Nanopore DNA Sequencing Can Help Diagnose Angelman, Study Shows
Technology can check for abnormalities in thousands of genes with a single test
Nanopore adaptive sequencing — a recently developed technology that determines the sequence of a strand of DNA by measuring changes in electrical activity as the DNA strand is fed through a tiny opening — can be used to diagnose Angelman syndrome and the related condition Prader-Willi syndrome (PWS), a new study reports.
“Nanopore adaptive sequencing represents a very efficient one step assay for diagnosing PWS and [Angelman syndrome], as well as for delineating the underlying mechanism, which is essential for precise genetic counseling,” researchers wrote.
The study, “Diagnosis of Prader-Willi syndrome and Angelman syndrome by targeted nanopore long-read sequencing,” was published in the European Journal of Medical Genetics.
Angelman and PWS caused by abnormalities in same region of chromosome 15
Both Angelman syndrome and PWS are caused by genetic abnormalities in the same region of chromosome 15. Everyone inherits two copies of this chromosome, one from each biological parent.
Within the SNRPN gene on chromosome 15, there is a sequence called a CpG island. Normally, the copy of chromosome 15 that’s inherited from the biological mother is methylated at the CpG island, while the copy inherited from the biological father is not methylated at this location. (Methylation is a chemical modification to DNA that affects how genes are “read”).
Assessing this region is key to diagnosing both Angelman and PWS: in Angelman, only the unmethylated paternal copy is present, whereas in PWS there is only the methylated copy from the mother. Several well-established laboratory assays are available to assess methylation status to help diagnose Angelman syndrome or PWS.
Nanopore adaptive sequencing is a recently developed technology that has attracted substantial interest in the scientific community because it can determine the sequence of a single long strand of DNA. This sets it apart from other sequencing technologies, which generally work by cutting up a long strand into small pieces that need to be reassembled.
Nanopore adaptive sequencing represents a very efficient one step assay for diagnosing PWS and [Angelman syndrome], as well as for delineating the underlying mechanism, which is essential for precise genetic counseling
In addition to determining the sequence of DNA, nanopore technology has been shown to be capable of detecting methylation status in laboratory tests. A team led by scientists at Keio University School of Medicine, in Japan, conducted a study to see whether the technology could be applied to help diagnose Angelman and PWS.
“Several articles have described the performance of nanopore technology for the detection of CpG methylation, but clinical applications are still awaited,” the researchers wrote.
One major factor that has limited the clinical application of nanopore technology is the high cost, the researchers said. They suggested that one potential way to bring costs down would be to sequence only specific DNA parts of interest.
Nanopore sequencing accurately identified specific mutations in 7 patients
For this study, the team identified 3,601 genes where mutations are known to cause disease in humans, including genes on chromosome 15 relevant to Angelman and PWS. Focusing on only these genes, nanopore sequencing was used to assess DNA from three people with Angelman syndrome and four with PWS.
Results showed that the nanopore sequencing accurately identified all of the Angelman and PWS patients. Not only could the one-step sequencing accurately diagnose patients, it also accurately identified the specific types of mutations in each patient, which had already been determined by traditional lab tests.
“We have developed a new assay that is applicable to molecular diagnosis of PWS and [Angelman syndrome] and to definition of the underlying [disease-causing] mechanisms,” the researchers concluded.
They noted that standard laboratory tests are “much less expensive” than this nanopore-based technique, but highlighted that the nanopore can be used to check for abnormalities in thousands of genes with a single test.
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