The Probably Genetic 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.
The Probably Genetic 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 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 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 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 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.
Autism, Global Developmental Delay, & Intellectual Disability
In a recent publication, doctors and researchers at the Boston Children's Hospital recommended whole exome sequencing as the first-tier diagnostic for children with neurodevelopmental conditions, including autism, global developmental delay and intellectual disability. Autism, global developmental delay, or intellectual disability, may be a symptom of an underlying, more serious condition and hence it is particularly beneficial to patients with any of these diagnoses. In fact, research shows that the cause of autism is likely to be 80%-90% genetic.
The Probably Genetic test can benefit anyone with unexplained symptoms that may have a genetic cause. Rare genetic conditions can impact people of all ages, from infants through retirement. Hence, if you or your child has a personal or a family history of a specific set of symptoms or reason to believe the symptoms are genetic, the Probably Genetic test might be right for you.
No, the Probably Genetic test does not diagnose autism and neither does any other genetic test. The test may determine the genetic cause of a condition, one of the symptoms of which is autism. Autism is an observational diagnosis based on behaviors and we recommend speaking to your doctor if you have concerns that your child may have autism.
Chromosomal microarrays (CMAs) are an older and different type of genetic testing technology. CMAs look at the structure of your chromosomes to identify abnormal changes involving extra or missing pieces of DNA. It is a much less complete test than whole exome sequencing. For this reason, the chances that an individual with a neurodevelopmental condition will find receive get a result from a CMA test is only 15%-20%. In contrast to that, the same individuals are likely to find an answer ~30%-50% of the time using whole exome sequencing (see this publication). Hence, researchers are now advocating for the use of whole exome sequencing rather than CMAs as a first-tier diagnostic for children with neurodevelopmental conditions.
Genetic Testing and Observationally Diagnosed Disorders
Fibromyalgia is a disorder of complex symptoms that is often characterized by chronic pain. There is no known genetic cause of Fibromyalgia but since it is known to run in families, some have suggested that genetics play a role in whether someone develops the condition. Symptoms of Fibromyalgia include concentration and memory problems, often described as “Fibro Fog”. Other symptoms include (i) pain and tender points, (ii) sleep problems, (iii) numbness, and tingling in hands, arms, feet, and legs. Some of the more severe symptoms can include chronic pain and chronic kidney disease. Even though there is no known genetic cause of Fibromyalgia, certain genetic conditions share symptoms with Fibromyalgia. One example of such a condition is Ehlers-Danlos Syndrome (EDS).
Familial Dysautonomia is a genetic condition that impacts how certain types of nerve cells develop and survive. There are many other types of Dysautonomia including: (i) Postural Orthostatic Tachycardia Syndrome (POTS), (ii) Neurocardiogenic Syncope (NCS), the most common subtype, and (iii) Multiple System Atrophy (MSA). Many types of Dysautonomia share symptoms with each other, including lightheadedness and fainting, possibly caused by low blood pressure upon standing. POTS symptoms may include chest pain, exercise intolerance, and tachycardia, which is a heart rate that is faster than normal when resting. Additional symptoms of NCS are cluster headaches, feeling pins and needles and irregularities with sweating. MSA is the most severe form of Dysautonomia and can include migraines and being bedridden.
Some rare conditions, such as Charcot-Marie-Tooth Disease (CMT) and Ehlers-Danlos Syndrome (EDS), share several symptoms with certain forms of Dysautonomia. POTS shares several symptoms with Catecholaminergic polymorphic ventricular tachycardia (CPVT or CASQ2-CPVT). And, NCS shares symptoms with the rare genetic disorder Hereditary (familial) ATTR amyloidosis (hATTR).
Chronic Fatigue Syndrome (CFS), also known as myalgic encephalomyelitis (ME) or systemic exertion intolerance disease (SEID), is a disorder characterized by extreme tiredness. Symptoms of CFS include profound or extreme fatigue, extreme exhaustion lasting more than 24 hours after physical or mental exercise, sleep abnormalities, including unrefreshing sleep, and unexplained joint or muscle pain. There is no known genetic cause for CFS; however, researchers are actively studying this avenue as there may be some evidence for a heritable predisposition. Possible genetic conditions that share similar symptoms with CFS are Fanconi Anemia and Hereditary Hemochromatosis.
Systemic lupus erythematosus (Lupus or SLE) is a chronic condition characterized by inflammation in connective tissues. There is no single cause of Lupus; however, there are numerous genetic factors that can increase the risk of developing Lupus. It is important to note that not all people with Lupus show variants in these known genes while others that have the genetic variants never develop the condition. Some of the symptoms of Lupus include red patches on your skin, sensitivity to light, ulcers in your mouth or nose, and protein in your urine. Certain genetic conditions share symptoms with Lupus, including Wiskott-Aldrich Syndrome.
There are many vision problems including a disturbed center of vision, poor night vision, light sensitivity, and reduced visual acuity. Some of the symptoms are known to be caused by Macular Degeneration, rod cone dystrophy, or Retinitis pigmentosa (RP). These disorders could have genetic causes such as mutations in RPE65.
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 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. We do not currently offer reanalysis.
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 to report VUSs back to patients that are associated with their reported symptoms. Patient will also be appropriately counseled by a board-certified genetic counselor on what a VUS result means. As guidelines change, certain variants may be reclassified. Please contact firstname.lastname@example.org 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 you or your loved one's physician as the test result does not provide a diagnosis. The test results may contain important information that you and your loved one'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 loved one'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.
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 changes in a gene that are not related to the purpose of testing. At the moment, Probably Genetic does not report secondary findings. To further elaborate, our Whole Exome Sequencing (WES) does test for unknown issues. Patients do not have to have a suspicion for what disease they may have. All they do is state their symptoms on the intake questionnaire after ordering a test, and we report back any variants we find that could match their symptomatic profile. For example, if a patient states, “I have symptoms related to mitochondrial disease, but I also have an autism diagnosis," then we report variants both for mitochondrial disease and for autism or for a disease that presents with a phenotype similar to mitochondrial disease and autism simultaneously.
Yes! The patient dashboard will contain information on how to download your result report again, how to make the report available to your doctor, and how to download any of your raw data. For patients that haven't yet had a genetic counseling session, it will give you access to book an appointment with a certified genetic counselor. Finally, it will provide you with updates relating to reanalysis and our service in general.
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, a VCF file will be generated. 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, the link will expire after a certain amount of time so that your data is not exposed to 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. Please 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.
Question still not answered?
Feel free to get in touch!