RCIGM Scientists Detect Cause of Rare Pediatric Brain Disorder

Rady Children’s Institute for Genomic Medicine Leads Mutation Discovery

Feb. 20, 2019—An international effort led by physician-scientists at Rady Children’s Institute for Genomic Medicine (RCIGM) has identified the cause of a devastating pediatric brain disorder paving the way for the first step in developing potential therapies for this rare neurodegenerative condition.

Investigators performed advanced genetic tests on blood samples from seven children with neuro-development disabilities who were evaluated by doctors in San Diego, Montreal and Cairo. This led to the discovery of mutations in the VARS gene, which had not previously been linked to human disease.

“These children showed epileptic seizures and abnormalities evident on brain MRI scans,” said Joseph Gleeson, MD, director of neurodevelopmental genetics at RCIGM and professor of neuroscience and pediatrics at UC San Diego School of Medicine. “Although no treatment currently exists for this condition, the results are important as the first step in guiding research directed at targeted therapies.”   

The genetic mutations identified in the study led to a defect in the enzyme responsible for generating proteins containing the amino acid valine which is necessary for cellular health. Genetic variations that damage these types of enzymes are associated with a variety of human diseases including microcephaly and neuropathy.

In this study, the team found that, enzymatic activity was significantly reduced in cells from the young patients. The findings suggest that children with this disorder may benefit from treatments to support the synthesis of new valine containing proteins in the brain.

For many children with genetic disabilities, the cause of their disease is never identified. This limits the ability of doctors to develop precise treatment plans. Researchers at RCIGM have pioneered the use of Whole Genome Sequencing to rapidly diagnose and guide medical management of rare childhood diseases.

Both whole exome and whole genome testing were conducted as part of this study. These tests search an individual’s genetic code for imperfections that are the source of disease.

“Trying new approaches to understand what these children have is important because it helps families when they have an answer about what it is that’s making their child so sick,” adds study co-author Geneviève Bernard, MD, MSc, FRCPc, pediatric neurologist at the Montreal Children’s Hospital of the McGill University Health Centre (MUHC) and a researcher with the Child Health and Human Development Program of the Research Institute of the MUHC.

Patient evaluation and testing for this study was conducted at Rady Children’s Hospital-San Diego, Montreal Children’s Hospital of the McGill University Health Centre and the National Research Center in Cairo. Medical research institutions in Amsterdam, Hong Kong, Qatar and Egypt also played a supporting role in confirming the biologic impact of the mutation in the VARS gene.

“For ultra-rare conditions such as this one, collaboration among multiple research institutions is crucial to confirm that changes identified in the genetic code may be common to multiple children with similar clinical symptoms,” said study co-author Jennifer Friedman, MD, neurologist at Rady Children’s Hospital and professor at UC San Diego School of Medicine.

“Such cooperation and patient matching plays a critical role in the identification of new genes and provision of diagnoses to geographically dispersed individuals with the same rare disorder,” Dr. Friedman said.

In future experiments, the researchers hope to test whether dietary supplementation with valine or gene therapy may help to restore the altered protein in the brain of these children.

Results of the study were published in the journal Nature Communications under the title “Biallelic mutations in valyl-tRNA synthetase gene VARS, are associated with a progressive neurodevelopmental epileptic encephalopathy.”  DOI: 10.1038/s41467-018-07067-3 https://www.nature.com/articles/s41467-018-07067-3

Rady Children’s Institute for Genomic Medicine Appoints New VP of Research

Dr. Charlotte A. Hobbs joins the executive leadership team

February 11, 2019—The Rady Children’s Institute for Genomic Medicine (RCIGM) is pleased to announce that physician-scientist Charlotte A. Hobbs, MD, PhD, has assumed the role of Vice President of Research and Clinical Management.

Dr. Hobbs brings a wealth of experience as a distinguished clinician, researcher, medical educator and hospital administrator. She has directed national studies of birth defects and pediatric health funded by NIH and CDC, among others. She recently completed a $6.1 million NIH-funded Genome Wide Association study involving more than 8,000 individuals in eight states.

“We are very pleased to have recruited Dr. Hobbs to join the Institute’s executive leadership,” said Stephen Kingsmore, MD, DSc, President and CEO of the Rady Children’s Institute for Genomic Medicine. “She brings deep expertise in building biomedical research programs and a passion for improving patient outcomes. That combination makes her uniquely qualified to join us in our mission to transform pediatric care.”

In her new role, Dr. Hobbs will guide the growing research and clinical programs at RCIGM. She will oversee the clinical genomics team, including physicians, nurses, genetic counselors and project managers, providing them with the intellectual and administrative infrastructure to support the Institute’s initiatives and goals.

Prior to joining the Institute in January of this year, Dr. Hobbs was Executive Associate Dean for Clinical and Translational Research at the University of Arkansas for Medical Sciences (UAMS) and Arkansas Children’s Hospital. In that role, she supported faculty scientists in their mission to develop biomedical knowledge leading to improved healthcare.

At UAMS she held a number of key leadership positions. Until her departure in December 2018, she was also Chief Research Information Officer. During 2016-2017, as a professor in the Department of Pediatrics, she fulfilled the role of director and co-principal investigator of the NIH-funded Data Coordinating and Operations Center for the 17-site Pediatric Clinical Trial Network in 2016-2017. Throughout her career, she continued her clinical service in neonatology attending in Level I to III nurseries.

“I am delighted to be part of the Institute’s pioneering team bringing precision genomic medicine to the cribs and bedsides of critically ill infants and children,” said Dr. Hobbs. “I finished pediatric residency 23 years ago, before the first human genome was sequenced. At that time, it was beyond my wildest imagination that someday I would have the opportunity to bring together my experience and skills in clinical medicine, informatics and genomics to join an extraordinary team combining science and medicine to improve the health of babies and children for generations to come.”

Dr. Hobbs is married to Jim Robbins, PhD, a native of Little Rock, AR and a health service researcher. They have three adult children between the ages of 21 to 23, who are currently in college.

Whole Genome and Exome Sequencing are Superior Diagnostic Tests for Children with Suspected Genetic Diseases

First meta-analysis of scientific literature underscores the greater clinical and diagnostic utility of sequencing compared to standard genetic testing

July 9, 2018–Whole Genome Sequencing (WGS) and Whole Exome Sequencing (WES) of children with suspected genetic diseases are more useful than the current first-line test, according to a study published today by the Rady Children’s Institute of Genomic Medicine in the journal npj Genomic Medicine.

The study compared the usefulness of the current most established testing method—
chromosomal microarray (CMA)—to relatively new, more advanced tests: WGS and WES—in detecting the cause of genetic anomalies and guiding medical management of patients.

“What we learned is that WGS and WES offer greater diagnostic and clinical utility than CMA, leading us to conclude that WGS and WES should be considered first-line genomic tests for children with suspected genetic diseases,” said Michelle Clark, PhD, statistical scientist at the Rady Children’s Institute of Genomic Medicine (RCIGM) and the first author of the study.

Genetic diseases are the leading cause of death in infants in North America affecting an estimated four percent of newborns. Rare genetic diseases also account for approximately 15 percent of admissions to children’s hospitals.

Since 2011, Whole Genome and Whole Exome sequencing have been increasingly used for diagnosis of genetic diseases, primarily on an experimental basis as guidelines do not yet exist for their use. In addition, medical insurance reimbursement for is available on a very limited basis for WES but not for WGS. As a consequence, while these tests are more useful, they are not widely available.

The basis for the publication was a thorough, systematic review of scientific literature covering nearly seven years (January 2011 to August 2017). The study, led by RCIGM president and CEO Stephen Kingsmore MD, DSc, analyzed the results of 37 research studies involving more than 20,000 children with suspected diseases and compared the diagnostic and clinical utility of WGS, WES and CMA in these cases.

The Institute team has engineered a Whole Genome Sequencing process to rapidly decode, analyze and interpret the cause of genetic disorders in newborns and children in intensive care in a matter of days.

WGS is a single genetic test that can screen a blood sample for thousands of genetic anomalies and quickly identify the root causes of a child’s condition. As part of their research protocols, the RCIGM team is working to equip clinicians with this critical information to facilitate medical decision making.

Most important, early intervention may avoid unnecessary treatment, invasive surgeries, and reduce hospitalization time, ultimately reducing suffering, bringing down the cost of care and improving quality of life for affected babies and children.

“Our hope is that Whole Genome Sequencing will soon become routine so that all children who need it can have access to this life-saving technology,” said Kingsmore.

Currently, RCIGM is offering rapid Whole Genome Sequencing (rWGS) only through research studies offered to patients at Rady Children’s Hospital-San Diego and children’s hospitals participating in RCIGM’s clinical trials. Among the hospitals collaborating with RCIGM are Children’s Hospital of Orange County, Children’s Minnesota, Colorado Children’s and Nicklaus Children’s Hospital (Miami).

Children’s Hospitals Collaborate Using Genomic Medicine to Change Pediatric Care

**Sanford Children’s Genomic Medicine Consortium ** SIOUX FALLS, S.D. — Seven children’s hospitals across the United States are collaborating to rapidly integrate genetics and genomics into primary and specialty pediatric care.

The mission of the Sanford Children’s Genomic Medicine Consortium is to work together on innovative clinical program development, advocacy for children, cutting-edge research and educational programs for the future of genomic medicine.

The seven member hospitals include: Sanford Children’s (Sioux Falls and Fargo), Children’s Minnesota (Minneapolis and St. Paul), Children’s Hospital Colorado (Aurora), Children’s Hospital Los Angeles, Rady Children’s Institute for Genomic Medicine and Rady Children’s Hospital – San Diego, Banner Children’s at Diamond Children’s Medical Center (Tucson) and Nicklaus Children’s Hospital (Miami).

Sanford Health has provided $500,000 in seed funding for Consortium projects over the next year.

The initial projects funded by the Consortium include a study of rapid whole genomic sequencing in critically ill newborn infants, and a study evaluating the routine use of an extensive, pediatric-focused, next generation sequencing panel in the diagnosis of childhood cancers.

Genetic diseases are a leading cause of morbidity and mortality in infants in Neonatal and Pediatric Intensive Care Units (NICU, PICU). These children often undergo an extensive and expensive diagnostic process that may not lead to a final diagnosis. Stephen Kingsmore, M.D., D.Sc., president and CEO of Rady Children’s Institute of Genomic Medicine (RCIGM) is leading rapid whole genomic sequencing in critically ill newborn infants to determine the complete DNA sequence of a child’s genome at one time to identify the risk of genetic diseases. Currently, the average turn-around time for sequencing to diagnosis by the RCIGM team is under a week. That is significantly faster than the common timetable for this type of work, which can take weeks to complete.

“The future of pediatric medicine is being transformed by the ability to rapidly decode the genomes of the most fragile newborns to deliver exact diagnoses and targeted treatment,” said Kingsmore.

Pediatric cancers have different genetic origins compared with adult cancers. Current panels for detecting the genetic origins of a tumor primarily focus on adult cancers. OncoKidsSM developed at Children’s Hospital Los Angeles, is specifically formulated to detect the genomic alterations of pediatric cancers including leukemias, lymphomas, bone, soft tissue and brain tumors.

“The ability to identify the precise underlying genomic alterations in individual tumors with OncoKidsSM allows us to personalize care and innovate how we treat children with cancer,” said Alexander R. Judkins, M.D., Pathologist-in-Chief and Executive Director of the Center for Personalized Medicine (CPM) at Children’s Hospital Los Angeles.

Extending precision medicine to children’s health through this Consortium is inspired by the vision of Denny Sanford. In 2014, the health care philanthropist gave $125 million to Sanford Health to create Sanford Imagenetics, the first program in the nation to embed the latest in genomic medicine with primary care.

“I am thankful to each member for their participation in the Sanford Children’s Genomic Medicine Consortium,” said Gene Hoyme, M.D., Medical Director, Sanford Children’s Genomic Medicine Consortium. “So much can be gained for the care of children through the collaboration of these hospitals.”

WGS Helps Diagnosis and Reduces Healthcare Costs for Neonates in Intensive Care

European Society of Human Genetics 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

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

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