexual chromosomes was not involved was the genetic differences between males and females,” commented co-author Dr Nicola Pirastu, from the University of Edinburgh, Edinburgh, United Kingdom. «Therefore our analyses should have come out completely negative."

The team carried out an association study of data from over three million individuals1 looking at which genetic variants showed differences in study participation frequencies between males and females. «To our surprise, we found over 150 loci with such differences. For example, we saw more body mass index-raising alleles2 among men than women, suggesting that genetically higher-weight women were less likely to participate in population studies than men. This can only have been related to differences in the characteristics that drive men and women to participate. And we saw a similar effect in different cohorts, which confirmed our hypothesis," said Dr Pirastu.

These findings emphasise the importance of scientists’ awareness of the necessity of careful study design and the meticulous choices of cases and controls when conducting genetic studies. In order to draw useful conclusions, the risk of participation bias should be minimised. If these kinds of bias exist in a study involving men and women, it will be far more difficult to distinguish between true results and those arising from biases when looking at disease. "For example, in the recent pandemic we know that those people who have been tested for Covid-19 were not chosen at random and share common characteristics, so making the right choice of controls to be used to understand if there are any genetic determinants involved is very important. I think our study shows what the risks are if this is not done," says Dr Ganna.

At the moment, all the evidence is that participation biases are mild enough not to be a major problem. But it is important to take them into account when planning the collection of data from large cohorts and when data from participants is collected at multiple time points. Genotyping a random set of the population, for example, from the blood spots collected at birth, would be a good way of further verifying if these biases exist. "We have shown that it would allow us to correct the statistical analyses. In addition, it would cost very little in comparison of what it has cost to date to create these studies. We really need to do this if we are to be able to draw the right conclusions from our analyses," Dr Ganna will conclude.

Chair of the ESHG conference, Professor Joris Veltman, Dean of the Biosciences Institute at Newcastle University, Newcastle upon Tyne, UK, said: “This fascinating study shows us how important it is to be aware of unexpected biases in participation in genetic association studies as well as other large scale ‘population’ studies, as this can significantly impact results if not properly corrected for.”

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1. Data from the UK BioBank, 23andMe, iPSYCH FinnGen, and Biobank Japan.
2. An allele is a variant form of a gene.

Abstract no: C21.1 A genome-wide association study of sex at birth in 3 million individuals reveals widespread sex-differential participation bias with potential implications for GWAS interpretation

Osteoporosis affects more than 200 million people worldwide and demographic change means that these numbers are continuing to increase. Osteoporosis- related fractures have a significant effect on the quality of life of older people and also on the cost of healthcare provision. Now, a group of genetic researchers from The Netherlands, the US, and Norway, have shown the way to predicting not only which patients are likely to have fractures but also make an approximation of when. This could make an important contribution to improving the health of older people, they say.

Dr Carolina Medina-Gomez, from the Laboratory of Human Genetics, Erasmus MC, Rotterdam, The Netherlands, will present the team’s work to the 53rd annual conference of the European Society of Human Genetics, being held entirely on-line due to the Covid-19 pandemic, today [Tuesday 9 June]. "Using a genome-wide association study, we were able to develop a genetic risk score to help identify individuals who are likely to fracture early. Some of these individuals can have normal bone mass density, so would not be deemed as osteoporotic by the usual scans. It is important to be able to identify such patients so that we can offer them the right treatment at an early stage," she says.

The researchers studied the fracture history of 11,351 participants in the Rotterdam Study with up to 20 years of follow up. The aim of the Rotterdam study, which started in 1990, is to investigate factors that determine the occurrence of disease in elderly people.

The genetic risk score (GRS) was derived from the largest genome-wide association study (GWAS) on BMD to date, carried out in data from the UK BioBank. A GWAS analyses a genome-wide set of genetic variants in different individuals to see if any of the variants is associated with a trait or disease.

Physical activity during the course of a life has an impact on the onset of osteoporosis and campaigns promoting exercise at all ages are important for preventing its early onset. But people with a genetic predisposition to early fracture could benefit from targeted interventions, not only to increase bone mass density in adulthood but also to prevent falls, for example by improving balance and muscle power. So being able to identify these patients at an early stage could lead to a better outcome for these individuals.

Widening the research to include non-European populations will be an important step forward. Until now genetic risk scores have been generated from GWAS containing mainly European populations, and do not always yield the same results in people from different backgrounds. Even though the prevalence of osteoporosis is much higher in Europeans, the study of how well the GRS can predict time to fracture in other populations is crucial, say the researchers.

"The current method of classifying patients based on bone density scans is effective, but we are trying to help those individuals with apparently normal bone mass density who suffer fractures, and it is these people the bone research community is trying to identify so that we can offer them the right intervention and treatment,» says Dr Medina-Gomez. "We will still need to be able to fine tune which PRS weighting system will allow us a more precise identification of these people, and to assess the added value of using a PRS as compared to a Fracture Risk Assessment Tool (FRAX)* assessment as used at present by clinicians. If the PRS can help clinicians identify the group of individuals who would benefit from medication, for example, it would be an extraordinary achievement."

Chair of the ESHG conference, Professor Joris Veltman, Dean of the Biosciences Institute at Newcastle University, Newcastle upon Tyne, UK, said: “Genetic information often tells us whether a person is at increased risk to develop a disorder or not. Unfortunately, it mostly does not tell us when these disorders will develop, and that minimises the use of genetics for practical medical decision-making. In this study, the authors have pioneered the use of a genetic risk score to identify people at risk of developing bone fractures early in life. If replicated and fine-tuned, this would provide relevant information to a group of people and their health care providers.”

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*A FRAX assessment involves a computer questionnaire to calculate the risk of fracture over the next ten years. It includes details of age, sex, height and weight, certain related conditions and steroid use, and smoking and drinking habits and, if available, bone mineral density.

Abstract no: C30.4 Genetic assessment of age-associated fracture risk
The research was funded by the Netherlands Organization for Health Research and Development (ZonMw VIDI 016.136.367).

June 15-18, 2019, Gothenburg, Sweden

Gothenburg, Sweden:  High levels of iron in the liver are linked to a number of serious health conditions including cancer, diabetes, high blood pressure and cardiovascular as well as liver disease. But measuring liver iron is difficult and until recently could only be done through an invasive biopsy.

Now researchers from University of Exeter, UK, together with colleagues from the University of Westminster,London, UK,  Lund University, Sweden and Perspectum Diagnostics, Owford, UK,  have shown that genes regulating iron metabolism in the body are responsible for excess liver iron. 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 8200 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 the production of hepcidin, a protein that regulates the entry of iron into the blood. The results were validated in 1500 individuals whose data had been collected in the pan-European Diabetes Research on Patient Stratification (DIRECT) Consortium. «This is the first time such a study has been carried out in an unselected, large population,» says Dr Yaghootkar.

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. « There are animal studies that indicate that fat cells trigger macrophages, a type of white blood cell, to cause inflammation, and that this in turn leads to defective iron handling in the liver. We need to research this association further, but it is a plausible explanation of the phenomenon, » says Dr Yaghootkar.

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 100,000 individuals in the Biobank study. « This will allow us to find many more genetic factors associated with this trait. We are also interested in performing such studies in other ethnicities, since our current results are only valid for people of European ancestry,  » Dr Yaghootar will conclude.

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University, Newcastle upon Tyne, UK, said: “Iron overload is bad for the body and needs to be tightly regulated. 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.”

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Abstract no: C. 21.5 Genome-wide association study of MRI liver iron content in 9,800 individuals yields new insights into ist link with hepatic and extrahepatic diseases

The research was funded by the Wellcome Trust, Diabetes UK, and Innovate UK Knowlege Transfer Partnership. The DIRECT Consortium is funded by the Innovative Medicines Initiative, part of the EU’s 7th Research Framework Programme.

Gothenburg, Sweden:  High levels of iron in the liver are linked to a number of serious health conditions including cancer, diabetes, high blood pressure and cardiovascular as well as liver disease. But measuring liver iron is difficult and until recently could only be done through an invasive biopsy.

Now researchers from University of Exeter, UK, together with colleagues from the University of Westminster,London, UK,  Lund University, Sweden and Perspectum Diagnostics, Owford, UK,  have shown that genes regulating iron metabolism in the body are responsible for excess liver iron. 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 8200 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 the production of hepcidin, a protein that regulates the entry of iron into the blood. The results were validated in 1500 individuals whose data had been collected in the pan-European Diabetes Research on Patient Stratification (DIRECT) Consortium. «This is the first time such a study has been carried out in an unselected, large population,» says Dr Yaghootkar.

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. « There are animal studies that indicate that fat cells trigger macrophages, a type of white blood cell, to cause inflammation, and that this in turn leads to defective iron handling in the liver. We need to research this association further, but it is a plausible explanation of the phenomenon, » says Dr Yaghootkar.

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 100,000 individuals in the Biobank study. « This will allow us to find many more genetic factors associated with this trait. We are also interested in performing such studies in other ethnicities, since our current results are only valid for people of European ancestry,  » Dr Yaghootar will conclude.

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University, Newcastle upon Tyne, UK, said: “Iron overload is bad for the body and needs to be tightly regulated. 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.”

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Abstract no: C. 21.5 Genome-wide association study of MRI liver iron content in 9,800 individuals yields new insights into ist link with hepatic and extrahepatic diseases

The research was funded by the Wellcome Trust, Diabetes UK, and Innovate UK Knowlege Transfer Partnership. The DIRECT Consortium is funded by the Innovative Medicines Initiative, part of the EU’s 7th Research Framework Programme.

Gothenburg, Sweden:  Having a child with a developmental disorder can cause parents to worry about the outcome of further pregnancies. 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. But in some families, the risk of having another affected child is as high as 50%. 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.

At the annual conference of the European Society of Human Genetics today (Sunday), Dr Ummi Abdullah, a Postdoctoral Researcher in Molecular Genetics at the MRC-Weatherall Institute of Molecular Medicine (WIMM), University of Oxford, UK, will present her team’s PREGCARE study, which aims to provide healthy couples who have a child affected by a developmental disorder with a personalised pre-conception risk evaluation. This will allow the determination of the likelihood that a future child will also be affected by the same condition (the ‘recurrence risk’).

"Our focus is on families where the disease-causing mutation has been identified in the affected child but not detected in either parent on routine analysis. These are termed ‘de novo’ mutations or DNMs, and are estimated to affect around one in 295 live births  -  0.34% of all births, or about 3,500 births per year in the UK alone, » says Dr Abdullah. « If the mutation is present in multiple gonadal cells (semen or ova) of the parents, a process termed ‘gonadal mosaicism’, the risk of an affected child is high".

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. « This is the situation we set out to remedy, » says Dr Abdullah.

Dr Abdullah will discuss results from the first 20 families to be investigated in PREGCARE. 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.

"Given our current understanding of mosaicism, we should be able to reassure around three out of every four of these couples that their recurrence risk is negligible," Dr Abdullah says.

 The researchers say that the study shows that there is a clear benefit in analysing the fathers’ semen sample for a direct recurrence risk estimate for DNMs of proven paternal origin. « Furthermore, we also aim to show the importance of analysing several different somatic tissues of various embryonic origins to identify cases of mosaicism.

"This should also help us establish whether a given somatic tissue may be a good surrogate for gonadal cells. This will be particularly useful for mutations of maternal origin, as clearly the mothers’ ova are not readily accessible for such genetic analysis," says Dr Abdullah.

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.

"I was struck to find out that, while our participants understand that this is a research study and not a diagnostic service, many of them have expressed their intention of waiting for our results before they decide on trying for another child," Dr Abdullah says. "This really reflects the anxieties of parents who have already had a child with a serious disorder."

Because children diagnosed with a disorder caused by a DNM often have severe learning disability, serious developmental disorders or birth defects, it is understandable that their parents are frequently concerned by the risk of another child being affected. 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.

"The ability to provide personalised estimation of transmission risk prior to conception is likely to impact on family planning decisions, but also more generally on clinical practice. I feel that the PREGCARE approach, although conceptually very simple, represents an important step towards so-called ‘precision medicine’ and should allow parents to make more informed reproductive decisions and reduce both the financial and psychological/emotional costs associated with a new pregnancy," Dr Abdullah will conclude. 

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University, Newcastle upon Tyne, UK, said: "Developmental disorders are often caused by mutations in the DNA that are arising before or during the formation of sperm or eggs. 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."

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Abstract no: C08.2 The PREGCARE study: precision genetic counselling via personalised evaluation of recurrence risk for families with a child affected by a disorder caused by a de novo mutation

The research is funded by NewLife – The Charity for Disabled Children.

Gothenburg, Sweden:  Sickle cell disease (SCD) is a form of anaemia that is inherited when both parents are carriers of a mutation in the haemoglobin gene. 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. Now, researchers from Guy’s and St Thomas’ NHS Foundation Trust and Viapath Analytics, London, UK, in collaboration with non-invasive healthcare company Nonacus Ltd., Birmingham, UK, have developed a non-invasive prenatal test for the disease, the annual conference of the European Society of Human Genetics will hear tomorrow (Sunday).

Dr Julia van Campen, research scientist at Guy’s and St Thomas’, explains: « We have developed a method of testing for SCD using cell-free fetal DNA - DNA from the fetus that circulates in the maternal bloodstream. 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. »

In couples who are at risk of having a baby with SCD, each partner carries a mutation in the haemoglobin gene, which means that any fetus has a one in four chance of inheriting both mutations and therefore being affected by SCD. Non-invasive prenatal diagnosis (NIPD) of conditions that are inherited in this way is difficult. “The development of a non-invasive prenatal assay for sickle cell disease has been attempted before and, until now, has not been successful,”says Dr van Campen.

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 300 000¹ children born with SCD each year. It is the most common genetic haematological disorder, with millions of people currently affected across the globe. There are about 14 000 people living with SCD in the UK, or one in 4600. Approximately 560 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.

« However, many couples are unaware that they are at risk until pregnancy occurs, even though carrier testing and follow-up genetic counselling is available through the UK National Health Service for those who are concerned that they may carry SCD, » says Dr van Campen. « It is important to raise awareness of SCD, which currently is limited. »

Research is ongoing, and before the assay can be introduced into clinical practice it needs to be tested further to be sure that it performs well enough to be used as a diagnostic test. « We also need to work to ensure that it can provide results rapidly enough to give women answers at the right time in their pregnancy, and that it can be performed at a cost that healthcare providers can afford. I am excited that this work has given better results than I had expected, and am hopeful that people will be able to build on this work to make this test available in the near future,” » Dr van Campen will conclude.

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University, Newcastle upon Tyne, UK, said: “The development of non-invasive genetic tests that can be safely used during pregnancy is important to identify fetuses with severe disorders. 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.”

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1Piel et al. Global Burden of Sickle Cell Anaemia in Children under Five, 2010–2050: Modelling Based on Demographics, Excess Mortality, and Interventions  https://doi.org/10.1371/journal.pmed.1001484

²Hill, M., Oteng-Ntim, E., Forya, F., Petrou, M., Morris, S., & Chitty, L. S. (2017). Preferences for prenatal diagnosis of sickle-cell disorder: A discrete choice experiment comparing potential service users and health-care providers., Health expectations: an international journal of public participation in health care and health policy, 20(6), 1289–1295

Abstract no: C08.5 Non-invasive prenatal diagnosis of sickle cell disease by next generation sequencing of cell-free DNA

The research was funded by Guy’s and St Thomas’ Charity.

Gothenburg, Sweden:  Developmental disorders are neurologically-based conditions that affect the acquisition of specific skills such as attention, memory, language and social interaction. Although they have a genetic cause, this is often difficult to detect through standard genetic analysis of the parents. The mutation found in the affected child is therefore termed a ‘de novo’ mutation (DNM).

« Although many new developmental disorders have been identified in recent years, there are many more to be discovered.  Identifying them means that we will be able to give an accurate diagnosis to more patients and therefore allow them to have appropriate treatment and care, » Ms Joanna Kaplanis, a PhD student at the Wellcome Sanger Institute, Hinxton, UK, will tell the annual conference of the European Society of Human Genetics today (Saturday).

In the largest study to date on developmental delay, the researchers analysed genomic data from over 31,000 parent-child trios obtained from the UK’s Deciphering Developmental Disorders Project, GeneDx, a US-based genetic testing company, and Radboud University Medical Centre in The Netherlands. Analysis of these trios yielded more than 45,000 DNMs. They developed an improved method to test for the enrichment (over-representation) of damaging DNMs in individual genes. « We found 307 significantly enriched genes, 49 of which are novel. With all of these genes we were able to explain about 51% of the DNM burden in our dataset. We then modelled different underlying genetic scenarios to get an idea of where the remaining de novo burden lies and how we can go about finding it,” says Ms Kaplanis.

About 40% of developmental disorders are caused by DNMs, equivalent to about one birth in every 295 in the UK alone. 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, we were expecting to be able to explain more of the DNM burden than we did. This means that half of the DNM burden in patients with developmental disorders still remains unexplained, » says Ms Kaplanis. « This fact alone gives us clues about where the remaining burden lies and why we do not yet have the capacity to discover the remaining genes. »

A possible explanation is that the DNMs in the genes as yet undiscovered are less penetrant, i.e. they present symptoms in fewer people. « We may need to adapt our system of gene discovery in order to capture these less penetrant genes, » says Ms Kaplanis. « Incorporating more data from healthy populations may help to try and build a better picture of what they might be. « 

The researchers also hope to increase their sample size in order to try to detect ever more genes associated with developmental disorders.  However, the identification of 40 new genes already provides valuable information to clinicians and to drug developers. « Returning a genetic diagnosis is important when deciding on the best treatment and care for an individual, as well as providing new drug targets in rare diseases,” Ms Kaplanis will conclude.

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University, Newcastle upon Tyne, UK, said: “Developmental delay is often caused by new mutations arising during the formation of sperm or eggs. By combining data on new mutations identified in the DNA of more than 30.000 patients, the scientists could implicate a role for 49 new genes in developmental delay. 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.”

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Abstract no: PL2.4 Discovery and characterisation of 49 novel genetic disorders from analysing de novo mutations in 31,058 parent child trio exomes

The Deciphering Developmental disorders study was funded by the Wellcome Trust and the UK Department of Health. This is a collaboration with GeneDx and Radboud University Medical Centre

Gothenburg, Sweden:  Infertility – the failure to conceive after a year of unprotected intercourse - affects one in every six couples worldwide, and the man is implicated in about half of these cases. Despite the known importance of genetic factors in the event of the man producing no sperm, only about 25% of these cases can be explained currently. 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.

« These de novo mutations are found in every individual and are part of the normal evolution of the genome, » Ms Oud explains. « Mostly they do not affect our health. 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. »

The researchers studied DNA from 108 infertile men, and also from their parents. Comparison of the parental DNA with that of the offspring enabled the identification of the de novo mutations. « We found 22 in genes involved in spermatogenesis, » says Ms Oud, « none of them previously known to cause infertility in human. »

Currently it is too early to give these patients a definitive diagnosis and further studies are ongoing. 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. « We are studying the role of these genes in material from testis biopsies of our patients and performing experiments in fruit flies to see whether disruption of these genes cause infertility in them, » Ms Oud says.

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. «Infertility is not something you normally inherit from your parents; they were clearly both fertile. But with the introduction of assisted reproductive technologies, it is becoming an inherited disorder in some cases, » Ms Oud explains.

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. « We therefore expect that there are more infertile men in the world who have mutations in the same group of genes as the group of patients we studied. 

« We were surprised to find so many de novo mutations with a potential role in male infertility, given the fact that in previous years only a few novel genes have been discovered in this condition. People still tend to think that failure to conceive is more likely to be caused by a female factor. We are pleased to have been able to make this contribution to the understudied field of male infertility, » Ms Oud concludes.

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University, Newcastle upon Tyne, UK, said: “The link between genetics and male infertility is something of a mystery, as we pass on our genes but can’t pass on infertility. 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.”

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Abstract no: C04.4 Exome sequencing reveals de novo mutations and deletions in severe idiopathic male infertility

The research was funded by the Netherlands Organisation for Scientific Research and the Wellcome Trust.

The Council of Europe’s protocol on genetic testing for health purposes* came into force yesterday (Sunday 1 July). 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). It has also been signed by five others – the Czech Republic, Finland, France, Iceland and Luxembourg. 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.  “It was a major effort on our part,” says Professor Milan Macek, President of the Czech Society, “and we are delighted by the result.”

“At a time when genetics and genomics are advancing so rapidly, issues surrounding genetic testing take on an even greater importance than before,” says ESHG President Professor Gunnar Houge, University of Bergen, Norway. “New technologies and discoveries provide huge potential for the improvement of human health, but alongside that can go the potential for misuse. 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.”

*https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986683/pdf/ejhg200984a.pdf).

The winner of this year’s Leena Peltonen prize, to be awarded at the ESHG annual meeting in Milan, is Dr Tuuli Lappalainen, from Columbia University, New York Genome Center, NY, USA.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 2009, and contributed greatly to the identification of disease genes for human diseases.

After obtaining an MSc in Genetics from the University of Turku, Finland and a PhD atInstitute for Molecular Medicine Finland,University of Helsinki,Finland,Dr Lappalainen pursued her 

career first in Switzerland, and then in the US. Today she is Assistant Professor in the Department of Systems Biology at Columbia, andAssistant Investigator and Core Member at the New York Genome Center. 

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. To date, the largest project she has been involved in is the GenotypeTissueExpression(GTEx) Consortium where she has been a key member since 2011. She iscurrentlyco-leadingtheanalysis for the finalmainpaperoftheconsortium, building the largest map in existence of genetic effects on gene expression across dozens of tissues.

“Tuuli’s commitment to international collaboration as well as her philosophy of empowering and inspiring the next generation of genomic researchers mirrors Leena Peltonen’s values and vision for advancing the field,” said a member of the award’s nominating committee, Samuli Ripatti, PhD, Professor of Biometry Public Health, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Broad Institute of MIT and Harvard.

June 16-19, 2018, Milan, Italy

Milan, Italy:  More than a million neonatal deaths worldwide each year are estimated to be due to sepsis¹. In the UK there are approximately 90,000 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. 

Dr John McDermott, from the Manchester Centre for Genomic Medicine, Manchester, UK, will tell the annual conference of the European Society of Human Genetics tomorrow (Saturday) that their simple test for bedside use can produce a result in around 40 minutes. « In the absence of a point of care testing approach we are reliant on core hospital testing facilities, which can take up to three days to provide a result.  This is inadequate, considering that life-saving antibiotics need to be given in the first hour of admission, » he says. « Our test, developed together with a Manchester based company, uses a cheek swab and can allow tailored prescribing.  We are thus able to avoid the antibiotic-related deafness that can occur in infants with this genetic mutation. »

Although there are several antibiotics that can be used to treat sepsis, the UK National Institute for Health and Care Excellence (NICE) recommends a combination of penicillin and gentamicin because the combination has a narrow spectrum of activity and hence a lower risk that the patient might develop antibiotic resistance. But, in new-borns, a particular mutation in mitochondrial DNA²that is present in one in every 500 of the population, means that a single dose of gentamicin can cause profound and irreversible hearing loss.

 “The development of our test has provided us with an exciting opportunity to explore how genetic information can be used in acutely unwell patients, » says Dr McDermott. « As genomic data become ever more prevalent in the population, studies like this will be essential in establishing how patients, clinicians and healthcare systems respond to genetic information being used to personalise treatment as part of everyday healthcare. »

The collaboration plan to undertake a multi-centre feasibility study introducing the test into several neonatal centres around the UK³. All children admitted to these centres will be tested for the genetic change and antibiotics tailored accordingly. « This represents the first example of a point of care genetic test being used in the acute setting, » Dr McDermott will say. « Acute neonatal disease is hugely distressing for all concerned, and we are delighted to be able to contribute to the safety and efficacy of its treatment. »

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University in Newcastle, United Kingdom, said: “This study shows us the importance of rapid genetic tests to prevent severe side effects from the use of antibiotics in a small group of sepsis patients who carry a mutation in their DNA. 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.” 

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Abstract no: C01.3. 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, 16:00 - 18:30 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. It is essential that treatment is started as quickly as possible. 

2 DNA found in the mitochondria (organelles within a cell that convert chemical energy from food into a form that cells can use) makes up a small proportion of the total DNA found in cells.  It encodes for a very small number of genes and is inherited solely from the mother. 

3 The initial study will take place in two large neonatal units in Manchester and Liverpool, and will expand nationwide at a later date.

The research was funded by Action on Hearing Loss.

Milan, Italy:  Giving personal genomic information to individuals can have a major, long-term effect on their lifestyle, researchers have found. The Finnish GeneRISK study, providing information on the risk of cardiovascular disease (CVD) based on their genome and traditional risk factors to 7,328 people inspired changes for the better in areas such as weight loss and smoking cessation. Nearly 90% of them said the information had made them take better care of their health, the annual conference of the European Society of Human Genetics will hear today (Saturday).

Although there is plenty of evidence that genomic factors have an important impact on the risk of common diseases, to date there has been little use of this information in prevention. Elisabeth Widen, MD, a senior scientist at the Institute for Molecular Medicine, University of Helsinki, Finland, and colleagues have developed a web-based tool that allows patients and doctors to see and manage genomic information based on 49,000 disease-associated genetic variants and lifestyle-associated risk factors.

« Delivering the results of the tool KardioKompassi® directly to patients, they were able to see their 10-year risk for ischemic heart disease. The tool combines risk information based on traditional risk factors such as age, sex, cholesterol levels and blood pressure with a polygenic risk score. Where a patient’s overall disease risk was elevated, KardioKompassi advised the participant to contact their doctor in order to discuss how best to reduce it, » Dr Widen will say.

When reassessed eighteen months later, the results were impressive. Compared with a 4% smoking cessation rate in the general population, 17% of smokers in the study had given up, and sustained weight loss had been achieved by 13.7% of participants. Overall, risk-reducing behaviour such as weight loss, giving up smoking, or visiting a doctor was 32.4% in those with a predicted CVD risk of more than 10% and 18.4% in those at lower risk.

« As many as 40% of participants with a high risk of CVD were smokers at the start of the study, so these results are encouraging. We believe that giving information on their genetic profile to individuals is particularly motivating, perhaps simply because it is new information. For example, many of the participants already knew that they had high levels of cholesterol. But it was receiving information on their personal genetic risk that triggered changes, » Dr Widen says.

GeneRISK participants will be recalled for follow-up studies over the next 20 years and their health status will be closely followed. The researchers believe that those who have already made lifestyle changes are likely to continue them. « Since they have managed to maintain these changes for 1.5 years, we expect them to persist, » says Dr Widen.

The general trend towards patient participation is particularly important in disease prevention, say the researchers. Empowering individuals by giving information on their personal risk of disease, as opposed to something more generalised, is clearly effective in encouraging them to follow healthier lifestyles.

« Our results show that this approach to managing and interpreting genomic data for individuals is feasible and effective. We think that our study provides a model for the use of such data in healthcare that can be easily adapted to other diseases, where we believe that it is likely to be equally valuable, » Dr Widen will conclude.

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University, Newcastle, United Kingdom, said: “It is impressive to see how genomic information can be used successfully to promote a healthier lifestyle in people at higher risk of developing heart disease. Clearly in the population there will also be many people with a relatively lower genetic risk of developing common diseases, and I do wonder what would happen if these people are informed about this; would they start showing an unhealthier lifestyle? This field of predictive genomic medicine is only just emerging, with lots of opportunities for further research.”

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Abstract no: C01.2 Returning cardiovascular disease risk prediction back to individuals motivates beneficial lifestyle changes : Preliminary results from the GeneRISK study
Session C01 - Precision and Predictive Medicine, Saturday, June 15, 16:00 - 18:30 hrs

The research was funded by Business Finland with support from the University of Helsinki, Carea - Kymenlaakso social and health care services, Kotka, Finland, Mehiläinen Oy, Helsinki, Finland, and the Finnish Red Cross Blood Service.

Milan, Italy:  Children who are born severely ill or who develop serious illness in the first few weeks of life are often difficult to diagnose, with considerable implications for their short and longer-term care. Whole genome sequencing*carried out quickly has the potential to provide an early diagnosis, and thus improve the clinical care of these infants as well as reducing its cost, the annual conference of the European Society of Human Genetics will hear tomorrow (Sunday).

Dr Shareef A. Nahas, Senior Director, Rady Children’s Institute for Genomic Medicine, San Diego, CA, United States, will report on his team’s study of rapid whole genome sequencing (rWGS) of all inpatient children under one year of age who were nominated for genetic investigation at Rady Children’s Hospital. Rapid WGS is able to return results in 48 to 96 hours, whereas standard genetic testing takes six to eight weeks to provide a result. They then noted subsequent changes in medical care that occurred while the child was still in hospital. Where there was a significant change in care due to a new diagnosis, the cases were reviewed by an independent expert panel who tried to determine what they believed would have happened had the child not received rWGS.

After 12 months of testing, 363 patients had been enrolled in the study and rWGS interpreted in 340 of them.  This yielded a diagnosis in 115 cases (about 34%). Diagnosis occurred quickly, on average within 96 hours. Changes in management as a result of diagnosis were identified in 77 patients, or about 67% of those diagnosed. Such changes ranged from specific changes, for example surgical interventions, to guidance in palliative care. Among the first 42 infants diagnosed, rWGS provided over $1.3million in net cost saving over the projected standard care.

“To date, our studies have shown a considerable clinical and economic benefit of sequencing children who were identified by clinicians as being suspected of having a genetic disorder.  In the course of the study, one child was spared devastating neurological damage,and one had a significantly reduced risk of death. The net cost savings totalled several hundred thousand dollars, even when we included the cost of analysing the genome of the child and both parents, » says Dr Nahas. 

Although many studies have shown that WGS improves the diagnosis if genetic disorders in infants and can lead to beneficial changes in their management, the new research has shown that, by implementing rapid sequencing, cost savings will also ensue.« We are now in a situation where we have a technology that leads to improved diagnosis and improved outcomes but is also not a net burden on healthcare resources. This means that for large healthcare payers, there is not a logical cost barrier to implementing rWGS in neonates suspected to have a genetic disorder. There will need to be further data on who else can benefit from early use of this technology  but implementation in the current cohort should not be delayed, » says Dr Nahas.

Currently, the use of WGS among sick neonates is very infrequent across the world, and there are few healthcare systems that have the ability to turn round genetic testing quickly enough to be clinically relevant, the researchers say. This is vital if medical management needs to be changed during the childrens’ hospitalisation. In the course of Dr Nahas’ study, one child was spared devastating neurological damage and another had a significantly reduced risk of death.

« The logic for the use of rWGS in these patients, both diagnostic and economic, is totally convincing. We have demonstrated that early sequencing saves money during admission. We were surprised by the proportion of children who received a change in care during that admission – around 25% of children sequenced and 80% of those diagnosed. This rate is much higher than other published rates for neonates who received WGS. We believe that this difference is due to the fact that the children received results at a much younger age, at a point where medical decisions were yet to be made.

 « There is an ethical imperative to act in the best interest of neonates, but implentation will require a concerted effort across all healthcare systems, and this will need to be at government level in Europe. Consistent with many diagnostic tests in the post-natal period, rWGS has the potential to identify conditions associated with lifelong disability or shortened lifespans, » Dr Nahas will conclude.

In a second presentation, Courtney French, PhD, a research associate/bioinformatician at the University of Cambridge, Cambridge, UK, will describe how she and colleagues carried out WGS analyses on 145 severely ill babies and children with an unidentifiable disease.  As a result, they were able to identify the cause of disease in more than 15% of cases.

« We have developed a rapid, affordable turnaround pipeline for this sequencing within the UK National Health Service system. This means that we can feed back clinically relevant information to doctors and parents in a timescale that allows care to be affected. Because it is hard to tell from observation alone who will benefit from genomic diagnosis, we think that it should be carried out on all eligible children, rather than doctors deciding on individual cases based on previous clinical knowledge. By comparing the entire DNA sequence in children to that of their parents we can identify quickly the likely cause of disease, » says Dr French.

The researchers are using their current data to investigate how rare genetic diseases present at an earlier stage than they are usually diagnosed in newborns. « Greater numbers of patients will expand our ability to do this, and we hope that our work will serve as a model for expanding the programme to other hospitals and regions, » Dr French will say. « The success of this project will depend on people working together across the health research and healthcare system. The translation of this work to routine care will require significant investment of resources in achieving consent from parents, and in giving information at what is a very stressful time for them. »

Many of the conditions characterised through WGS to date can be treated more effectively once identified. In the Cambridge dataset, several epilepsies that respond better to some medications than others were found. And there were cases where the diagnosis was able to prompt better screening for the clinical consequences of a condition and enabled the creation of a properly focused care plan, for example cardiac surveillance, renal follow up, or dietary advice. Even where there is no effective treatment available, having a diagnosis can provide reassurance to families that all that could be done has been done, and it can also provide useful information to parents when they are considering the most appropriate care for their child in the future.

« We were pleasantly surprised at the enthusiastic welcome parents gave to our study, with more than half of those approached wanting to take part. Despite the complications of getting samples from both parents, as well as their child, we managed to achieve this in 85% of families. We were also surprised at the huge range of clinical conditions we were able to diagnose, and particularly to find that when a child was already known to have learnng disability or developmental delay we were more likely to make a genetic diagnosis. This reflects the enormous increase in genetic knowledge over the last decade; ten years ago we would not have been able to do this even if we had sequenced the genome.

« Genome sequencing is currently rare in newborns and paediatric cases, but our research has shown that it can be extremely effective in providing rapid answers in difficult to diagnose cases. It is also be cost-effective, since it can reduce the time spent as an in-patient. Early diagnosis of neonatal and paediatric disease is not only important in pointing the way to the best care and treatment, but also in reducing anxiety for parents, » Dr French will conclude.

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University, Newcastle, United Kingdom, said: “Both these studies confirm the value of genome sequencing to detect the cause of unexplained disease. The study of Nahas shows that this can now even be done within four days, which is very impressive. This greatly increases the practical use of genetics in an acute clinical setting where treatment decisions can now be made based upon this powerful test. Personalised genomic medicine is becoming a reality!”

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*. Whole genome sequencing is the process of determining the complete DNA sequence of an individual, including all the chromosomal DNA and that contained in the mitochondria.

Nahas: Abstract no: CO7.5. Rapid Whole Genome Sequencing Improves Clinical Utility and Cost Effectiveness of Acutely Ill Children admitted to Neonatal Intensive Care Units
Session C07. NGS Doagnostics, Sunday, June 17, 13:00 - 14:30 hrs

The research was funded by the US National Institutes of Health and the Rady Family Foundation

French:Abstract no: CO7.4 Next Generation Children Project: Whole genome sequencing for rapid diagnosis of severely ill children in intensive care

The research was funded by Rosetrees Trust and NIHR BioResource and Cambridge Biomedical Research Centre.

Milan, Italy:  Pregnancy loss and the death of a newborn baby are devastating events, and as of today around 25% of these perinatal deaths are unexplained despite autopsy. Discovering the cause of such a loss is of great importance for the bereaved parents, both in providing an explanation and in helping them to understand the likelihood of a recurrence in future pregnancies. Researchers in Australia have used state of the art genetic testing in order to to help provide answers in such cases.

Associate Professor Christopher Barnett, a clinical geneticist who is Head of the Paediatric and Reproductive Genetics Unit at the Women’s and Children’s Hospital, North Adelaide, will tell the European Society of Human Genetics conference today (Monday) how he and colleagues are using whole exome sequencing (WES)¹ and whole genome sequencing (WGS)² to detect causes of neonatal death in cases where this has so far remained unidentified. Using data from 43 families referred to the genetics unit, where samples were available from both parents and the fœtus (the prospective cohort), and 60 from stored autopsy samples from the fœtus or newborn (the retrospective cohort), the researchers were able to uncover an underlying genetic cause in 23% of the prospective cohort, and have found a single promising candidate in a further 26%.

Solved cases included new disease gene discoveries, new syndrome identification and novel severe fœtal presentations of existing rare paediatric disease. In the retrospective cohort, strong candidates for the cause of death were found in 18% of cases.

« This study has contributed directly to the birth of healthy babies, » Prof Barnett will tell the conference. « We have had numerous couples who, with successful preimplantation genetic diagnosis via in vitro fertilisation in subsequent pregnancies, or through prenatal testing during pregnancy, have been able to avoid the genetic condition experienced in a prior pregnancy. Of course, this can only be offered to couples if a definitive genetic diagnosis is made in the earlier affected pregnancy, and this is the primary aim of our study. These conditions are often extremely rare and, indeed, in some cases they are totally new. »

According to the World Health Organisation, in 2009 there were 2.6 millions stillbirths (the death of the fœtus at or after 22 weeks of pregnancy) across the world, with more than 8200 deaths per day. Among the 133 million babies born alive each year, 2.8 million die in the first week of life.

In Australia, a standard perinatal autopsy is done in about 60% of cases of unexplained fœtal or neonatal death and termination of pregnancy for congenital abnormalities. Some genetic testing is done, but it is limited, usually to chromosomal analysis. As in most other countries, specific genetic sequencing is not a standard part of the autopsy process and when it does occur it is generally limited to a particular condition or a relatively short list of genes. « We are offering the testing of all human genes so that we can increase the rate of diagnosis as much as possible,» says Prof Barnett.

One of the main ethical features of the study is that it involves testing the parents as well as the fœtus/newborn. This means that the consent procedure needs to be rigorous, and occur in a face to face setting with the clinical geneticist at the time of the counselling that is provided for follow-up of the first autopsy. The genetic diagnoses of the parents may have the potential to affect their health later in life, and the consent process allows them to opt out from knowing these results if they so wish.

« Our results provide new insights into the molecular mechanisms of early development. We are not surprised that a significant proportion of ‘unexplained’ fœtal and newborn deaths and congenital abnormalities have an underlying genetic cause, and we believe that genomic autopsy should be used routinely in the investigation of pregnancy loss and perinatal death, » Prof Barnett will conclude.

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University in Newcastle, United Kingdom, said: “It is often unclear what the cause is of pregnancy loss or the death of a newborn baby. This work shows how state-of-the-art genomic testing can be used as part of the routine autopsy procedure to reveal a genetic cause in up to a quarter of all neonatal cases. A genetic diagnosis can be used to prevent complications in future pregnancies and provide much needed answers to the families involved.”

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1.Whole exome sequencing is a technique for sequencing all the genes in a genome that code for proteins. Because disease-causing genes are much more likely to be found in the protein-coding sequence, focusing on this limited area costs much less than whole genome sequencing but is still able to provide a high yield of results.

2. Whole genome sequencing is the process of determining the complete DNA sequence of an individual, including all the chromosomal DNA and that contained in the mitochondria.

Abstract no: C15.5. The Genomic Autopsy Study: using genomics as an adjunct to standard autopsy to unlock the cause of complex fetal and neonatal presentations
Session C15 Syndrome Updates 2, Monday, June 18, 2018, 13:00 - 14:30 hrs

The research was funded by the Australian National Health and Medical Research Council (NHMRC), and sequencing support provided by the Broad Institute in Boston, USA.

Milan, Italy:  Interest in the origins of human populations and their migration routes has increased greatly in recent years. A critical aspect of tracing migration events is dating them. However, the radiocarbon techniques*, that are commonly used to date and analyse DNA from ancient skeletons can be inaccurate and not always possible to apply. Inspired by the Geographic Population Structure model that can track mutations in DNA that are associated with geography, researchers have developed a new analytic method, the Time Population Structure (TPS), that uses mutations to predict time in order to date the ancient DNA.

Dr Umberto Esposito, a postdoctoral research in the laboratory of Dr Eran Elhaik, Department of Animal and Plant Sciences at the University of Sheffield, Sheffield, UK, will tell the annual conference of the European Society of Human Genetics today (Monday) that TPS can calculate the mixtures of DNA deriving from different time periods to estimate its definitive age. “This introduces a completely new approach to dating.  At this point, in its embryonic state, TPS has already shown that its results are very similar to those obtained with traditional radiocarbon dating. We found that the average difference between our age predictions on samples that existed up to 45,000 years ago, and those given by radiocarbon dating, was 800 years. This study adds a powerful instrument to the growing toolkit of paleogeneticists that can contribute to our understanding of ancient cultures, most of which are currently known from archaeology and ancient literature,” says Dr Esposito.

Radiocarbon technology requires certain levels of radiocarbon on the skeleton, and this is not always available. In addition, it is a delicate procedure that can yield very different dates if done incorrectly. The new technique provides results similar to those obtained by radiocarbon dating, but using a completely new DNA-based approach that can complement radiocarbon dating or be used when radiocarbon dating is unreliable.

 « This permits us to open a powerful window on our past. The study of genetic data allows us to uncover long-lasting questions about migrations and population mixing in the past. In this context, dating ancient skeletons is of key importance for obtaining reliable and accurate results, » says Dr Esposito. « Through this work, together with other projects that we are working on in the lab, we will be able to achieve a better understanding of the historical developments that took place from the beginning of the Neolithic period, with the introduction of farming practices in Europe, and throughout the Bronze and Iron Ages. These periods include some of the most crucial events involving the population movements and replacements that shaped our world. »

The technique is also expected to be valuable for genealogy. « When applying our ancient DNA dating technology to modern genomes, we have seen that some populations have more ancient genomes than others, and this can be helpful in establishing individual origins » says Dr Esposito.

Health research will benefit too. Since the study of genetic disorders is closely tied up with questions of ancestry and population stratification, being able to analyse the homogeneity of populations is of vital importance to epidemiologists.

The researchers are currently compiling a larger dataset to increase the geographical/time coverage of their model and improve its accuracy. « Given the rapid increase in the number of ancient skeletons with published DNA, we believe that our technique will be useful to develop alternative hypotheses,» Dr Esposito will say.

Chair of the ESHG conference, Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University in Newcastle, United Kingdom, said: “This study shows how DNA derived from ancient skeletons can be used to more accurately determine the age of the skeleton than traditional radiocarbon tracing methods. This is another example of the power of modern genomics technologies to assist in helping us understand where we come from, how the journeys of our forefathers have helped shape our current genome and how this now impacts our current abilities and weaknesses, including risks of disease.”

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*Radiocarbon dating is a method for determining the age of an object by analysing the amount of radioactive carbon dioxide it contains. When an animal or plant dies, it stops exchanging carbon with its environment, and measuring the amount that remains provides a method of determining when it died.

Abstract no: C16.4 Time informative markers to date ancient skeletons
Session C16. Multi-Omics 2, Monday, June 17, 2018, 13:00 - 14:30 hrs

The research was funded by the UK Engineering and Physical Sciences Research Council and the DNA Diagnostics Centre (DDC).

For immediate release: Thursday 8 September 2016

The law requiring compulsory DNA testing of all Kuwaiti residents, as well as of all those visiting the country for whatever purpose, is a serious assault on the right to privacy of individuals, and is also likely to lead to the isolation of Kuwaiti scientific research and researchers, the European Society of Human Genetics (ESHG) said today [Thursday 8 September]. In a letter addressed to the Prime Minister and the Council of Ministers of the State of Kuwait, the Society calls upon the government to amend the law.

According to the Kuwaiti government, the new measure has been introduced to try to tackle the problem of terrorism in the country.  It provides for the imposition of a one-year prison term and a fine on those who refuse to provide samples. “Not only does this law constitute a disproportionate response to the problem, but the very existence of such a comprehensive database of human DNA could be dangerous in the future, in the event of hacking or a regime change, for example,” said Professor Olaf Horst Rieß, ESHG President.

Another concern for the Society is the potential effect of the compulsory testing of all visitors, including scientists. “We believe that this is likely to lead to the isolation of Kuwaiti research institutions, as visiting scientists may refuse to give samples and therefore will not attend valuable scientific conferences in the country”, said Professor Rieß.  “The current global challenges in human health and demography must be addressed by all industrialised countries in a collaborative effort.”

“We see this new law as a major threat to joint actions in the field of genomic health that involve national European genetic societies, and therefore we request the Kuwait government to reconsider and to amend this law so that human DNA is collected for legal purposes only from individuals suspected of having committed serious crimes,” said Professor Martina Cornel, Chair of the ESHG Public and Professional Policy Committee.

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Reproduction of an article in the New Scientist.

Kuwait’s mass DNA database is a huge attack on genetic privacy
The Gulf State will soon be the first nation to force all residents and visitors to hand over DNA, risking its reputation and more, warns geneticist Olaf Rieß

Could collecting DNA have prevented the suicide attack at this Kuwaiti mosque in June 2015? It’s hard to see how 

By Olaf Rieß

Compulsory DNA testing of all citizens and visitors sounds like an Orwellian nightmare, but this is the new reality in a wealthy Gulf State. Kuwait has become the first country to order blanket genetic sampling – a worry on so many fronts.

What happens if the DNA database is hacked? And even if the current government can keep the database secure, what might happen in the event of a regime change?

The Kuwaiti government says DNA testing, reportedly due to begin within weeks, is needed to combat terrorism, and introduced the measure in the wake of a bombing that killed 27 people there last year. While the need to have a swab taken may discourage attackers from entering the country, we should not forget that a lot of terrorism these days is home-grown. And who ever heard of a suicide bomber being dissuaded because they might be identified after blowing themselves up?

The government has also said the database could help identify victims. But if a bomb causes many fatalities, DNA will not help much in distinguishing the attacker from those killed. The terrorism argument is so spurious that even the least suspicious among us might begin to wonder whether there is an ulterior motive for this wholesale collection of DNA.

Let’s just try to imagine some of the other potential uses. Worrying examples spring easily to mind: checking paternity in a country with severe adultery laws or trying to uncover someone’s ethnic origin in order to discriminate. And we know from history that many initiatives that started out with the best of intentions have ended up used for nefarious purposes.

Matching names to genes: The end of genetic privacy?

It seems to me, too, that the Kuwaiti government could cause irreparable harm to the country’s economy and reputation. Tourists may not know that their DNA will be collected upon arrival; neither will they understand all that this implies. Some may accept the sampling, but others will choose to stay away.

There are implications for business and science. European industry and research has benefited hugely from the loosening of travel restrictions and the subsequent boosting of trade with Kuwait. Companies will now think twice about opening facilities there.

And will scientists from abroad still wish to attend conferences in Kuwait in the knowledge that their right to privacy will be invaded so dramatically? I think not. This could have a major impact on Kuwait’s standing as a conference host and hinder joint research projects.

As a scientist using genetics to seek medical advances, I also worry that compulsory collection of DNA might affect public willingness elsewhere to support research. If sampling becomes linked to coercion in the public eye, this is likely to reduce people’s readiness to include their genome in research databases, which are so important in the quest to better understand and treat disease.

Kuwait has invested heavily in genetic technology, so collecting DNA on this scale would probably be feasible, at least in the first instance. But the question is not whether it is feasible, but rather whether it is desirable.

The answer is clear; it is neither appropriate nor helpful in tackling the dangers it is designed to confront, and the threat posed in the event of its misuse is highly alarming.

Article amended on 12 September 2016
Since this article was first published, the context of some potential (mis)uses of DNA sampling in Kuwait has been made clearer.

Olaf Rieß is a medical geneticist and president of the European Society of Human Genetics, which has called on Kuwait to abandon blanket sampling