llumina, Inc., Children’s National Health System and The University of Queensland (UQ) announced that a study using whole exome sequencing (WES), a method to look at all the genes in the genome at once, yielded clinical diagnoses for 42 per cent of patients with white matter abnormalities that had been unresolved an average of eight years.

White matter disorders are progressive and involve age-related weakness in the part of the nerves that connect various parts of the brain to each other and to the spinal cord. This group of disorders are found in 1 per 7,000 children born each year. The study brought together 28 named collaborators, led by Children’s National and included researchers from Illumina and The University of Queensland.

The results of the study, entitled “Whole exome sequencing in patients with white matter abnormalities,” are available online in the Annals of Neurology and the full article can be accessed here. The paper will also be published in the June print edition (Volume 79, Issue 6).

“The term ‘rare’ genetic disease is something of a misnomer, since up to 350 million people across the world can be impacted by these disorders,” said Adeline Vanderver, M.D., director of the Myelin Disorders Program at Children’s National and lead author on the study. “Our study found that next generation sequencing could shine a diagnostic light on an especially challenging group of genetic disorders that impact the brain’s white matter.”

“We were delighted by the power of this approach,” adds co-author Ryan J. Taft, Ph.D., Director of Scientific Research at Illumina. “In this study, use of next-generation sequencing-based WES dramatically increased the diagnostic yield and reduced the time to diagnosis.”

“White matter disorders can have a devastating impact on patients and their families,” said study co-author Cas Simons, Ph.D., from the Institute for Molecular Bioscience Centre for Rare Diseases Research at UQ. “Access to a timely and accurate diagnosis is critical to inform many health care decisions and improve quality of life for patients.”

More than 100 genetic disorders are linked to white matter abnormalities in the central nervous system. At least 10 different chemicals make up the myelin, a fatty insulation layer, and the myelin sheath plays a critical role in smooth transmission of electrical impulses along nerve cells. A cluster of rare genetic disorders known as the leukodystrophies, which cause progressive degeneration of the brain’s white matter, are tied to genetic flaws in how myelin makes or uses its essential mix of chemicals.

Standard approaches to diagnose white matter disorders fail in nearly 50 per cent of these children, complicating their care and exacting a substantial psychological toll on families, Dr. Taft says. The human genome contains roughly 3 billion letters of DNA. The exome, the protein-coding region of the genome, represents just 2 per cent of this genetic code but contains most of the variants known to be related to disease.

MRI (magnetic resonance imaging) has been tapped for the last 20 years to recognize telltale patterns of leukodystrophies, yet nearly half of patients lack concrete diagnoses. Because WES ferreted out diagnoses for other stubbornly unsolved genetic disorders, the research team has proposed that the technique could answer genetic cold cases thought to be leukodystrophies.

The research team identified 191 families with unresolved cases of leukoencephalopathy thought to be genetic in nature. Of this group, they diagnosed 101 families using MRI pattern recognition followed by standard biochemical and genetic testing. For the 90 cases that remained undiagnosed, 71 family groups of at least three people were included in the study and provided the high-quality samples needed for WES analyses by the research team. While patients ranged from 3 to 26 years old at the time of sequencing, for some, symptoms began at birth. This research was performed utilizing Illumina technology.

According to the study, adding WES to the diagnostic tools already at clinicians’ disposal “may decrease the number of patients with unsolved genetic white matter disorders from 50 percent to less than 30 percent. Taking into consideration the clinical and psychosocial costs of prolonged diagnostic odysseys in these families, this is substantial.” The diagnoses led to additional precision in some patients’ clinical care, with families with certain mutations being referred to specialized clinics to undergo monitoring for cancer. Based on these results the team is now investigating the use of whole genome sequencing, which could further increase the diagnostic yield, in a multi-site prospective study of children with neurodevelopment disorders.