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

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).