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.