The Probably Genetic Complete whole exome sequencing test offers you affordable, clinical-grade access to the information stored in the more than 20,000 genes in your or your child's DNA.
If you are participating in one of our sponsored testing programs, the test is entirely free of charge and we will never ask for credit card or insurance information.
The Probably Genetic Complete test can benefit individuals that present with symptoms that may have a genetic cause. Often, inheritance of a disease within a family or a complex medical history can indicate that a condition might be genetic. The test may also be beneficial for other family members to determine whether they carry a disease-causing mutation and the likelihood of passing it on to one of their children. If you or your child has any unexplained symptoms, the test might be right for you.
The Probably Genetic Complete test can detect genetic conditions caused by disease-causing variants that occur in exons, the regions of the genome that encode for proteins, where single chemicals in the DNA have been changed, as well as insertions or deletions shorter than a certain number of base pairs, where sequences of letters are either inserted or removed from the genome. We only report on variants that are categorized as either “pathogenic” (i.e. those that may cause disease) or “likely pathogenic” according to the 2015 guidelines published by the American College of Medical Genetics and Genomics. Examples of conditions that can be related to the variants that we can detect include: Rett Syndrome, Angelman Syndrome, DDX3X Syndrome, MPS III, Brunner Syndrome, Raynaud-Claes Syndrome, and Tuberous Sclerosis. A full list of rare genetic and mendelian conditions that can be detected with whole exome sequencing can be found here and here. Note that we do not report on genetic variants for which not enough information is available to determine if they are pathogenic.
Genes are regions of your DNA that serve as recipes for proteins. While genes only represent approximately 1%-2% of your or your child's DNA, it is estimated that 95% of all of the variants that cause disease are located in genes. These are the variants we are looking for with the Probably Genetic Complete test.
Genetic variants can be either inherited, meaning they are passed down from a parent, or de novo, meaning they were not inherited from either parent. In the case of inherited variants, these can be either heterozygous (meaning the variant occurs in only one copy of the gene) or homozygous (meaning the variant occurs in both copies of the gene). If the Probably Genetic Complete Test identifies a variant, it can give you information on both the type of variant as well as whether it is inherited or de novo, if a trio test is ordered. This information is best used by your or your child's doctor to determine options for treatment and family planning.
The test analyses your or your child's entire exome. The exome is the region of the DNA that contains all the genes that represent recipes for proteins, where an estimated 95% of pathogenic genetic variants are expected to occur. The Probably Genetic Complete test is an affordable and efficient way to gain clinical-grade information on pathogenic variants in your or your child's genome and may be used as both a first-line test or a secondary test if previous, more targeted genetic testing showed negative results.
DNA, or deoxyribonucleic acid, is the chemical building block of nearly all living organisms. It is passed down from parents to offspring and is located in every cell of the human body. DNA is comprised of four different chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). There are approximately 3 billion pairs of these bases in human DNA.
Strands of DNA are arranged into different structures, the largest of which are chromosomes. Humans have 23 pairs of chromosomes. One set of chromosomes is inherited from the mother and the other from the father. Certain genetic conditions are caused by extra or missing chromosomes. An example of such a condition is Trisomy 21, more commonly known as Down Syndrome, where a person has three copies of chromosome 21 instead of two.
Within chromosomes, DNA is arranged into genes, sections of DNA that span in length from a few hundred letters or bases to more than 2 million. Like chromosomes, each person has two copies of most of their genes, one from their mother, and one from their father. It is estimated that the human genome contains between 20,000 and 25,000 genes. Many genes represent instructions to create proteins. Variants in a gene can impact things like how the protein is made, how much is made, if it is made, or what protein is made. In certain cases, the variant might significantly impact the function of the gene such that it leads to a condition or disease. It is these types of variants that we aim to look for with our Probably Genetic Complete Test.
Genetic variants are most often either dominant or recessive. In the dominant case, only one copy of a non-functioning gene will need to be inherited by a person for them to have a genetic condition. In contrast, in most cases, a person will need to inherit two mutations, one from the mother and one from the father, in order to be affected. If each parent has only one copy of the gene, there is a 25% chance that the child will inherit the condition. An exception to this occurs in conditions that are linked to the sex chromosomes. Certain conditions are more often expressed in males compared to females because they possess only one X and one Y chromosome.
A positive result indicates that we have identified a variant that is categorized as either “pathogenic” or “likely pathogenic” according to the 2015 guidelines of the American College of Medical Genetics and Genomics (ACMG) that is consistent with your or your child's reported symptoms or condition. In the case of a positive result, a board certified genetic counselor will review the results with you. Furthermore, a downloadable PDF result report will be delivered for use by you and your or your child's physician to discuss a clinical diagnosis, treatment options, and family planning.
A negative result indicates that no variants that have been categorized as either “pathogenic” or “likely pathogenic” following the 2015 guidelines established by the American College of Medical Genetics and Genomics (ACMG) have been found in your or your child's exome that are consistent with your or your child's reported symptoms or condition. We stress that a negative result does not necessarily mean that you do not carry a pathogenic variant. Our test has certain limitations (see the FAQ on limitations) and does not cover all possible pathogenic variants. Your or your child's risk of having a pathogenic variant is impacted by certain factors such as your or your child's medical and family history and thus it is important to talk to your or your child's doctor about whether other testing options are right for you. Furthermore, it is important to understand that genetics is an evolving field and the number of variants that are interpreted as pathogenic or likely pathogenic following the 2015 guidelines of the ACMG increases every year. Thus, one might consider having their results reanalyzed periodically as evidence about the linkage between variants and diseases increases over time. Please contact firstname.lastname@example.org if this is of interest.
The American College of Medical Genetics and Genomics provides guidelines to classify certain variants as “variants of uncertain significance” (VUS). In this case, there is not often enough information available in order to determine whether the variant is pathogenic or benign. Probably Genetic has made a conscious decision not to report any VUSs back to patients as it is not recommended to make medical decisions based on a variant with such a classification. As guidelines change, certain variants may be reclassified. Please contact email@example.com if you are interested in such updates.
A “normal” or negative result does not exclude the possibility that the patient has a genetic condition. Testing may not identify certain genetic variants, or the genetic test may not be designed to identify every type of alteration present in different people. In some people a gene or chromosome change (mutation) cannot be found. This does not necessarily mean there is no change. Some genetic variants are very difficult to find with current laboratory techniques. Genetic counseling is strongly recommended to further understand the result, risks, benefits and limitations of the test. Please feel free to contact us for details on how to access genetic counseling.
You should not make medical decisions based on your test results without the advice of your or your child's physician as the test result does not provide a diagnosis. The test results may contain important information that you and your child's physician should consider before you act on any of the test results. We strongly recommend that you speak to a genetic counselor or your or your child's physician about the test results.
Physical Risks: Generally, genetic tests have little physical risk. Saliva, blood and cheek swab tests have almost no risk. Genetic testing can have emotional, social and financial risks. It is strongly advised that you have a counseling session with a genetic counselor, geneticist or physician to go over the results.
Getting Genetic Testing Results Can Cause Worry: Concerns about the results of the test make some people feel uneasy, angry, depressed, anxious, or guilty. In some cases, genetic testing creates tension within a family because the results can reveal information about other family members in addition to the person who is tested. We strongly recommend that you speak to a genetic counselor or your or your child's physician throughout the testing process.
Once you have the results of a genetic test there is no going back: This is why it is important to be sure about the decision you make. Remember that making an appointment to have a discussion does not mean that you have to go ahead with testing.
Even though a genetic test may confirm a diagnosis, there may be no intervention or treatment available: such an outcome may have emotional, legal, or economic implications. For example, in a worst case scenario you could find out that you or your child has a genetic condition that may be fatal in the long term without a treatment.
There may be errors or delays in testing and its results: Genetic testing may be delayed, indeterminate or falsely negative due to errors in sample collection, current testing technical limitations, or the patient’s prior medical treatments such as a bone marrow transplant. Testing delays or errors can occur because of sample mishandling, misidentification, and contamination. Additional samples from the patient may be requested if this occurs, which will cause delays in test results.
Three of the most common concerns that parents have before getting their children tested are the cost of the test, the risk or pain associated with the test, and a fear of the results. We wrote a blog post on these topics which can be found here. In short, we arguably provide one of the least expensive clinical whole exome sequencing tests on the market, there is very limited physical risk in taking the test and since saliva can be used, it is completely noninvasive and painless. Finally, we make sure that the turnaround time for the test is as fast as possible to limit anxiety associated with waiting for results while also providing a session with a genetic counselor so that an expert can help you and your family understand what your results mean.
This test aims to detect all clinically relevant variants within the genes analyzed related to the indication for testing. The majority of these genes are assessed for variants within all regions of a gene that encode a protein (also called ‘exons’), as well as adjacent regions that do not encode a protein (also called ‘introns’).
Other types of genetic variation cannot be detected with this test, for example complex rearrangements such as translocations, or chromosomal aneuploidy. This test does not reliably detect mosaicism. The sensitivity for detecting deletions of maximum 200 base pairs, as well as insertions that overlap less than 200 base pairs of contiguous coding sequence is limited. The detection sensitivity can be decreased by the presence of large insertions that might interfere with the chemistry used for targeting genes of interest. The identity and sequence of large insertions might also not be completely resolved. Regions of low/high GC content, homopolymers, and simple sequence repeats limit the sensitivity to detect variants.
Probably Genetic only reports on findings within the genes that are covered by whole exome sequencing. It is important to understand that there may be variants in those genes that current technology is not able to detect. Additionally, there may be genes associated with the patient’s symptoms whose clinical association has not yet been definitively established. Positive results do not imply that there are no other contributions, genetic or otherwise, to the patient’s phenotype. The test may therefore not detect all variants that are relevant for the patient. Furthermore, in the event that a variant is detected that is associated with a disorder other than your phenotype, this information will not be included in the report. For example, if the test was ordered due to a neurodevelopmental condition the patient is affected by, but the patient also carries a different variant associated with an elevated risk of cancer, the cancer-associated variant will not be included in this report. Genetic counseling and/or physician consultation way be warranted to ensure complete understanding of the test results.
In rare circumstances, the presence of somatic or donor variants can complicate germline DNA analysis, for example due to circulating hematolymphoid neoplasms, a recent blood transfusion, or an allogeneic bone marrow transplant. Recent chemotherapy treatments may also affect the patient’s DNA sample quality.
Importantly, a genetic test cannot diagnose conditions which are typically diagnosed by clinical observation. For example, a genetic test cannot confirm the diagnosis or presence of autism spectrum disorder, intellectual disability, or developmental delay in an individual. While a genetic test can increase the suspicion of some of these symptoms, a clinical evaluation may still be required for confirmation.
Although you request a test from our website for either yourself or on behalf of your child, all Probably Genetic tests are ordered by a physician with an independent clinician network (PWNHealth). One of PWNHealth’s physicians will review your information to evaluate whether the test is appropriate for you and to decide whether to approve the test request. Someone from PWNHealth may reach out to you if they have any questions during this process.
23andMe uses a technology called genotyping, where only a small number of variants associated with specific conditions in your DNA are tested. Unfortunately, rare diseases can be caused by mutations all throughout your DNA and thus in order to identify most of these mutations, one needs to sequence the whole exome where 85% of pathogenic mutations occur. Using a 23andMe test to identify a rare disease test would be the equivalent of searching the first Harry Potter novel for a typo and stopping after 15 words.
If you already did a clinical-grade whole exome or whole genome sequencing test Probably Genetic can reanalyze your data and give you a second opinion. Please reach out to firstname.lastname@example.org if this is of interest. We do not reanalyze data from services like 23andMe or AncestryDNA as they do not provide the coverage of your genome relevant for rare genetic conditions. Furthermore, we will not reanalyze sequencing data that has not been generated in a CLIA-certified and CAP-accredited facility and is not clinical-grade.
After the Results
Genetic counseling is included as part of the test. After your DNA has been sequenced and analyzed by expert bioinformaticians, a link will become available in your patient portal to book an appointment with a genetic counselor.
If the independent physician network recommends genetic counseling to discuss your or your child's results, you will receive an email with a link to schedule that appointment. Some results will be provided through a consult with a PWNHealth genetic counselor. Genetic counseling is included in the price of the test and occurs over the phone or via a video chat with a board certified genetic counselor.
The benefits of genetic counseling include: helping you better understand the test results, walking you through the next steps, outlining inheritance patterns and implications for family planning, and answering any questions you may have for what the results mean for you and your family.
If you consent, Probably Genetic will contact you to periodically re-analyze your data and provide you with updates in case your results change. On average, researchers discover five new rare diseases each week and genetics is a constantly evolving field. If any of the relevant variants that we discover in your or your child's DNA change due to an update following the 2015 guidelines of the American College of Medical Genetics and Genomics, we will keep you informed if you consent to this service.
Secondary findings are variants in your genome that are identified by our test that are not related to the cause of testing. For example, a whole exome sequencing test may identify a BRCA1 mutation, which is associated with a higher lifetime risk of cancer and has nothing to do with the condition of concern, in an individual that was being tested for a neurodevelopmental delay. At the moment, Probably Genetic does not report secondary findings. If this is a service that you are interested in, please reach out to email@example.com.
Quality Assurance & Data Protection
Probably Genetic is partnered with a sequencing lab that has both CLIA certification and a CAP accreditation, which hold it to the highest regulatory standards and accountability for quality assurance. The bioinformatics analysis is executed in a HIPAA compliant environment and all result reports are signed out by a certified clinical lab director.
No, Probably Genetic will never share any of your personal data without your permission and informed consent. Your data belongs to you and we will delete it upon request. Probably Genetic takes a patient-centric approach to clinical genetics. Unlike other companies, we believe that we can become successful by offering the highest-quality product without exploiting patients and always keep their concerns at the forefront of our service.
Probably Genetic employs the Privacy by Design methodology where, throughout our entire engineering process, we aimed to ensure that all data is protected. All information is encrypted at rest and in transit (end-to-end) and our databases and web app operate in a HIPAA compliant environment. We use https so that information you send to us over your computer is encrypted with SSL. We employ an internal privacy officer that constantly monitors our systems and limits access to all Personal Health Information(PHI) to the minimum necessary to run our services. All third parties that we use signeda Business Associate Agreement (BAA) dictating their responsibilities when it comes to health information. Finally, we manage all of our HIPAA compliance and training via Accountable, a HIPAA compliance management platform, in order to hold us to the highest regulatory standards.
During sequencing and analysis, three important data files will be generated: a VCF, a FASTQ, and a BAM file. After your results are reported, the VCF file will be made accessible to you via a secure download link that can be generated from your patient portal. For your data protection, these links will expire after a certain amount of time so that your data is not exposed on our servers for longer than it has to be. You can always regenerate another link from your patient portal if you find that the original has expired. Due to file size, it is impractical to allow direct downloads of the FASTQ and BAM files as they can be much larger than 100Gb. For this reason, if you are interested in obtaining these files, please contact firstname.lastname@example.org and we will arrange a special file transfer. Note that running your raw data through 3rd party services runs the risk of incorrect reinterpretation and we highly recommend that you fully understand the process before opting to do so.
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