Turnaround time in genetic testing for rare disorders

Genetic testing: a complex workflow.

Patients and physicians sometimes complain about the turnaround time (TAT) of genetic testing. Now, it should be mentioned that genetic testing is technically complex, requiring several steps of sample manipulation. Especially for what concerns genetic testing for rare disorders, there's also a final step, maybe the most important one, which is the clinical interpretation of the results. Genetic testing has nothing do to with routine blood analysis, where a machine itself is able to give black or white results, which can be printed out and signed and that's it. Genetic data must be deeply interpreted.

Next Generation Sequencing: the phases.

If you are interested in all the steps that compose the entire process of Next Generation Sequencing, you can read our most read post here. We want to summarize here all the main steps, which may give you an idea of the time required to performed an analysis of high-throughput sequencing (in the following example: whole exome sequencing): (1) DNA extraction from blood or other support, (2) DNA quality control (usually by Nanodrop or PicoGreen), (3) DNA library preparation, (4) library quality control, (5) exome capturing (the pahse of capturing the coding regions of the human genome, which are the region we want to sequence and read with this technique), (6) capturing quality control, (7) sequencing with the production of raw data (the so called FASTQ files), (8) raw data quality control, (9) Secondary Bioinformatic analysis (production of alignment files, starting from the FASTQ files, and production of the variant calling file - so called vcf), (10) Tertiary Bioinformatic analysis (filtering of the vcf to exclude unwanted regions and annotion of the vcf itself based on major disease and mutation database to get a senseful list of variants to read). After this, we come to the very sensitive phase of (11) clinical interpretation of the results based on the patient's clinical data (the so called phenotype-driven analysis). This is a very long phase, which is all based on Clinical Scientist experience and medical Geneticist know-how.

Clinical interpretation of genetic data: a human work.

I personally have absolutely no prejudice in high functioning artificial intelligence (A.I.) and I would be very grateful if a computer would be able to discover the pathogenic mutation of a patient in seconds, without mistakes and no false negatives. The point is that we are simply not at that level of artificial power. In our practice at Breda Genetics, we have tried several excellent Bioinformatics platforms, with different algorithms of variant prioritization, but none of them ever reached the sensitivity of the human interpretation. While being of help in some cases, in some others it's not infrequent that even the best algorithm lacks in the identification of the real pathogenic variant of a patient. So, coming again to the turnaround time of clinical genetic testing, human work is a key factor. And human work is probably the most critical variable in calculating the expected time of a genetic analysis, together with other very important factors such as the laboratory workload and backlogs.

So, what is the ideal TAT for whole exome sequencing and whole genome sequencing?

As said above, the human work is probably the real bottleneck in any lab. Also considering the high costs of specialized human work, it's unavoidable that most labs keep the scientific team at what they think to be the best critical mass (i.e. not too few, not too many). The immediate consequence is that a sudden sprout in orders has the consequence to lengthen the turnaround time.

This I would consider as a good TAT for whole exome sequencing, in normal conditions: 6-8 weeks (30-40 business days). The TAT for whole genome sequencing? This is fun! Because most sequencing labs have orders for exome sequencing, whole genome sequencing raw data may come at even faster TATs than exome. However, the burden of the human work for whole genome sequencing interpretation remains considerable, so the final TAT would not be too much different (or even longer) than whole exome sequencing. Many factors can influence the standard TAT: (1) if the lab externalizes its sequencing (this usually ends up in a week or more just for DNA quality control and 2-4 days more of sample traveling and customs clearance), (2) if the lab does has to follow many other routine activities, from genetic counseling to other types of tests (e.g. cytogenetics), (3) the machines (sequencing platforms) run by the lab: as most sequencing platforms, to be cost effective, needs to start fully loaded (just like airplanes!), labs with smaller machines may start immediately and offer shorter TATs, whereas labs with larger equipments (e.g. the Illumina Novaseq) may offer longer TAT, unless they have a word-class business which allows them to collect samples from all over the world. Operating smaller machines may offer a shorter TAT, but the side effect is usually the final price, as running an exome on small platforms is very expensive.

Some traditional labs with their own equipment are really able to offer astounding TATs of 2-3 weeks. However, we must always remember that a shorter TAT is not always a warranty of quality in the results.

Sanger sequencing, MLPA, qPCR: are these test shorter in terms of TAT?

Sanger sequencing for one mutation or two (e.g. in the context of family segregation studies for variants arisen from whole exome sequencing) may be surely faster, with a TAT ranging from 3 to 10 working days as a maximum (sometimes the TAT in Sanger is longer because the first pair of primers designed to isolate the variant do not work and the scientist need to design a second pair). MLPA, which is ultimately a Sanger application and takes advantage of commercially available, pre-made kits, usually have a TAT of 3-4 weeks. qPCR (quantitative PCR) for large deletion/duplication testing takes usually much longer, as it is a very customized assay. 7-10 weeks for a qPCR would not be an exception.

TAT or quality?

Genetic testing for rare disorders is rarely a question of emergency, although sometimes there may be at least a question of urgency, especially in the context of prenatal diagnosis. I would recommend choosing a lab based on its reputation in terms of quality of the results rather than in pure terms of TAT. It's certainly undeniable that faster results are of advantage for everybody (the patient first), however DNA sequencing is not at Hollywood dream standards yet, where you can imagine getting a Medical Report in minutes from the hair of a patient. Quality needs work, commitment, dedication, and, yes, even the time to help other labs with our own knowledge (see the Breda Genetics submissions in the ClinVar database).


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Posted in Academia, Last Update, Medical Genetics, Technohub.


  1. We are currently implementing whole exome sequencing testing in our lab. The biggest issue we are facing is the available data analysis tools that don’t seem to fulfill our requirements.

    • Dear Sohaila, glad to know you’re heading to whole exome sequencing in your lab! Send us an email to learn how we can assist you: from sequencing only services, to tailored Bioinformatics, up to the final Medical Report, we have all you need!

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