Whole genome sequencing proven superior for identifying genetic causes of rare diseases – InventUM
By: Josh Baxt | June 12, 2024 | 4 min. read |
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- Dr. Pankaj Agrawal co-authored a paper showing that whole genome sequencing better identifies the genetic causes of rare diseases than whole exome sequencing.
- Whole-exome sequencing has been used for this type of identification more often, largely because of a cost disparity that has narrowed.
- Dr. Agrawal hopes that whole-genome sequencing will become the standard for diagnosing rare diseases.
A large international research collaboration has shown that whole genome sequencing (WGS) can better determine the genetic causes of rare diseases than whole exome sequencing (WES).
WES reads only the genes that make proteins, about 2% of the genome, according to a study published in New England Journal of Medicine.
“For many years, people have asked whether the genome or the exome is the best approach,” said Pankaj Agrawal, MD, chief of the Division of Neonatology in the Department of Pediatrics and Jackson Health System at the University of Miami Miller School of Medicine, and co. – author on paper. “This is probably the largest study to investigate this question and shows that WGS finds genetic variation in exome sequencing.”
The clear benefit of whole genome sequencing
Until recently, WGS was significantly more expensive than WES, leading many laboratories to choose the latter even though WES can miss a number of genetic variants and has failed to diagnose many patients with rare diseases. Clinicians have often considered WES and WGS diagnostic tests equivalent, but this study confirms the clear benefit of WGS over WES.
The study investigated more than 800 patients and their families who likely had rare variants of the disease but remained undiagnosed after WES. In 8% of these cases, WGS found variations that WES failed to identify.
“For many of these families, exome sequencing was not providing answers,” said Dr. Agrawal. “The whole genome provided answers in 29% of these cases, but we realized that many of these findings could have been obtained if the exome data had been reanalyzed. However, there was this unique group, 8% of cases, that could not be diagnosed at all by exome sequencing.
A better method of diagnosing the disease
The exome may be the most important part of the genome, as it contains all the actual genes. But this eliminates potential regulatory elements that regulate whether genes are turned on or not, as well as recessive copies that may be hidden in non-protein coding sequences. WGS also does a better job of evaluating gene copy variations, mitochondrial DNA, and other defects.
These advantages can be further magnified when focusing on specific diseases. For example, complex neuromuscular conditions can be diagnosed at an even higher rate with WGS. In general, Dr. Agrawal and his co-authors would like to see WGS become the standard of care for the diagnosis of rare genetic diseases.
“In terms of their prices, genome and exome are now pretty close,” said Dr. Agrawal. “This study further confirms that we should start with the genome first, wherever possible. In clinical diagnostics, 8% is a large number and we need to identify these issues so that we can provide the best possible care for these patients.
Label: Dr. Pankaj Agrawal, genetics, genomics, neonatology, rare diseases, whole genome sequencing
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Image Source : news.med.miami.edu
