Washington, DC—Whole exome sequencing (WES), a method to look at all the genes in the genome at once, yielded clinical diagnoses for 42 percent of patients whose white matter abnormalities had been unresolved an average of eight years, ending families’ “prolonged diagnostic odyssey,” according to an international study team that includes researchers from Children’s National Health System, Illumina, and the University of Queensland (UQ), located in Australia
White matter disorders are progressive and involve age-related weakness in the region of the nerves that connect various parts of the brain to each other and to the spinal cord. This group of disorders affects one per 7,000 children born each year.
Nine of 28 named authors of the study, published online May 9, 2016 in Annals of Neurology, are affiliated with Children’s National, including lead author Adeline Vanderver, MD, Director of the Leukodystrophy and Myelin Disorders Program.
“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,” Dr. Vanderver said. “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. For 42 percent of families who had exhausted other diagnostic approaches, WES provided an answer that had eluded them for years: ‘What is causing my child’s health condition?’ With this long-sought diagnosis in hand, clinicians already are directing more patients to personalized clinical care.”
Co-author Ryan J. Taft, PhD, Director of Scientific Research at Illumina, adds, “We were delighted by the power of this approach. In this study, use of next-generation sequencing-based (NGS) WES dramatically increased the diagnostic yield and reduced the time to diagnosis.”
Study co-author Cas Simons, PhD, of the Institute for Molecular Bioscience Centre for Rare Diseases Research at UQ, says, “White matter disorders can have a devastating impact on patients and their families. Access to a timely and accurate diagnosis is critical to inform many healthcare decisions and to 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 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 percent of these children, complicating their care and exacting a substantial psychological toll on families, Illumina’s Dr. Taft says.
The human genome contains roughly three billion letters of DNA. The exome, the protein-coding region of the genome, represents just two percent of this genetic code but contains most of the variants known to be related to disease.
Magnetic Resonance Imaging (MRI) 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 hypothesized 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.
According to the study authors, 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 now is investigating the use of whole genome sequencing, which could further increase the diagnostic yield, in a multi-site prospective study of children with neurodevelopmental disorders.
In the team’s next study
, they are also pursuing the use of whole genome sequencing in these patients, which will enable them to examine the patient’s entire genome to identify exceedingly rare or complex genetic variants.
Lauren Lytle or Diedtra Henderson at 202-476-4500.