Genome analysis could improve diagnostic efficiency

Whole-genome sequencing significantly improves the diagnosis of genetic diseases, especially in cases where exome sequencing does not reveal a possible cause of the disease, according to a recent study by scientists from the University Medical Center Leipzig, the Broad Institute and Harvard University.

In recent years, exome sequencing has become a major advance in diagnosing diseases of genetic origin. However, this strategy, which analyzes about 2% of the genome that codes for proteins, does not detect certain types of variants that can cause disease, such as complex structural variants or variants located in non-coding regions. As a result, In two out of three patients, exome analysis does not allow a diagnosis to be made.

He Genome-wide analysis provides more opportunities to detect all types of genetic variants. However, this requires more analytical resources, which means higher costs. The question that remains to be addressed is the extent to which genome-wide analysis can improve diagnostic results in clinical practice.

A recent study published in the journal New England Journal of Medicineindicates that genomic sequencing can diagnose 8% of patients in addition to exome sequencing.

“Our data show that genome sequencing should be used more quickly, especially when exome sequencing has not provided clarity,” said Rami Abu Jamra, professor of genomics at the University of Leipzig and director of the project. “In the past, there was uncertainty in the literature about when genome sequencing was appropriate. Now, thanks in part to the work carried out in Leipzig, the resulting large data set demonstrates that the results are definitely suitable for clinical application.”

Genomic analysis in the diagnosis of rare diseases

To evaluate the diagnostic performance of genome-wide analysis, the researchers sequenced and analyzed the genomes of 822 families with suspected rare monogenic disease. In all of these, previous molecular analysis, targeted sequencing, or exome analysis did not lead to a diagnosis.

Of the participating families, 744 belonged to Rare Genomes Project or were diagnosed at the Broad Center for Mendelian Genomics and 78 in the replication group at the independent clinical center of the Institute of Human Genetics of the University Hospitals in Leipzig, Germany.

In 218 families of the original cohort (29.3%), the researchers identified a possible molecular cause of the disease, mainly nervous system diseases or syndromic diseases. Most variants showed affected genes already associated with diseases (157 of 218 families diagnosed).

In addition, the researchers calculated that In 61 of the diagnosed families (8.2%), identification of a possible genetic cause would not have been possible without whole genome analysis.. Neither the initial exome analysis nor reanalysis using updated information on new variants would have detected the variants involved. In these cases, which primarily involved copy number variants of DNA fragments and deletions, variants could be identified through technical approaches typical of genome analysis, such as analysis of rare structural variants or analysis of pathogenic tandem expansions.

In the replication cohort, results were similar, with an additional 8% of cases diagnosed through genome sequencing.

Increasing genomic analysis productivity in anticipation of cost optimization

The results of the work show that Whole genome sequencing provides superior diagnostic performance compared with exome sequencing in patients with previously undiagnosed rare diseases.

“Compared with exome sequencing, genome sequencing provided clarity in an additional 8% of cases: that is, significantly more,” explains Rami Abu Jamra. “This method is particularly useful if the genetic mutation causing the disease is due to the absence of very small sections of DNA, the extension of nonspecific sequences, or if the mutation is not located in the coding region at all.”

Genome sequencing reveals several types of pathogenic variants that are not easily identified by exome sequencing. In addition, the ability to reanalyze genomic data as new genetic mutations associated with disease are discovered increases the long-term value of whole-genome sequencing strategies.

“Our data show that genome sequencing should be used more quickly, especially when exome sequencing has not provided clarity,” says Professor Rami Abu Jamra. “In the past, there was uncertainty in the literature about when genome sequencing was appropriate. Now, thanks in part to the work carried out in Leipzig, the resulting large data set demonstrates that the results are definitely suitable for clinical application.”

However, at this time, the authors acknowledge that the economic and resource costs of genomic sequencing using short-term methods like those used in the study may limit its routine use for genetic diagnosis. However, the rapid development of other strategies, such as long DNA sequencing and optimization of sequencing costs, should make it easier to overcome these obstacles. In this scenario, genomic analysis can be used as a standard approach to treat many diseases.

Research Article: Voichik M.Kh. and others. Genome sequencing for the diagnosis of rare diseases. N Engl J Med. June 6, 2024; 390(21): 1985–1997. doi: 10.1056/NEJMoa2314761.

Other sources: When is genome sequencing appropriate? https://www.uni-leipzig.de/en/newsdetail/artikel/wann-ist-eine-genom-sequenzierung-ratsam-2024-06-07

If you liked this news and want to learn more about genetics in medicine, you are interested in our courses and university training, such as “Master of Precision Medicine and Clinical Genetics” or “Expert in Clinical Genetics and Rare Diseases” or “Panels, Exomes and Genomes in clinical practice”, as well as our audiovisual channel Genotipia TV.