Fields marked with "*" are required to fulfill.
Current genome sequencing diagnosis success

Current genome sequencing diagnosis success

Posted by:


Everyone is hearing about DNA sequencing, including its medical utility. Examples abound in published literature on individual cases, and as more clinics adopt the use of technology, more data is being delivered in terms of population studies. While I am an advocate of population screening including asymptomatic individuals, the debate on this issue is obviously far from being settled.

It cannot be denied that next-generation sequencing has tremendously impacted clinical diagnostic potential. If you suffer from a genetic disease that continues to be unsuccessfully diagnosed using traditional approaches (referred to as a “diagnostic odyssey”), then there is a good chance that genome sequencing will be a viable solution.

Image of article quote on genetic testing

For example, a recent report by the Garvan Institute of Medical Research in Australia stated a 53.5% diagnostic success rate in a clinical setting in a sample size of 308 patients. Furthermore, they reported their cost as nearly the same as that of a clinical exome thanks to their use of Illumina’s HiSeqX machines that are dedicated to sequencing human genomes at the current lowest market cost.

Exome sequencing (the genome portion responsible for the coding of all proteins), appears to be less successful, but has seen a more rapid adoption due to lower costs. So I will bring up an example of one of the earlier studies demonstrating the diagnostic yield of exome sequencing, as it was filled with plenty of interesting morsels of information.

Image of article quote on disease diagnoses progress

The study was performed on 250 patients at the Baylor College of Medicine in Houston, Texas, whom were mostly children that presented with neurologic phenotypes. This included symptoms such as developmental delay, speech delay, autism, intellectual disability, ataxia or seizure. Of these, 62 individuals were diagnosed based upon mutations found in disease genes that were either known or assumed to likely be the cause of disease. That is a diagnostic yield of 25%. Actually, the number of patients studied was much larger, but not reported on in this publication, although the success rate of diagnosis was still observed to be the same. And here come the interesting morsels!

Of the successfully diagnosed persons, only 36% were recurrent diseases; the rest were rare genetic disorders that were only seen once in the course of the study. Furthermore, 25% of the diagnoses were made based on disease-gene discoveries made in the two years prior to publication.

This single presented finding was the original reason I actually read the paper. It clearly presents two facts about human genome sequencing: that it is still fairly novel technology, and that while information is rapidly accumulating as we sequence more people, there is still plenty yet to be discovered. So the more people that are sequenced, the more advanced the future utility of this technology will be.

Image of article quote on personal genome sequencing progress

I rarely come across information that reports the age of discoveries in the context of diagnosis. But the pace is definitely increasing! Dr. Benjamin Solomon of the Inova Translational Medicine Institute presented data in November of 2015 showing that over 12 new disease genes per month have been discovered in last 2 years alone. This also strongly argues the need for research in a broader genome context as opposed to genotyping specific known points along the genome. Down the road the genotyping will rule the world, but we still need to continue finding what it is that needs to be genotyped.

Image of article quote on genetic disorders discovery

A fantastic case in point, also from the same publication: the authors compared the diagnostic yield of exome sequencing with the 10 most commonly tested single genes in the same clinic. For seven of these, the diagnostic yield was 7% or less. Only two had a success rate of more than 10%, and only one gene test showed an impressive result of 47% for the CHD7 gene associated with Charge syndrome (and that is because apparently it is easier to identify the phenotype of this syndrome).

Exome diagnostic yield was also higher than karyotyping or microarray tests, which are typically performed as the first line of investigation in genetic disease diagnosis. This is remarkable because one exome test is equivalent in cost to 25-50 single gene Sanger sequencing tests. That amounts to a costly trial-and-error approach compared to the genome approach.

Image of article quote on DNA genotyping testing

More morsels of quality information: 53% of diagnosed diseases were autosomal dominant and 26% were autosomal recessive. For a recessive disease to materialize, a mutant gene has to be inherited from each parent (of course there are always unique exceptions), whereas in a dominant case, one mutant gene copy will suffice to result in a disease phenotype. Autosomal refers to the fact that the mutations were not on sex chromosomes. 15% of the diagnosed diseases were X-chromosome linked. Here is a shocker number one: 6% of the diagnoses were an overlap of two different diseases in the same individual! You can imagine the complexity of actually trying to diagnose such patients with overlapping symptoms of two different complications.

And shocker number two was that 83% of the dominant cases were actually de novo, meaning they were not inherited but rather appeared spontaneously! That is a really high number, and could suggest some thought-provoking conclusions. First is the actual frequency of potential problems occurring, but in the majority of cases they most likely lead to an unsuccessful development of a viable organism. Second is the plasticity of the brain organ and the nervous system in being able to accommodate such a high rate of spontaneous mutations, and yet lead to a viable organism and successful birth. While one could speculate that regions of the genome that are responsible for these neurologic phenyotypes are more prone to mutation, perhaps other organ systems are less forgiving to the damaging effects of DNA mutagenesis during early development. Unfortunately the paper did not discuss the treatment impact.

Image of article quote on undiagnosed illnesses

The final interesting piece of information provided was how all of these tests were paid for in the clinic. A great sign is that 50% of the cases were paid for by insurance companies with coverage similar to established genetic tests. This is great hope for those who might truly require such services. The remainder was billed to the referring institutions.

So thanks to such powerful technology as next-generation sequencing, medicine has a new tool at its disposal to help diagnose difficult cases. This is truly encouraging, considering that the majority of such cases remain undiagnosed. And by being able to probe directly into the genetic makeup of an individual, we can not only help such person directly, but also everyone else down the road that might depend on the same information in the future. So if you know someone who has journeyed through a diagnostic odyssey, then you better tell them about genomic sequencing! Here at Merogenomics we can in the least point you in the right direction.


This article has been produced by Merogenomics Inc. and edited by Kerri Bryant. Reproduction and reuse of any portion of this content requires Merogenomics Inc. permission and source acknowledgment. It is your responsibility to obtain additional permissions from the third party owners that might be cited by Merogenomics Inc. Merogenomics Inc. disclaims any responsibility for any use you make of content owned by third parties without their permission.


Products and Services Promoted by Merogenomics Inc.

genome sequencinggenomic counselingpathogenic variants verificationdna sequence data reanalysisdigital biobank storage