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Leukodystrophy Diagnoses Boosted by Exome Sequencing; Genome Sequencing Trial is Next

NEW YORK (GenomeWeb) – Exome sequencing solved 42 percent of patient cases of unresolved white matter abnormalities, according to a new study, boosting the overall diagnostic rate from 53 percent with standard imaging to almost 70 percent with a combination of the two approaches.

The study, led by researchers at Children's National Health System in Washington, DC, the University of Queensland in Australia, and Illumina, was published in the Annals of Neurology today.

Disorders of the brain's white matter, which include leukodystrophies, affect about one in 7,000 children born every year. Over the past decades, magnetic resonance imaging pattern recognition has significantly improved the diagnosis of leukodystrophies, but almost half of patients with suspicious clinical phenotypes remain undiagnosed.

For their study, the researchers examined 191 patients who had been referred to the Myelin Disorders Bioregistry Project between 2009 and 2013 with unresolved leukoencephalopathies that were thought to be of genetic origin. 

Of these, 101 patients were diagnosed using MRI pattern recognition followed by biochemical or other molecular tests.  For 71 of the remaining 90 cases, the researchers conducted exome sequencing, either on parent-child trios or on even more family members.

Exome sequencing was performed at the Queensland Centre for Medical Genomics, using either Illumina's Nextera Rapid Capture kit or the NimbleGen SeqCap EZ Human Exome Library to capture the exome and either the Illumina HiSeq 2000 or the NextSeq 500 for sequencing.

Based on those data, the researchers were able to unambiguously resolve 25 cases. Nine had mutations in genes associated with classic leukodystrophies, while the remaining patients had mutations in genes associated with genetic leukoencephalopathies. This, the authors wrote, suggests that panel testing for leukodystrophy-associated genes has limited value, as it would only have solved 13 percent of patients in this cohort.

In another four cases, the team identified at least one potentially damaging variant of uncertain significance that they said "did not reach the strict burden of proof required to be classified as pathogenic or likely pathogenic." However, neuroradiological findings, clinical features, and familial segregation of the variants were consistent with the published phenotype in each case, so the researchers decided to classify the variants as potentially pathogenic and added these patients to the clinically resolved cases.

Another patient had a pathogenic mutation in a gene that had previously only been associated with juvenile or adult disease onset, but based on other data, the researchers also classified this case as resolved.

Overall, they identified pathogenic or likely pathogenic variants in 30 patients, for a diagnostic rate of 42 percent.

Combined with the 101 families already diagnosed by MRI, exome sequencing increased the number of diagnoses to 131, yielding a total diagnostic rate of almost 70 percent.

Having a genetic diagnosis changed clinical care for several patients: based on their mutations, a couple of patients now undergo cancer screening, and one patient received treatment with an anticonvulsant to control epilepsy.

The researchers also screened the exome data for secondary findings in the 56 genes recommended for adults and 49 genes recommended for children by the American College of Medical Genetics and Genomics and found pathogenic or likely pathogenic variants in three of the 71 families, in genes associated with long QT syndrome and hereditary paragangliomas. Based on this, they wrote, "the impact of incidental findings is likely to be minimal, especially when weighed against the potential benefits of a successful genetic diagnosis in families with severe, life-threatening neurologic illnesses."

Additional research is needed, the authors concluded, to assess the potential value of sequencing as a first-line diagnostic tool, and to compare the effectiveness of exome sequencing, whole-genome sequencing, and targeted gene panels in this patient population.

In a clinical trial called "New Diagnostic and Therapeutic Approaches in Leukodystrophy (LeukoSeq) that is currently recruiting and aims to enroll 200 participants, researchers at Children's Research Institute, which is part of Children's National, and Illumina are going to study the ability of whole-genome sequencing to provide a diagnosis to patients with suspected leukodystrophy but no specific genetic diagnosis. That trial will also analyze the cost effectiveness and clinical utility of the approach.