New database to speed genetic discoveries

A new online database combining symptoms, family history and genetic sequencing information is speeding the search for diseases caused by a single rogue gene. As described in an article in the May issue of Human Mutation, the database, known as PhenoDB, enables any clinician to document cases of unusual genetic diseases for analysis by researchers at the Johns Hopkins University School of Medicine or the Baylor College of Medicine in Houston. If a review committee agrees that the patient may indeed have a previously unknown genetic disease, the patient and some of his or her family members may be offered free comprehensive genetic testing in an effort to identify the disease culprit.

“PhenoDB is much more useful than I even thought it would be,” says Ada Hamosh, M.D., M.P.H., a professor in the McKusick- Nathans Institute of Genetic Medicine at the Johns Hopkins University School of Medicine. “Bringing all of this information together is crucial to figuring out what our genetic variations mean.” The database is designed to capture a bevy of standardized information about phenotype, which Hamosh defines as “any characteristic of a person” – symptoms, personal and family health history, appearance, etc.

Hamosh and others developed PhenoDB for the Baylor-Hopkins Center for Mendelian Genomics (BHCMG), a four-year initiative that, together with its counterparts at Yale University and the University of Washington, is charged with uncovering the genetic roots of every disorder caused by a single faulty gene. There are an estimated 3,000 inherited disorders that have been described phenotypically in scientific papers but whose genetic causes have not yet been pinpointed, Hamosh says, but since many single-gene disorders are extremely rare, she suspects that many more have not yet made it into the literature.

The Centers for Mendelian Genomics have a powerful tool at their disposal, known as whole-exome sequencing. Just a few years ago, Hamosh explains, a geneticist trying to diagnose the cause of an inherited disease would have made an educated guess based on the patient’s signs and symptoms about which gene might be at fault, and ordered a test of that gene. If the test came back negative for a mutation, she would order a test of a different gene, and so on. But whole-exome sequencing, in which about 90% of a person’s genes are sequenced at one time, has been growing steadily cheaper, and it is this tool that the Centers will use to capture genetic sequencing information (whole-genome sequencing is the next step, but it remains too expensive for many uses, Hamosh notes, as it includes all of a person’s DNA, most of which contains no genes).

However, making sense of the deluge of data yielded by whole-exome sequencing presents its own challenges. “The average person has tens of thousands of variations from the standard genetic sequence,” Hamosh explains, “and we don’t know what most of those variations mean.” To parse these variations, she says, “one of the things that needs to change is that the lab doing the testing needs to have the whole phenotype, from head to toe.” Researchers will then be better equipped to figure out which variations may or may not be relevant to a patient’s illness. Another advantage of the database is that it enables colleagues at distant locations – such as Baylor and Johns Hopkins – to securely access the information and collaborate. Hamosh notes that the database enables different users to be afforded different levels of access – for example, a health provider will only be able to see the information he or she has entered – and that information is deidentified to protect patient privacy. In addition, providers must have patients’ consent to be included in PhenoDB.

PhenoDB would be useful for any research project that seeks to match genomic information with its phenotypic effects, Hamosh says, and with that in mind, the Baylor-Hopkins Center for Mendelian Genomics has made the PhenoDB software available for free download at http://phenodb.net. She predicts that similar tools will soon be incorporated into electronic health records as well, so that “doctors will have patients’ genomic information at their fingertips and can combine that with information about health history, disease symptoms and social situation to practice truly individualized medicine.”


phenoDB http://phenodb.net



Gene variant may play role in low back pain difference between sexes

More women than men develop chronic low back pain and sciatica. The explanation may lie with a gene variant that plays into the body’s pain regulation.

“In our study we were surprised to discover that the same gene variant may actually promote chronic pain in women and suppress pain in men,” says Professor Johannes Gjerstad, Senior Researcher at the Norwegian National Institute of Occupational Health (STAMI).

Professor Gjerstad headed a research project encompassing nearly 300 patients suffering from disc prolapse at Oslo University Hospital and at Haukeland University Hospital in Bergen. Patients were followed up for one year after admission.

Although everyone basically has the same genes, there are many genes that come in multiple versions – an ordinary one and a variant. Generally, the effects of this genetic variation are gender-independent, but there are exceptions.

“As expected, somewhat more men than women were referred to hospital with disc prolapse,” continues Professor Gjerstad. “In the course of the study we observed that the men recovered faster than the women.”

Previous research findings on animals provided the researchers with a clue that the gene coding for the OPRM1 receptor – involved in the body’s pain regulation – may be responsible for this.

It turns out that the women with the less ordinary variant of this gene often experienced twice as much pain as the men who had the same gene variant. One year after their prolapse, on a pain scale from 0 to 10, these women reported an average intensity of around four, while the men averaged around two.

Roughly one in four persons, independent of gender, carries this unfortunate gene variant.

Previous research data shows that a gene coding for the COMT receptor plays a role in the experience of pain half a year after a disc prolapse. The gene coding for the OPRM1 receptor, however, appears to become significant only after a full year.

The patients in the study reported their pain by questionnaire. One year postprolapse, two out of three back patients had healed completely. But the remaining third, most of them women, continued to experience discomfort.

The insights gained from the Norwegian study may ultimately help researchers to customise prevention and treatment better. The OPRM1 receptor has no direct significance for the back’s physical condition, but rather is known to play a key role in the brain’s regulation of pain. For this reason the researchers believe their findings may be relevant to other experiences of pain.

“We think that this OPRM1 gene variant is significant for long-term pain more generally, and we would like to investigate this further,” says Professor Gjerstad.



Researchers identify gene involved in epilepsy

Researchers at the University Department of Neurology at the MedUni Vienna have identified a gene behind an epilepsy syndrome, which could also play an important role in other idiopathic (genetically caused) epilepsies. With the so-called “next generation sequencing”, with which genetic changes can be identified within a few days, it was ascertained that the CNTN2 gene is defective in this type of epilepsy.

This was investigated by a team led by Elisabeth Stögmann in collaboration with Cairo’s Ain Shams University and the Helmholtz Centre Munich with reference to a particular Egyptian family, in which five sick children have resulted from the marriage of one healthy cousin to his, likewise healthy, second cousin. The children affected suffer from a specific epilepsy syndrome, in which different types of epileptic attacks occur. This constellation has the “advantage”, according to Stögmann, that both alleles of the gene, which is how one designates different forms of the gene, demonstrate this defect: “As a result the defect becomes symptomatic and identifiable.

“20,000 to 25,000 genes, including all the “protein coding” ones, were sequenced for this. When this was done a mutation was found in the CNTN2 gene. CNTN2 undertakes an important function in the anchoring of potassium channels to the synapses. The mutation makes it no longer possible to generate this protein and, as a consequence, the potassium channels no longer remain affixed to the synapses. The researchers suspect that the epilepsy in this family is triggered by the altered function of the potassium channels.

This discovery, which has now been published in the top journal “Brain”, is providing the stimulus for further research to investigate this particular gene in other epilepsy patients as well. Approximately one percent of the population suffers from active epilepsy in which regular epileptic fits occur. The danger of suffering from an epileptic fit once in your life lies at approximately four to five percent. Genetic factors play a major part in the occurrence of epilepsies.

doi: 10.1093/brain/awt068



Scientists identify 14 new genes for childhood arthritis

Scientists from The University of Manchester have identified 14 new genes which could have important consequences for future treatments of childhood arthritis. Scientists Dr Anne Hinks, Dr Joanna Cobb and Professor Wendy Thomson, from the University’s Arthritis Research UK Epidemiology Unit, whose work is published in Nature Genetics yesterday (21 April), looked at DNA extracted from blood and saliva samples of 2,000 children with childhood arthritis and compared these to healthy people.

Principal Investigator Professor Thomson, who also leads the Inflammatory Arthritis in Children theme at the National Institute for Health Research (NIHR) Manchester Musculoskeletal Biomedical Research Unit, said: “This study brought together an international group of scientists from around the world and is the largest investigation into the genetics of childhood arthritis to date. The success was, in large part, due to it being an international effort with collaborators with Cincinnati Childrens Hospital (Professor Sue Thompson), Wake Forest School of Medicine (Professor Carl Langefeld) and Emory University School of Medicine (Professor Sampath Prahalad).”

Dr Hinks, joint lead author of the study, said the findings were a significant breakthrough for understanding more about the biology of the disease and this might help identify novel therapies for the disease. “Childhood arthritis, also known as juvenile idiopathic arthritis (JIA), is a specific type of arthritis quite separate from types found in adults and there’s been only a limited amount of research into this area in the past,” she said. “This study set out to look for specific risk factors. To identify these 14 genetic risk factors is quite a big breakthrough. It will help us to understand what’s causing the condition, how it progresses and then to potentially develop new therapies.”

doi: :10.1038/ng.2614



 

                                   
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