SAN DIEGO—While it is extremely difficult for any family to face their child falling ill, it is an added blow to be unable to properly identify the disease, as without a concrete diagnosis, it is impossible to establish a treatment plan. Although industry interest in developing treatments and therapeutics for rare diseases has increased in the past decade, diagnostics have not always kept pace, which makes a recent collaborative study that proved the potential of whole-exome sequencing as a new diagnostic tool all the more promising.
The study in question applied whole-exome sequencing in white matter disorders, and was found to yield clinical diagnoses for 42 percent of patients with white matter abnormalities that had gone unresolved for an average of eight years. Children’s National Health System led the study, which brought together 28 collaborators, including Illumina Inc. and The University of Queensland.
There are more than 100 genetic disorders linked to white matter abnormalities in the central nervous system. The myelin is comprised of at least 10 different chemicals, and the myelin sheath plays a pivotal role in the transmission of electrical impulses along nerve cells. A set of rare genetic disorders known as the leukodystrophies, which cause progressive degeneration of white matter in the brain, are tied to genetic disruptions in how myelin produces or metabolizes its mix of chemicals.
“White matter disorders can have a devastating impact on patients and their families,” said study co-author Dr. Cas Simons of the Institute for Molecular Bioscience Centre for Rare Diseases Research at The University of Queensland. “Access to a timely and accurate diagnosis is critical to inform many healthcare decisions and improve quality of life for patients.”
According to the National Institute of Neurological Disorders and Stroke, “The most common symptom of a leukodystrophy disease is a gradual decline in an infant or child who previously appeared well. Progressive loss may appear in body tone, movements, gait, speech, ability to eat, vision, hearing and behavior. There is often a slowdown in mental and physical development. Symptoms vary according to the specific type of leukodystrophy, and may be difficult to recognize in the early stages of the disease.”
Indeed, at present, standard methods of diagnosing these disorders fail in roughly half of children, according to Dr. Ryan J. Taft, co-author of the paper and director of Scientific Research at Illumina. MRIs can highlight the patterns of leukodystrophies, but even with that, almost half of patients still go without firm diagnoses. Given the success of using whole exome sequencing to diagnose other unsolved genetic disorders, the researchers thought it could also shed light on unsolved cases presumed to be leukodystrophies.
“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,” added Dr. Adeline Vanderver, 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.”
In this study, a total of 191 families with unresolved cases of leukoencephalopathy believed to be genetic were identified, and of those, 101 families were diagnosed through MRI pattern recognition and standard biochemical and genetic testing. Of the 90 remaining undiagnosed cases, 71 family groups of at least three people were included in the study. Patients ranged from 3 to 26 years of age at the time of the sequencing, which was performed on Illumina technology. As noted in the paper’s abstract, “Diagnostic pathogenic variants were identified in 35 percent (25 of 71) of patients. Potentially pathogenic variants were identified in clinically relevant genes in a further 7 percent (five of 71) of cases.”
Given the effectiveness seen in this study, the researchers are looking into the use of whole genome sequencing in a multi-site prospective study of children with neurodevelopment disorders.
The results of the study were published in the paper “Whole exome sequencing in patients with white matter abnormalities,” which appeared online in the Annals of Neurology ahead of print.