The genetic testing market right now is like the wild west. With more than 70,000 different genetic tests on the market, offered by hundreds of different providers, it’s nearly impossible to know which one is right for you and your family. On top of that, regulatory oversight still is very limited for genetic testing companies which resulted in a variety of fraud cases in recent years.
Therefore, we want to prevent you from choosing the wrong genetic testing provider and give you the information you need to make an informed buying decision.
This guide should be seen as a living document. As we interact with labs, doctors, patients and their families, we are still learning every day and try to keep you up to date with our learnings.
Today, we are starting with choosing the right technology and factors you need to be aware of. Let’s jump right in!
Part 1 - How to Choose the Right Technology
Which types of genetic tests are out there?
Most DNA tests are based on one of the following technology platforms: Microarrays, gene panels, whole-exome sequencing (WES), and whole-genome sequencing (WGS):
Chromosomal Microarrays (CMA): Microarrays help you identify microdeletions and microduplications, abnormalities of chromosome number (e.g. Down syndrome), and rearrangements of chromosome structure (see this link for a great explanation).
Gene panels: Gene panels usually cover a couple hundred or a few thousand genes representing only a small fraction of the total number of genes in your DNA. Gene panels detect small variants (single nucleotide polymorphisms [SNPs] or small insertions or deletions). Microarrays can’t do [exactly] what panels do, and panels can’t do (exactly) what CMAs do.
Whole exome sequencing (WES): WES is like running a panel for all ~25,000 genes in the human body. Genes make up approximately 2% of your DNA and are the “blueprint” for the synthesis of all proteins that take over vital functions in our bodies. After some preprocessing steps in our bodies, these protein-coding parts are also called “exons” which gives the test its name.
Whole-genome sequencing (WGS): WGS analyzes your entire genome. WGS does everything a CMA can do, plus everything a WES test can do, plus all intronic variation. Intronic refers to the non-coding/regulatory parts of your DNA that are called “introns”. Although, for example, 85% of rare disease-causing variants occur in the exonic/protein-coding area of your DNA, you might consider WGS to gain full certainty.
Which types of genetic variation can be detected?
The Jackson Lab (JAX) provides a great overview over before-mentioned testing technologies. It also describes the types of genetic variation that different technologies can detect:
Single nucleotide variants (SNV): Changes to a single nucleotide within the DNA sequence, such as single base substitutions, insertions, or deletions.
Deletions and duplications: Missing or extra genomic information. Both very small (single nucleotides) and very large (whole chromosomes) insertions and deletions of genomic information can impact gene function. Indel (insertion/deletion) is the term typically used for deletions and duplications of less than 1 kb, or 1000 bases (nucleotides). CNV (copy number variation) is typically used for deletions and duplications of more than 1 kb. CNVs can be as large as an entire chromosome (e.g., Down syndrome).
Trinucleotide repeat (TNR) expansion: A type of duplication with an increased number of trinucleotide repeats (three specific nucleotides recurring multiple times in a row) beyond what is normally expected in a given area of a gene. TNRs can cause diseases (e.g., Friedreich’s ataxia).
Methylation (Methyl): The addition of methyl groups to DNA can turn the activity of a gene off. Changes to the methylation pattern can cause disease (e.g., imprinting disorders such as some types of Angelman syndrome). These changes do not change the DNA sequence.
Mitochondrial DNA variants (mtDNA): Changes to the DNA in the mitochondria can include single nucleotide variants and deletion/duplications (e.g., mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes or MELAS).
Technology Comparison
Now that we know about the most common DNA testing technologies and the genetic variation that each of those technologies can detect, let’s compare the technologies that we discussed:
Genetic testing technology overview including commonly assessed variants; adapted from: The Jackson Laboratory (JAX) *CMA is only able to detect deletions and duplications greater than 100kb, and the exact size depends on the specific CMA methodology used
Part 2 - How to Choose the Right Provider
In this second part, we are first going to talk about the two main criteria that we think you need to look for when deciding for or against a certain technology. Then, we are zooming out a little to better understand which criteria to consider when choosing the company providing a certain genetic test.
Which factors are important for choosing the right technology?
In order for you to evaluate which DNA testing technology to choose, we’d recommend looking at two factors: the price as well as the likelihood that the test actually gives you a result. Usually, the following hierarchy holds true:
Likelihood to give a result - The likelihood that a test will give someone a result (without knowing what their symptoms are), also called the “diagnostic yield”, increases from Microarrays to WGS: Microarrays < gene panel < WES < WGS
Cost: - Here, we need to differentiate between pure material cost and the cost that the respective provider is charging its customers. The cost of material usually follows the same order as the likelihood of success: Microarrays < gene panel < WES < WGS
As for the cost to patients, it dramatically depends on how the individual lab is pricing the test and what insurance you have. The price you see as a customer barely ever has much to do with how much it costs a lab to run the test. This also depends on a couple more factors, for example, whether diagnostic interpretation or genetic counseling are included in the package. However, keep the hierarchy and included services in mind when comparing providers.
Which factors are important for choosing the right provider?
Lab accreditation: If you want to get a clinical-grade test done in the US that can give you a result report that tells you if your symptoms are caused by a genetic mutation, order from a CLIA & CAP-accredited lab.
Output format: If you know how to analyze genetic data yourself, the raw data (FASTQ, BAM, or VCF) is all you need to get to your answer. If, however, you have symptoms for a specific disease and you want to know if they could be caused by a genetic variant, you need an actual lab report. In the US, the report should be created by a CLIA & CAP-accredited lab and signed by the lab’s director, as well as the licensed geneticist or pathologist that did the analysis.
Genetic counseling: Any trustworthy testing service will offer genetic counseling. Genetic testing results are difficult to interpret and you should make sure a professional tells you what the results mean.
Cost: Getting a clinical-grade result report with genetic counseling is, unfortunately, not cheap yet.
There are two ways to access testing.
Through your physician: Your physician can order testing for you directly. Many physicians, however, will refer you to a clinical geneticist, who will determine which test to get. There are only 1,600 licensed clinical geneticists in the US, the average wait time is ~half a year, and it’ll take another month or so until you have your answer. If you get a WES test, your insurance almost certainly won’t cover the (full) cost. List prices for clinical-grade WES for most labs are ~$4,500. If you’re lucky and you only have to pay for 30% of the test cost yourself, you’re still looking at $1,350 for the test, plus the bill for your physician visit and your clinical geneticist.
Through an online service: There are services that take the experience described above and put it online. You can order and collect your sample, and receive your results from a genetic counselor from the peace and quietness of your own home. No need to leave the house, make physician appointments or wait over half a year. That’s what we do.
Outlook
Right now, most providers will still order a microarray or a gene panel for most conditions. WES or WGS are only ordered when no results are found. That is changing. For neurodevelopmental conditions, for example, a large consortium of scientists and doctors from Boston Children’s Hospital just changed their guidelines to say that WES should be the first diagnostic test done for individuals with neurodevelopmental disorders. This is also why we chose WES as a platform for our test. We also think that it is currently the best balance between diagnostic yield and cost.
How Probably Genetic Helps
Probably Genetic makes it free an easy to talk to a genetics expert for free. Our staff has years of experience in this space, we have PhDs from or enrolled in the top universities in the world, including the University of Oxford and the University of Cambridge and are happy to talk to you at any time, on the phone, over Skype, or via email. Just let us know!
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