Whole Genome Sequencing Proven Superior for Identifying Genetic Causes of Rare Diseases

Double helix DNA with a red dot highlighting a mutation
Article Details
  • Dr. Pankaj Agrawal co-authored a paper that showed 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, mainly due to a disparity in cost that has narrowed.
  • Dr. Agrawal hopes 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 only reads protein-producing genes, around 2% of the genome, according to a study published in the New England Journal of Medicine.

“For many years, people have been asking whether genome or exome is the better approach,” said Pankaj Agrawal, M.D., chief of the Division of Neonatology at the University of Miami Miller School of Medicine Department of Pediatrics and Jackson Health System and co-author on the paper. “This is probably the largest study to investigate this question, and it shows that WGS finds genetic variations exome sequencing misses.”

Until recently, WGS was significantly more expensive than WES, leading many labs to choose the latter even though WES can miss a variety of genetic variants and has failed to diagnose many rare disease patients. Clinicians have often considered WES and WGS equivalent diagnostic tests, but this study confirms the clear benefit of WGS over WES.

Miller School of Medicine pediatrician Dr. Pankaj Agarwal
Dr. Pankaj Agrawal published a New England Journal of Medicine study comparing whole genome sequencing to whole exome sequencing.

The study investigated more than 800 patients and their families, who likely harbored rare disease variations but remained undiagnosed after WES. In 8% of these cases, WGS found variations WES failed to identify.

“For a lot of these families, exome sequencing was not providing answers,” said Dr. Agrawal. “Whole genome gave answers in 29% of these cases, but we realized that many of these findings could have been picked up if the exome data had been reanalyzed. However, there was this unique group, 8% of cases, that could not have been diagnosed by exome sequencing at all.”

The exome may be the most significant part of the genome, as it harbors all the actual genes. But that elides potential regulatory elements that govern whether genes are turned on or off, as well as recessive copies that could be hiding in non-protein coding sequences. WGS also does a better job assessing gene copy variations, mitochondrial DNA and other defects.

These advantages could be further magnified when focusing on specific diseases. For example, complex neuromuscular conditions could be diagnosed at an even higher rate with WGS. Overall, Dr. Agrawal and his co-authors would like to see WGS become the standard of care for rare genetic disease diagnosis.

“In terms of their prices, genome and exome are now quite close,” said Dr. Agrawal. “This study further confirms that we should start with genome first, wherever possible. In clinical diagnostics, 8% is a big number, and we need to identify these issues so we can provide the best possible care for these patients.”

Tags: Dr. Pankaj Agrawal, genetics, genomics, neonatology, rare diseases, whole genome sequencing